lansoprazole/amoxicillin/clarithromycin (Rx)

>10%

Clarithromycin

• GI effects, general (13%)

1-10%

Clarithromycin

• Headache (6%)
• Rash (children 3%)
• Abdominal pain (adults 2%, children 3%)
• Abnormal taste (adults 3-7%)
• Diarrhea (3-6%)
• Dyspepsia (2%)
• Heartburn (adults 2%)
• GI intolerance (oral-dose related)
• Nausea (adults 3-6%)
• Vomiting (adults 1%; children 6%)
• Decreased WBC, elevated BUN (4%), elevated PT (1%)

Lansoprazole

• Fatigue (< 3%)
• Headache (2.5-4.7%)
• Abdominal pain (1.8%)
• Diarrhea (8%)
• Nausea (3.7%)

<1%

Clarithromycin

• QT prolongation
• Anxiety, dizziness, hallucinations, manic behavior, neuromuscular blockade, psychosis, seizures
• Anorexia, glossitis, pancreatitis
• AST increased, bilirubin increased, elevated LFTs, hepatic dysfunction, hepatitis, increased alkaline phosphate, jaundice
• Hypoglycemia, leukopenia, neutropenia, thrombocytopenia
• Increased serum creatinine
• Dyspnea
• Anaphylaxis, C Diff colitis, Stevens-Johnson syndrome

Frequency Not Defined

Amoxicillin

• Headache
• Rash
• Diarrhea, nausea, vomiting
• Anemia
• AST/ALT elevation
• Acute exanthematous pustulosis
• Exfoliative dermatitis
• Seizure
• Insomnia
• Hemorrhagic colitis
• Toxic epidermal necrolysis
• Urticaria
• Stevens-Johnson syndrome
• Anaphylaxis
• Candidiasis (mucocutaneous), pseudomembranous colitis, serum sickness

Clarithromycin

• Torsade de pointes (rare)
• Allergic reactions: urticaria & skin eruptions, leukocytoclastic vasculitis, toxic epidermal necrolysis, pruritus, rash
• Transient CNS effects: psychosis, anxiety, behavioral changes, confusional states, depersonalization, disorientation, hallucinations, insomnia, nightmares, tinnitus, tremor, and vertigo
• Hepatic failure
• Stomatitis
• Acute renal failure
• Reversible hearing loss (hypoacusis)

Lansoprazole

• Fundic gland polyps

Contraindications

Lansoprazole

• Hypersensitivity to lansoprazole or other proton pump inhibitors
• Coadministration with rilpivirine containing products

Amoxicillin

• History of severe hypersensitivity reactions (eg, anaphylaxis or Stevens-Johnson syndrome) to amoxicillin or other beta-lactam antibiotics (eg, penicillins and cephalosporins)
• Infectious mononucleosis (relative)

Clarithromycin

• Documented hypersensitivity
• Clarithromycin/ranitidine bicitrate contraindicated in: severe renal impairment (CrCl<25 mL/min); history of acute porphyria
• QT prolongation or ventricular cardiac arrhythmia, including torsades de pointes
• Concomitant administration with HMG-CoA reductase inhibitors
• History of cholestatic jaundice/hepatic dysfunction associated with prior use of clarithromycin
• Coadministration with colchicine in patients with renal or hepatic impairment

Cautions

Consider possibility of superinfections with fungal or bacterial pathogens during therapy; if superinfections occur, discontinue therapy and institute appropriate therapy; prescribing therapy either in absence of proven or strongly suspected bacterial infection is unlikely to provide benefit to patient and increases risk of development of drug-resistant bacteria

Lansoprazole

• Liver disease may require dosage reduction
• Published observational studies suggest that proton pump inhibitor (PPI) therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine; particularly with prolonged (>1 yr), high-dose therapy
• Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) reported with PPIs; avoid using for longer than medically indicated; discontinue if signs or symptoms consistent with CLE or SLE are observed and refer patient to specialist
• Hypomagnesemia may occur with prolonged use (ie, >1 year); adverse effects may result and include tetany, arrhythmias, or seizures; in 25% of cases reviewed, magnesium supplementation alone did not improve low serum magnesium levels and the PPI had to be discontinued
• PPIs possibly associated with increased incidence of Clostridium difficile-associated diarrhea (CDAD); consider diagnosis of CDAD for patients taking PPIs with diarrhea that does not improve
• Symptomatic response to therapy with lansoprazole does not preclude the presence of gastric malignancy; consider additional follow-up and diagnostic testing in adult patients who have a suboptimal response or an early symptomatic relapse after completing treatment with a PPI; in older patients, also consider endoscopy
• PPIs may elevate and prolong methotrexate or its metabolite serum levels, possibly leading to toxicity
• PPI therapy is associated with increased risk of fundic gland polyp; risk increases with long-term use >1 year; patient may be asymptomatic; problem usually identified incidentally on endoscopy; use shortest duration of therapy appropriate to condition being treated
• Acute interstitial nephritis (AIN) observed in patients taking proton pump inhibitors (PPIs) including lansoprazole; acute interstitial nephritis may occur at any point during PPI therapy and is generally attributed to an idiopathic hypersensitivity reaction; discontinue lansoprazole if AIN develops

Amoxicillin

• Allergy to cephalosporins, carbapenems
• Endocarditis prophylaxis: use only for high risk pts, per recent AHA Guidelines
• High doses may cause false urine glucose test by some methods

Clarithromycin

• Caution in severe renal or hepatic impairment; in presence of severe renal impairment with or without coexisting hepatic impairment, decreased dosage or prolonged dosing intervals of clarithromycin may be appropriate
• Do not refrigerate oral solution
• Endocarditis prophylaxis: use only for high risk patients, per recent AHA Guidelines
• Drug has been associated with prolongation of QT interval and infrequent cases of arrhythmia; cases of torsades de pointes spontaneously reported during postmarketing surveillance; fatalities reported; avoid therapy in patients with ongoing proarrhythmic conditions such as uncorrected hypokalemia or hypomagnesemia, clinically significant bradycardia and in patients receiving Class IA (quinidine, procainamide) or Class III (dofetilide, amiodarone, sotalol) antiarrhythmic agents; elderly patients may be more susceptible to drug-associated effects on the QT interval
• Concomitant use of clarithromycin and oral hypoglycemic agents and/or insulin can result in significant hypoglycemia
• There is a risk of serious hemorrhage and significant elevations in INR and prothrombin time when clarithromycin is co-administered with warfarin; monitor INR and prothrombin times
• Hepatic dysfunction, including increased liver enzymes, and hepatocellular and/or cholestatic hepatitis, with or without jaundice, reported with drug; hepatic dysfunction may be severe and usually reversible; in some instances, hepatic failure with fatal outcome reported and generally associated with serious underlying diseases and/or concomitant medications; symptoms of hepatitis can include anorexia, jaundice, dark urine, pruritus, or tender abdomen; discontinue clarithromycin immediately if signs and symptoms of hepatitis occur

• Hypersensitivity reactions

  • Individuals with a history of penicillin hypersensitivity who have experienced severe reactions when treated with cephalosporins reported
  • Before initiating therapy perform careful inquiry regarding previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens
  • In the event of severe acute hypersensitivity reactions, such as anaphylaxis, Stevens-Johnson Syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS), and Henoch-Schonlein purpura discontinue therapy immediately and urgently initiate appropriate treatment

Drug interaction overview

Serious adverse reactions reported with clarithromycin concomitantly with CYP3A4 substrates; these include colchicine toxicity with colchicine; rhabdomyolysis with simvastatin, lovastatin, and atorvastatin; hypoglycemia with disopyramide, and hypotension and acute kidney injury with calcium channel blockers metabolized by CYP3A4 (eg, verapamil, amlodipine, diltiazem, nifedipine); most reports of acute kidney injury with calcium channel blockers metabolized by CYP3A4 involved elderly patients 65 years of age or older; clarithromycin should be used with caution when administered concurrently with medications that induce cytochrome CYP3A4 enzyme

Pregnancy

Clarithromycin

• No adequate and well-controlled studies in pregnant women; do not use clarithromycin in pregnant women except in circumstances in which no alternative therapy is appropriate
• If pregnancy occurs while taking clarithromycin, inform patient of paotential hazard to fetus; drug has demonstrated adverse effects of prengnacy outcome and/or embryofetal development in monkeys, rats, mice, and rabbits at doses that produced plasma levels 2 to 17 times serum levels achieved in humans treated at maximum recommended human doses

Lansoprazole

• Available data from published observational studies overall do not indicate an association of adverse pregnancy outcomes with lansoprazole treatment; estimated background risk of major birth defects and miscarriage for the indicated populations are unknown
• Available data from published observational studies failed to demonstrate an association of adverse pregnancy-related outcomes and lansoprazole use; methodological limitations of these observational studies cannot definitely establish or exclude any drug-associated risk during pregnancy
• No adverse effects on embryo-fetal development occurred in studies performed in pregnant rats at oral lansoprazole doses up to 150 mg/kg/day (40 times the recommended human dose [30 mg/day] based on body surface area) administered during organogenesis and pregnant rabbits at oral lansoprazole doses up to 0 mg/kg/day (16 times the recommended human dose based on body surface area) administered during organogenesis

Amoxicillin

• Adverse events not observed in animal reproduction studies; maternal use has not resulted in increased risk of adverse fetal effects; however, possible association with cleft lip with cleft palate observed in some studies; more data needed

Lactation

Caution should be exercised when clarithromycin is administered to nursing women; the development and health benefits of human milk feeding should be considered along with the mother’s clinical need for clarithromycin and any potential adverse effects on human milk- fed child from the drug or from underlying maternal condition

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

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

Amoxicillin: Inhibits bacterial cell wall synthesis by binding to one or more penicillin binding proteins that in turn inhibit the final transpeptidation step of peptoglycan synthesis in cell wall biosynthesis

Clarithromycin: Inhibits protein synthesis by binding to 50S ribosomal subunit causing antibacterial activity

Lansoprazole

Half-Life: 0.9-1.5 hr

Bioavailability: 81-91% (empty stomach); 50-70% (30 minutes after food)

Clearance Total Body: 0.7 L/hr/kg

Onset of action: 1-3 hr (gastric acid suppression)

Renal: 517 mL/min

Metabolism: Gastric parietal cells: acidic pH converts lansoprazole to its active sulfenamide metabolites

Liver: by hepatic CYP2C19; slow metabolizers are deficient in CPY2C19 enzyme & can have plasma conc can increase 5 times or higher

Metabolites Active: cyclic sulfenamide & disulfide metaboliteInactive: 5-hydroxy-lansoprazole, sulfide metabolite, omeprazole sulfone, sulfone metabolite, hydroxysulfide metabolite, hydroxysulfone metabolite

Excretion: Feces (bile): 77%

Urine: 14-25%

Peak Plasma Time: 1.5-3 hr

Protein Bound: 97-99%

Vd: 14-18 L

Dialyzable: No

Enzymes inhibited: CYP2C19

Amoxicillin

Half-Life: 3.7 hr (neonates, full term); 1-2 hr (infants and children); 0.7-1.4 hr (adults); 7-21 hr (CrCl < 10 mL/min in adults)

Absorption: 74-92%

Distribution: most body fluids and bone, CSF<1%

Peak Plasma Time: 2hr (capsule); 3.1 hr (extended release tablet); 1 hr (suspension)

Protein Bound: 17-20%

Metabolism: Partially hepatic

Excretion: Urine

Clarithromycin

Half-Life: 3-7 hr

Peak Plasma Time: 2-3 hr (immediate release); 5-8 hr (extended release)

Absorption: Highly stable in presence of gastric acid (unlike erythromycin); food delays but does not affect extent of absorption

Distribution: Widely into most body tissues except CNS

Protein binding: 42-70%

Metabolism: partially hepatic (P450 enzyme CYP3A4); converted to 14-OH clarithromycin (active metabolite)

Renal Clearance: approximates normal GFR

Excretion: primarily urine

Oral Administration

Contains enteric coated granules (acid labile); do not chew or crush