amoxicillin/omeprazole/rifabutin (Rx)

>10%

Rifabutin

• Discoloration of urine (30%)
• Neutropenia (25%)
• Leukopenia (17%)
• Rash (11%)

1-10%

Omeprazole

• Acid regurgitation (1.9%)
• Upper respiratory infection (1.9%)
• Constipation (1.5%)
• Dizziness (1.5%)
• Rash (1.5%)
• Asthenia (1.3%)
• Back pain (1.1%)
• Cough (1.1%)

Rifabutin

• Incr AST/ALT (7-9%)
• Thrombocytopenia (5%)
• Abdominal pain (4%)
• Diarrhea (3%)
• Eructation (3%)
• Headache (3%)
• Nausea/vomiting (3%)
• Anorexia (2%)
• Flatulence (2%)
• Anemia
• Myalgia

Frequency Not Defined

Amoxicillin

• Headache
• Rash
• Diarrhea, nausea, vomiting
• Anemia
• AST/ALT elevation
• Anaphylaxis
• Candidiasis (mucocutaneous), pseudomembranous colitis, serum sickness

Omeprazole

• Fracture of bone, osteoporosis-related
• Hepatotoxicity (rare)
• Hip fracture
• Interstitial nephritis (rare)
• Pancreatitis (rare)
• Rhabdomyolysis
• Toxic epidermal necrolysis (rare)

Selected adverse reactions reported ≥1% by patients receiving therapy

• Diarrhea
• Headache
• Nausea
• Abdominal pain
• Chromaturiac
• Rash
• Dyspepsia
• Vomiting
• Oropharyngeal pain
• Vulvovaginal candidiasis

Postmarketing Reports

Acute tubulointerstitial nephritis

See individual drug monographs for more information

Contraindications

Hypersensitivity to drug components or excipients

Concomitant administration with rilpivirine containing products (due to omeprazole, a drug component)

Concomitant administration with delavirdine or voriconazole (due to rifabutin, a drug component)

Cautions

Serious and fatal hypersensitivity reactions reported with all the drug components; inquire about history of hypersensitivity reactions to drug components before initiating therapy; institute immediate therapy, if hypersensitivity reactions occur

Clostridioides difficile-associated diarrhea (CDAD) ranging in severity from mild diarrhea to fatal colitis reported with all drug components; may occur over two months after initiating therapy; assess for CDAD all patients who present with diarrhea following therapy administration; discontinue if confirmed; institute appropriate fluid and electrolyte management, protein supplementation, antibacterial drug treatment of C. difficile as clinically indicated

Therapy may reduce efficacy of hormonal contraceptives; additional non-hormonal highly effective method of contraception should be used while receiving therapy

Acute tubulointerstitial nephritis (TIN) reported in patients taking PPIs; TIN may occur at any point during PPI therapy; patients may present with varying signs and symptoms from symptomatic hypersensitivity reactions, to non-specific symptoms of decreased renal function (eg, malaise, nausea, anorexia); in reported case series, some patients were diagnosed on biopsy and in the absence of extra-renal manifestations (eg, fever, rash or arthralgia); discontinue drug and evaluate patients with suspected acute TIN

Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) reported in patients taking PPIs; reported as both new onset and an exacerbation of existing autoimmune disease; discontinue therapy and evaluate as appropriate if symptoms consistent with CLE or SLE develop while administering therapy

A high percentage of patients with mononucleosis who receive amoxicillin develop an erythematous skin rash; avoid therapy in patients with mononucleosis

Due to the possible occurrence of uveitis, carefully monitor patients when drug, is given in combination with clarithromycin (or other macrolides) and/or fluconazole and related compounds; if uveitis suspected, refer for an ophthalmologic evaluation and, if considered necessary, suspend therapy

Serum chromogranin A (CgA) levels increase secondary to drug-induced decreases in gastric acidity; the increased CgA level may cause false-positive results in diagnostic investigations for neuroendocrine tumors; assess CgA levels at least 14 days after therapy and consider repeating the test if initial CgA levels are high

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

Drug interaction overview

• Avoid concomitant use with other CYP2C19 or CYP3A4 inducers (e.g. St. John’s Wort, rifampin) as they can substantially decrease omeprazole concentrations
• Avoid concomitant use of with CYP2C19 and/or CYP3A4 inhibitors (e.g. fluconazole, itraconazole) as it may significantly increase plasma concentration of drug component (s)
• Depending on protease inhibitor, concomitant use of drug should be avoided (e.g. amprenavir, indinavir) or dose adjustments for a concomitantly administered protease inhibitor(s) may be required
• Concomitant use of PPIs with methotrexate (primarily at high dose) may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities; avoid therapy in patients on high-dose methotrexate
• Concomitant use of clopidogrel and omeprazole reduces pharmacological activity of clopidogrel; avoid therapy in patients on clopidogrel; when administering drug, consider alternative anti-platelet therapy

Pregnancy

Based on animal reproduction studies, therapy may cause fetal harm when administered to pregnant women; there are no adequate and well controlled studies of amoxicillin, omeprazole, or rifabutin (used separately or together) in pregnant women; therapy is generally not recommended for use in pregnancy; if therapy administered during pregnancy, advise pregnant women of potential risk to fetus

Rifabutin

• Fetal malformations not observed in rat or rabbit reproduction studies given rifabutin at dose levels up to 200 mg/kg (6 to 13 times recommended human dose); in rats, given rifabutin at 200 mg/kg/day (about 6 times recommended human daily dose), there was a decrease in fetal viability; increased skeletal anomalies were observed in rats and rabbits at 40 and 80 mg/kg/day, respectively (corresponding to approximately an equivalent dose and 5 times the recommended human daily dose); maternal toxicity was noted at 80 mg/kg in rabbits

Omeprezole

• There are no adequate and well-controlled studies in pregnant women; available epidemiologic data fail to demonstrate an increased risk of major congenital malformations or other adverse pregnancy outcomes with first trimester omeprazole use; reproduction studies in rats and rabbits resulted in dose-dependent embryo-lethality at omeprazole doses that were approximately 1.13 to 11 times an oral human dose of 120 mg
• Teratogenicity was not observed in animal reproduction studies with administration of oral esomeprazole (an enantiomer of omeprazole) magnesium in rats and rabbits during organogenesis with 23 times and 14 times, respectively, of an oral human dose of 120 mg esomeprazole or omeprazole; changes in bone morphology were observed in offspring of rats dosed through most of pregnancy and lactation at doses equal to or greater than approximately 11 times an oral human dose of 120 mg esomeprazole or omeprazole; when maternal administration was confined to gestation only, there were no effects on bone physeal morphology in offspring at any age

Amoxicillin

• Available data from published epidemiologic studies and pharmacovigilance case reports over several decades with amoxicillin use have not established drug-associated risks of major birth defects, miscarriage, or adverse maternal or fetal outcomes; no adverse developmental effects were observed in animal reproduction studies with administration of amoxicillin to pregnant mice and at doses up to 3 to 6 times an oral human dose of 3 grams

Contraception

• Drug components interact with hormonal contraceptives resulting in lower levels of these contraceptives; female patients taking hormonal contraceptives should use an additional non-hormonal highly effective method of contraception while receiving therapy

Infertility

• Based on findings in rodents, drug may impair fertility in males of reproductive potential

Lactation

The developmental and health benefits of breastfeeding should be considered along with mother’s clinical need for therapy and any potential adverse effects on breast-fed child from drug or from the underlying condition

Rifabutin

• There are no data on presence of drug in human milk, effects on breast-fed infant or on milk production

Omeprazole

• There are no clinical data on effects of drug on breast-fed infant or on milk production

Amoxicillin

• Data from a published clinical lactation study reports that drug is present in human milk; published adverse effects with amoxicillin exposure in breast-fed infant include diarrhea; There are no data on the effects of amoxicillin on milk production

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

Rifabutin: Elicits antibacterial effects by inhibiting DNA-dependent RNA polymerase

Omeprazole: Proton pump inhibitor; binds to H+/K+-exchange ATPase (proton pump) in gastric parietal cells resulting in blocking acid secretion

Amoxicillin: Ampicillin derivative; elicits antibacterial effect by inhibiting biosynthesis of cell wall mucopeptide

Amoxicillin

• Absorption

  • Rapidly absorbed
  • Bioavailability: 74-92%
  • Peak plasma time: 2hr (capsule); 3.1 hr (extended release tab); 1 hr (suspension)

• Distribution

  • Most body fluids and bone, CSF <1%
  • Protein bound: 17-20%

• Metabolism

  • Hepatic

• Elimination

  • Excretion: Urine
  • Half-life: 3.7 hr (full-term neonates); 1-2 hr (infants and children); 0.7-1.4 hr (adults)

Omeprazole

• Absorption

  • Bioavailability: 30-40%
  • Onset of action: 1 hr (antisecretory effect)
  • Duration: 73 hr
  • Peak plasma time: 0.5-3.5 hr
  • Peak response (PUD): 2 hr (initial); 5 days (peak)

• Distribution

  • Protein bound: 95-96%
  • Vd: 0.39 L/kg

• Metabolism

  • Metabolized extensively by hepatic CYP2C19; slow metabolizers are deficient in CYP2C19 enzyme system; plasma concentration can increase by 5-fold or higher in comparison with that found in persons with the enzyme
  • Metabolites: Hydroxyomeprazole, omeprazole sulfone, omeprazole sulfide (inactive)
  • Enzymes inhibited: CYP2C19

• Elimination

  • Half-life: 0.5-1 hr; increases to 3 hr with hepatic impairment
  • Dialyzable: No
  • Total body clearance: 500-600 mL/min
  • Excretion: Urine (77%); feces (16-19%; mainly in bile)

• Pharmacogenomics

  • CYP2C19 poor metabolizers:
  • Asians have ~4-fold higher exposure to omeprazole than whites
  • CYP2C19, a polymorphic enzyme, is involved in the metabolism of omeprazole
  • ~15-20% of Asians are CYP2C19 poor metabolizers
  • Tests are available to identify a patient’s CYP2C19 genotype
  • Avoid use in Asian patients with unknown CYP2C19 genotype or those who are known to be poor metabolizers

Rifabutin

• Absorption

  • Readily absorbed: 53%
  • Bioavailability, absolute (HIV infected individual): 20%
  • Peak plasma time: 2-4 hr

• Distribution

  • Distributed in body tissues including the lungs, liver, spleen, eyes, & kidneys
  • Vd: 9.32 L/kg
  • Protein bound: 85%

• Metabolism

  • Metabolized by hepatic CYP3A4 to active and inactive metabolites

• Elimination

  • Half-life: 45 hr (range: 16-69 hr)

• Excretion

  • Urine: 10% as unchanged drug, 53% as metabolites
  • Feces: 10% as unchanged drug, 30% as metabolites

Oral Administration

Swallow capsules whole with a full glass of water (8 ounces); do not crush or chew capsules

Do not take with alcohol

Missed dose: Continue normal dosing schedule until medication is completed; do not take two doses at one time to make up for a missed dose