metronidazole/tetracycline/bismuth subsalicylate (Rx)

Brand and Other Names:
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Dosing & Uses

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Dosage Forms & Strengths

copackaged blister card

  • 14 blister packs, containing 8 chewable tablets (262.4mg/tablet) of bismuth subsalicylate plus 4 tablets (250mg/tablet) of metronidazole plus 4 capsules (500mg/capsule) of tetracycline

Duodenal Ulcer

Indicated for eradication of H pylori infection in patients with duodenal ulcer disease (active or history); use in combination with an H2 antagonist

Bismuth subsalicylate 525 mg (two 262.4 mg-chewable tablets), metronidazole 250 mg (one 250-mg tablet), and tetracycline hydrochloride 500 mg (one 500-mg capsule) PO QID for 14 days plus an H2 antagonist

Dosage Modifications

Renal impairment

  • Antianabolic action of the tetracyclines may cause an increase in blood urea nitrogen (BUN)
  • Severe: Contraindicated

Hepatic impairment

  • Mild-to-moderate: Monitor for metronidazole-associated adverse events
  • Severe: Not recommended

Dosing Considerations

Only treat indicated infections that are proven or strongly suspected to be caused by susceptible bacteria to reduce development of drug-resistant bacteria

Contraindicated

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Interactions

Interaction Checker

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            Adverse Effects

            Listed adverse drug reactions are of metronidazole/tetracycline/bismuth subsalicylate

            >10%

            Nausea (12%)

            1-10%

            Diarrhea (6.8%)

            Abdominal pain (6.8%)

            Melena (3%)

            Upper respiratory tract infection (2.3%)

            Constipation (1.9%)

            Anorexia (1.5%)

            Asthenia (1.5%)

            Vomiting (1.5%)

            Discolored tongue (1.5%)

            Headache (1.5%)

            Dyspepsia (1.5%)

            Dizziness (1.5%)

            Stool abnormality (1.1%)

            Duodenal ulcer (1.1%)

            Sinusitis (1.1%)

            Taste perversion (1.1%)

            Flatulence (1.1%)

            GI hemorrhage (1.1%)

            Pain (1.1%)

            Insomnia (1.1%)

            Anal discomfort (1.1%)

            Paresthesia (1.1%)

            <1%

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

            Skin: Acne, ecchymosis, photosensitivity reaction, 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

            Postmarketing Reports (Metronidazole)

            Blood and lymphatic system disorders: Reversible neutropenia (leucopenia), reversible thrombocytopenia

            Cardiac disorders: Flattening of the T-wave

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

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

            Metabolism and nutrition disorders: Pancreatitis

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

            Dermatologic disorders: Erythematous rash and pruritus

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

            Other: Dyspareunia, decrease of libido, proctitis, joint pains

            Postmarketing Reports (Tetracycline)

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

            Gastrointestinal disorders: Nausea, vomiting, diarrhea, anorexia, glossitis, black hairy tongue, dysphagia, enterocolitis, inflammatory lesions (with Candida overgrowth) in the anogenital region, esophagitis and esophageal ulceration

            Nervous system disorders: Intracranial hypertension including pseudotumor cerebri, tinnitus, and myasthenic syndrome

            Renal and urinary disorders: Increased BUN

            Skin and subcutaneous tissue disorders: Maculopapular and erythematous rashes, onycholysis, discoloration of the nails, exfoliative dermatitis, photosensitivity

            Liver: Hepatotoxicity, liver failure

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

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            Warnings

            Black Box Warnings

            Metronidazole has been shown to be carcinogenic in mice and rats

            Unknown whether metronidazole is associated with carcinogenicity in humans

            Contraindications

            Hypersensitivity to bismuth subsalicylate, metronidazole or other nitroimidazole derivatives, or tetracycline

            Coadministration with methoxyflurane; reports of fatal renal toxicity with concurrent use of tetracycline and methoxyflurane

            Use of disulfiram within previous 2 weeks; psychotic reactions reported with concurrent use of metronidazole and disulfiram

            Avoid alcohol or propylene glycol-containing products for at least 3 days after therapy with metronidazole-containing products are discontinued; disulfiram-like reaction may occur

            Severe renal impairment; tetracyclines may increase BUN; higher tetracycline serum concentrations may lead to azotemia, hyperphosphatemia, and acidosis

            Pregnancy

            Cautions

            Metronidazole shown to be carcinogenic in mice and rats; tumors affecting the liver, lungs, mammary and lymphatic tissues detected in several studies of metronidazole in rats and mice; unknown whether metronidazole is associated with carcinogenicity in humans

            Tetracycline can cause fetal harm when administered to a pregnant woman (see Pregnancy)

            Tetracycline administered during pregnancy at high doses (>2 g IV) associated with rare but serious cases of maternal hepatotoxicity (see Pregnancy)

            Use of tetracyclines during tooth development (last half of pregnancy, infancy, and childhood to the age of 8 years) may cause permanent discoloration of the teeth (yellow-gray-brown); this adverse reaction is more common during long-term use of the drug, but has been observed following repeated short-term courses

            Known or previously unrecognized candidiasis may present more prominent symptoms during therapy with metronidazole that requires treatment with an antifungal agent

            Photosensitivity, manifested by an exaggerated sunburn reaction, observed in patients taking tetracycline

            Bismuth-containing products may cause temporary and harmless darkening of the tongue and/or black stools, generally reversible within several days after treatment is stopped

            Metronidazole is a nitroimidazole, and should be used with care in patients with evidence of or history of blood dyscrasias

            Skin and subcutaneous disorders including Stevens-Johnson syndrome, toxic epidermal necrolysis and DRESS syndrome (drug rash with eosinophilia and systemic symptoms) reported

            Cases of severe hepatotoxicity/acute hepatic failure, including cases with a fatal outcome with very rapid onset after treatment initiation in patients with Cockayne syndrome reported with products containing metronidazole for systemic use

            Prescribing therapy in absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria

            Metronidazole may interfere with certain types of determinations of serum chemistry values, such as AST, SGOT, ALT, SGPT, LDH, triglycerides, and hexokinase glucose

            Bismuth absorbs x-rays and may interfere with x-ray diagnostic procedures of gastrointestinal tract

            Use of bismuth subsalicylate/metronidazole/tetracycline is not recommended in children and teenagers who have or who are recovering from varicella (chicken pox) or influenza due to the risk of Reye syndrome, a rare but serious illness

            Central and peripheral nervous system effects

            • Metronidazole
              • Convulsive seizures, encephalopathy, aseptic meningitis and peripheral neuropathy reported
              • Encephalopathy reported in association with cerebellar toxicity characterized by ataxia, dizziness, and dysarthria; CNS lesions seen on MRI described in reports of encephalopathy
              • CNS symptoms are generally reversible within days to weeks upon discontinuation of metronidazole
            • Tetracycline
              • Intracranial hypertension (IH), including pseudotumor cerebri, associated with the use of tetracyclines
              • Clinical manifestations of IH include headache, blurred vision, diplopia, and vision loss; papilledema can be found on funduscopy
              • Women of childbearing age who are overweight or have a history of IH are at greater risk for developing tetracycline associated IH
            • Bismuth-containing products
              • Cases of neurotoxicity associated with excessive doses of various bismuth-containing products reported
              • Effects have been reversible with discontinuation of bismuth therapy
              • Appearance of abnormal neurologic signs and symptoms demands the prompt evaluation of the benefit/risk ratio of the continuation of therapy

            Drug interactions overview

            • Avoid use with isotretinoin; both tetracycline and isotretinoin are known to cause intracranial hypertension
            • Tetracyclines may decrease effectiveness of oral contraceptives; instruct women to use backup contraception during treatment
            • Coadministration with anticoagulants may alter the effects of warfarin and other oral coumarin anticoagulants; metronidazole reported to potentiate the anticoagulant effect of warfarin, and other oral coumarin anticoagulants, resulting in a prolongation of prothrombin time; tetracycline shown to depress plasma prothrombin activity
            • In patients stabilized on relatively high doses of lithium, short-term use of metronidazole may cause elevation of serum lithium concentrations and signs of lithium toxicity
            • Metronidazole reported to increase plasma concentrations of busulfan, which can result in an increased risk for serious busulfan toxicity; do not administer concomitantly with busulfan unless the benefit outweighs the risk
            • Coadministration with drugs that inhibit CYP450 liver enzymes (eg, cimetidine) may result in a prolonged half-life and decreased plasma clearance of metronidazole
            • Coadministration with drugs that induce CYP450 liver enzymes (eg, phenytoin, phenobarbital) may accelerate the elimination of metronidazole, resulting in reduced plasma concentrations of metronidazole
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            Pregnancy & Lactation

            Pregnancy

            Contraindicated in women who are pregnant because treatment of H. Pylori infection can be delayed in pregnant women

            Use of tetracyclines during the second and third trimester pregnancy can also cause permanent discoloration of the teeth (yellow-gray brown) and possibly inhibit bone development in infant

            Administration of oral tetracycline to pregnant rats at various doses resulted in yellow fluorescence in teeth and bones in the newborn animals; maternal risks with high IV doses of tetracycline reported

            Metronidazole usage in pregnancy associated with certain congenital anomalies

            Tetracycline administered during pregnancy at high doses (>2 g IV) was associated with rare but serious cases of maternal hepatotoxicity; syndrome may result in stillborn or premature birth due to maternal pathology

            Lactation

            Tetracycline and metronidazole are present in human milk at concentrations similar to maternal serum levels

            It is unknown whether bismuth subcitrate is present in human milk It is unknown of the effect of therapy have the breastfed infant or on milk production

            Tetracycline binds with calcium in human milk

            Data indicate that oral absorption of tetracycline in infants is low due to the calcium binding in human milk

            Metronidazole transfers to human milk, and infant serum levels can be close to or comparable to infant therapeutic levels

            Because of the potential risk of tumorigenicity shown in animal studies with metronidazole, breastfeeding women should pump and discard human milk for the duration of therapy, and for 2 days after therapy ends, and feed her infant stored human milk (collected prior to therapy) or formula

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Metronidazole, tetracycline: Inhibits nucleic acid synthesis by disrupting DNA

            Bismuth Subsalicylate: Antisecretory effect by salicylate, antimicrobial action by bismuth

            Tetracycline: Binds to the 30S and possibly 50S ribosomal subunits of susceptbible bacteria to inhibit proteain synthesis

            Pharmacokinetics

            Metronidazole

            • Absorption: 80% from GI tract
            • Distribution: Widely distributed; 13-43% (normal meningers); 100% (inflamed meninges)
            • Metabolism: Liver (30-60%)
            • Protein binding: < 20%
            • Peak plasma time: 1-2 hr
            • Half-life: 25-75 hr (neonates); 6-8 hr (others); 21 hr (end stage renal disease)
            • Enzymes inhibited: hepatic CYP2C9
            • Excretion: Urine: 77%; feces: 14%

            Tetracycline

            • Absorption: 75%
            • Distribution: Small amount appears in bile; relative diffusion from blood into CSF
            • Protein bound: 65%
            • Half-life: 8-11 hr (normal renal function); 57-108 hr (end-stage renal disease)
            • Peak Plasma Time: 2-4 hr
            • Excretion: Urine (60% as unchanged drug); feces (as active form)

            Bismuth Subsalicylate

            • Half-Life: highly variable
            • Peak Plasma Time: Bismuth: 1.8-5 hr
            • Bioavailability: Bismuth: <1%; Salicylate: >90%
            • Onset: 4 hr
            • Protein Bound: 90% (bismuth);>90% (salicylate)
            • Metabolism: Stomach: bismuth subsalicylate is hydrolyzed in stomach to form the slightly soluble bismuth oxychloride (BiOCl) and salicylic acid
            • Metabolites: salicylate (active), [BiOCl, bismuth subcarbonate, bismuth phosphate] (activity unknown); unchanged bismuth subsalicylate passes into duodenum and reacts with other anions (eg, bicarbonate, phosphate) to form bismuth subcarbonate and bismuth phosphate salts; BiOCl, bismuth subcarbonate, bismuth phosphate, and undissociated bismuth subsalicylate react with hydrogen sulfide; salicylate is extensively metabolized in liver
            • Clearance: Bismuth: 50 mL/min
            • Excretion:
            • Bismuth: Urine & feces
            • Salicylate: Urine
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            Administration

            Oral Administration

            Administer tablets and capsules at mealtimes and at bedtime

            Bismuth subsalicylate tablets: Chew and swallow

            Metronidazole tablet and tetracycline hydrochloride capsule: Swallow whole with a full glass of water (8 ounces)

            Ingestion of adequate amounts of fluid, particularly with the bedtime dose, is recommended to reduce the risk of esophageal irritation and ulceration by tetracycline hydrochloride

            Missed dose: Continue normal dosing schedule until medication is gone; do not take double doses; if >4 doses are missed, contact prescriber

            Storage

            Blister packs: Store at room temperature (20-25°C [68-77°F])

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            Formulary

            FormularyPatient Discounts

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
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            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
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