bismuth subcitrate potassium/metronidazole/tetracycline hydrochloride (Rx)

Listed adverse drug reactions are of metronidazole/tetracycline/bismuth subcitrate potassium

>10%

Abnormal feces (15.6%)

1-10%

Nausea (8.2%)

Diarrhea (6.8%)

Headache (5.4%)

Abdominal pain (4.8%)

Dysgeusia (4.1%)

Asthenia (3.4%)

Vaginal infection (2.7%)

Dyspepsia (2.7%)

Flatulence (2.6%)

Dizziness (2.7%)

Laboratory test abnormal (2%)

Constipation (1.4%)

Dry Mouth (1.4%)

AST/ALT increased (1.4%)

Urine abnormality (1.4%)

Maculopapular rash (1.4%)

<1%

Rash

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

Contraindications

Hypersensitivity to bismuth subcitrate potassium, 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; 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 subcitrate potassium may cause temporary and harmless darkening of the tongue and/or black stools, generally reversible within several days after treatment is stopped

Metronidazole 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

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
• QT prolongation reported, particularly when metronidazole administered with drugs with potential for prolonging QT interval; flattening of T-wave may be seen in electrocardiographic tracings

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 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.

Mechanism of Action

Metronidazole, tetracycline: Inhibits nucleic acid synthesis by disrupting DNA

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

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

With omeprazole, therapy shown to be active against most isolates of H pylori both in vitro and in clinical infections

Absorption

Peak plasma time

• Fed: 3 hr (metronidazole); 4 hr (tetracycline); 3.5 hr (bismuth subcitrate)
• Fasted: 0.75 hr (metronidazole); 3.3 hr (tetracycline); 0.6 hr (bismuth subcitrate)

Peak plasma concentration

• Fed: 6835 ng/mL (metronidazole); 515.8 ng/mL (tetracycline); 1.7 ng/mL (bismuth subcitrate)
• Fasted: 8666.3 ng/mL (metronidazole); 773.8 ng/mL (tetracycline); 16.7 ng/mL (bismuth subcitrate)

AUC

• Fed: 6,835 ng·hr/mL (metronidazole); 5,840.1 ng·hr/mL (tetracycline); 18.4 ng·hr/mL (bismuth subcitrate)
• Fasted: 84,413.6 ng·hr/mL (metronidazole); 9,986.7 ng·hr/mL (tetracycline); 56.5 ng·hr/mL (bismuth subcitrate)

Distribution

Protein bound: >90% (bismuth subcitrate); <20% (metronidazole)

Metronidazole also appears in cerebrospinal fluid, saliva, and breast milk in concentration similar to those found in plasma

Tetracycline is absorbed (60-90%) in the stomach and upper small intestine

Tetracycline is distributed into most body tissues and fluids; distributed into the bile and undergoes varying degrees of enterohepatic recirculation; readily crosses the placenta and is excreted in high amounts in breast milk

Metabolism

Metronidazole: Side-chain oxidation and glucuronide oxidation

Elimination

Half-life: ~5 days (bismuth subcitrate); 8 hr (metronidazole)

Clearance: 10 mL/min/1.73²

Excretion

• Bismuth subcitrate: Urine (2.6% per day); feces
• Metronidazole and metabolites: Urine (60-80%); feces (6-15%)

Oral Administration

Administer 3 capsules after meals and at bedtime for 10 days

Take omeprazole 20 mg PO BID with Pylera after the morning and evening meal for 10 days

Swallow capsules 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

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