Lansoprazole, Amoxicillin, Clarithromycin

INDICATIONS AND USAGE H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence The components in lansoprazole delayed-release capsules, amoxicillin capsules, and clarithromycin tablets are indicated for the treatment of patients with H. pylori infection and duodenal ulcer disease (active or one-year history of a duodenal ulcer) to eradicate H. pylori . Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence (see CLINICAL STUDIES and DOSAGE AND ADMINISTRATION ). To reduce the development of drug-resistant bacteria and maintain the effectiveness of lansoprazole delayed-release capsules, amoxicillin capsules, and clarithromycin tablets and other antibacterial drugs, lansoprazole delayed-release capsules, amoxicillin capsules, and clarithromycin tablets should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

DOSAGE AND ADMINISTRATION H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence The recommended adult oral dose is 30 mg lansoprazole delayed-release capsules, 1 g amoxicillin, and 500 mg clarithromycin administered together twice daily (morning and evening) for 10 or 14 days (see INDICATIONS AND USAGE ). Lansoprazole delayed-release capsules, 30 mg, amoxicillin capsules, 500 mg, and clarithromycin tablets, 500 mg are not recommended in patients with creatinine clearance less than 30 mL/min.

ADVERSE REACTIONS LANSOPRAZOLE DELAYED-RELEASE CAPSULES, AMOXICILLIN CAPSULES, AND CLARITHROMYCIN TABLETS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The most common adverse reactions (≥3%) reported in clinical trials when all three components of this therapy were given concomitantly for 14 days are listed in Table 8. Table 8: Adverse Reactions Most Frequently Reported in Clinical Trials (≥3%) Adverse Reaction Triple Therapy n = 138 (%) Diarrhea 7.0 Headache 6.0 Taste Perversion 5.0 The additional adverse reactions which were reported as possibly or probably related to treatment (less than 3%) in clinical trials when all three components of this therapy were given concomitantly are listed below and divided by body system: Body as a Whole - abdominal pain Digestive System - dark stools, dry mouth/thirst, glossitis, rectal itching, nausea, oral moniliasis, stomatitis, tongue discoloration, tongue disorder, vomiting Musculoskeletal System - myalgia Nervous System - confusion, dizziness Respiratory System - respiratory disorders Skin and Appendages - skin reactions Urogenital System - vaginitis, vaginal moniliasis There were no statistically significant differences in the frequency of reported adverse events between the 10 and 14 day triple therapy regimens. Lansoprazole Delayed-Release Capsules The following adverse reactions from the labeling for lansoprazole delayed-release capsules are provided for information: Worldwide, over 10,000 patients have been treated with lansoprazole delayed-release capsules in Phase 2 or Phase 3 clinical trials involving various dosages and durations of treatment. In general, lansoprazole delayed-release capsules treatment has been well-tolerated in both short-term and long-term trials. Incidence in Clinical Trials The following adverse events were reported by the treating physician to have a possible or probable relationship to drug in 1% or more of lansoprazole delayed-release capsules-treated patients and occurred at a greater rate in lansoprazole delayed-release capsules-treated patients than placebo-treated patients: Table 9: Incidence of Possibly or Probably Treatment-Related Adverse Reactions in Short-Term, Placebo-Controlled Lansoprazole Delayed-Release Capsules Studies Body System/Adverse Event Lansoprazole Delayed-Release Capsules (N=2768) % Placebo (N=1023) % Body as a Whole Abdominal Pain 2.1 1.2 Digestive System Constipation 1.0 0.4 Diarrhea 3.8 2.3 Nausea 1.3 1.2 Headache was also seen at greater than 1% incidence but was more common on placebo. The incidence of diarrhea was similar between patients who received placebo and patients who received 30 mg of lansoprazole delayed-release capsules, but higher in the patients who received 60 mg of lansoprazole delayed-release capsules (2.9%, 4.2%, and 7.4%, respectively). The most commonly reported possibly or probably treatment-related adverse event during maintenance therapy was diarrhea. Additional adverse experiences occurring in less than 1% of patients or subjects who received lansoprazole delayed-release capsules in domestic trials are shown below: Body as a Whole – abdomen enlarged, allergic reaction, asthenia, back pain, candidiasis, carcinoma, chest pain (not otherwise specified), chills, edema, fever, flu syndrome, halitosis, infection (not otherwise specified), malaise, neck pain, neck rigidity, pain, pelvic pain Cardiovascular System – angina, arrhythmia, bradycardia, cerebrovascular accident/cerebral infarction, hypertension/hypotension, migraine, myocardial infarction, palpitations, shock (circulatory failure), syncope, tachycardia, vasodilation Digestive System – abnormal stools, anorexia, bezoar, cardiospasm, cholelithiasis, colitis, dry mouth, dyspepsia, dysphagia, enteritis, eructation, esophageal stenosis, esophageal ulcer, esophagitis, fecal discoloration, flatulence, gastric nodules/fundic gland polyps, gastritis, gastroenteritis, gastrointestinal anomaly, gastrointestinal disorder, gastrointestinal hemorrhage, glossitis, gum hemorrhage, hematemesis, increased appetite, increased salivation, melena, mouth ulceration, nausea and vomiting, nausea and vomiting and diarrhea, gastrointestinal moniliasis, rectal disorder, rectal hemorrhage, stomatitis, tenesmus, thirst, tongue disorder, ulcerative colitis, ulcerative stomatitis Endocrine System – diabetes mellitus, goiter, hypothyroidism Hemic and Lymphatic System – anemia, hemolysis, lymphadenopathy Metabolism and Nutritional Disorders – avitaminosis, gout, dehydration, hyperglycemia/hypoglycemia, peripheral edema, weight gain/loss Musculoskeletal System – arthralgia, arthritis, bone disorder, joint disorder, leg cramps, musculoskeletal pain, myalgia, myasthenia, ptosis, synovitis Nervous System – abnormal dreams, agitation, amnesia, anxiety, apathy, confusion, convulsion, dementia, depersonalization, depression, diplopia, dizziness, emotional lability, hallucinations, hemiplegia, hostility aggravated, hyperkinesia, hypertonia, hypesthesia, insomnia, libido decreased/increased, nervousness, neurosis, paresthesia, sleep disorder, somnolence, thinking abnormality, tremor, vertigo Respiratory System – asthma, bronchitis, cough increased, dyspnea, epistaxis, hemoptysis, hiccup, laryngeal neoplasia, lung fibrosis, pharyngitis, pleural disorder, pneumonia, respiratory disorder, upper respiratory inflammation/infection, rhinitis, sinusitis, stridor Skin and Appendages – acne, alopecia, contact dermatitis, dry skin, fixed eruption, hair disorder, maculopapular rash, nail disorder, pruritus, rash, skin carcinoma, skin disorder, sweating, urticaria Special Senses – abnormal vision, amblyopia, blepharitis, blurred vision, cataract, conjunctivitis, deafness, dry eyes, ear/eye disorder, eye pain, glaucoma, otitis media, parosmia, photophobia, retinal degeneration/disorder, taste loss, taste perversion, tinnitus, visual field defect Urogenital System – abnormal menses, breast enlargement, breast pain, breast tenderness, dysmenorrhea, dysuria, gynecomastia, impotence, kidney calculus, kidney pain, leukorrhea, menorrhagia, menstrual disorder, penis disorder, polyuria, testis disorder, urethral pain, urinary frequency, urinary retention, urinary tract infection, urinary urgency, urination impaired, vaginitis Postmarketing Additional adverse experiences have been reported since lansoprazole delayed-release capsules has been marketed. The majority of these cases are foreign-sourced and a relationship to lansoprazole delayed-release capsules has not been established. Because these events were reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events are listed below by COSTART body system: Body as a Whole – anaphylactic/anaphylactoid reactions, systemic lupus erythematosus Digestive System – hepatotoxicity, pancreatitis, vomiting Hemic and Lymphatic System – agranulocytosis, aplastic anemia, hemolytic anemia, leukopenia, neutropenia, pancytopenia, thrombocytopenia, and thrombotic thrombocytopenic purpura Infections and infestations – Clostridium difficile – associated diarrhea Metabolism and Nutritional Disorders – hypomagnesemia, hyponatremia. Musculoskeletal System – bone fracture, myositis Skin and Appendages – severe dermatologic reactions including erythema multiforme, SJS, TEN (some fatal), DRESS, AGEP cutaneous lupus erythematosus Special Senses – speech disorder Urogenital System – interstitial nephritis, urinary retention, erectile dysfunction Amoxicillin The following adverse reactions from the labeling for amoxicillin are provided for information: The most common adverse reactions (>1%) observed in clinical trials of amoxicillin capsules were diarrhea, rash, vomiting and nausea. The most frequently reported adverse events for patients who received triple therapy (amoxicillin/clarithromycin/lansoprazole) were diarrhea (7%), headache (6%), and taste perversion (5%). Infections and Infestations – Mucocutaneous candidiasis Gastrointestinal - Drug-induced enterocolitis syndrome (DIES), black hairy tongue, and hemorrhagic/pseudomembranous colitis. Onset of pseudomembranous colitis symptoms may occur during or after antibiotic treatment (see WARNINGS ). Hypersensitivity Reactions – Anaphylaxis (see WARNINGS ), serum sickness-like reactions, erythematous maculopapular rashes, erythema multiforme, Stevens-Johnson Syndrome, exfoliative dermatitis, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, linear IgA bullous dermatosis, hypersensitivity vasculitis and urticaria have been reported. Liver – A moderate rise in AST and/or ALT has been noted, but the significance of this finding is unknown. Hepatic dysfunction including cholestatic jaundice, hepatic cholestasis and acute cytolytic hepatitis have been reported. Renal – Crystalluria has also been reported (see OVERDOSAGE ). Hemic and Lymphatic Systems – Anemia, including hemolytic anemia, thrombocytopenia, thrombocytopenic purpura, eosinophilia, leukopenia and agranulocytosis have been reported. These reactions are usually reversible on discontinuation of therapy and are believed to be hypersensitivity phenomena. Central Nervous System – Reversible hyperactivity, agitation, anxiety, insomnia, confusion, behavioral changes, and/or dizziness have been reported rarely. Miscellaneous – Tooth discoloration (brown, yellow, or gray staining) has been rarely reported. Most reports occurred in pediatric patients. Discoloration was reduced or eliminated with brushing or dental cleaning in most cases. Clarithromycin The following adverse reactions from the labeling for clarithromycin are provided for information: The most frequent and common adverse reactions related to clarithromycin therapy for both adult and pediatric populations are abdominal pain, diarrhea, nausea, vomiting, and dysgeusia. These adverse reactions are consistent with the known safety profile of macrolide antibiotics. There was no significant difference in the incidence of these gastrointestinal adverse reactions during clinical trials between the patient population with or without preexisting mycobacterial infections. Adverse Reactions Observed During Clinical Trials of Clarithromycin The following adverse reactions were observed in clinical trials with clarithromycin at a rate greater than or equal to 1%: Gastrointestinal Disorders – Diarrhea, vomiting, dyspepsia, nausea, abdominal pain Hepatobiliary Disorders – Liver function test abnormal Immune System Disorders – Anaphylactoid reaction Infections and Infestations – Candidiasis Nervous System Disorders – Dysgeusia, headache Psychiatric Disorders – Insomnia Skin and Subcutaneous Tissue Disorders – Rash Other Adverse Reactions Observed During Clinical Trials of Clarithromycin The following adverse reactions were observed in clinical trials with clarithromycin at a rate less than 1%: Blood and Lymphatic System Disorders – Leukopenia, neutropenia, thrombocythemia, eosinophilia Cardiac Disorders – Electrocardiogram QT prolonged, cardiac arrest, atrial fibrillation, extrasystoles, palpitations Ear and Labyrinth Disorders – Vertigo, tinnitus, hearing impaired Gastrointestinal Disorders – Stomatitis, glossitis, esophagitis, gastroesophageal reflux disease, gastritis, proctalgia, abdominal distention, constipation, dry mouth, eructation, flatulence General Disorders and Administration Site Conditions – Malaise, pyrexia, asthma, chest pain, chills, fatigue Hepatobiliary Disorders – Cholestasis, hepatitis Immune System Disorders – Hypersensitivity Infections and Infestations – Cellulitis, gastroenteritis, infection, vaginal infection Investigations – Blood bilirubin increased, blood alkaline phosphatase increased, blood lactate dehydrogenase increased, albumin globulin ratio abnormal Metabolism and Nutrition Disorders – Anorexia, decreased appetite Musculoskeletal and Connective Tissue Disorders – Myalgia, muscle spasms, nuchal rigidity Nervous System Disorders – Dizziness, tremor, loss of consciousness, dyskinesia, somnolence Psychiatric Disorders – Anxiety, nervousness Renal and Urinary Disorders – Blood creatinine increased, blood urea increased Respiratory, Thoracic and Mediastinal Disorders – Asthma, epistaxis, pulmonary embolism Skin and Subcutaneous Tissue Disorders – Urticaria, dermatitis bollus, pruritus, hyperhidrosis, rash maculopapular The following adverse reactions have been identified during post approval use of clarithromycin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders – Thrombocytopenia, agranulocytosis Cardiac Disorders – Torsades de pointes , ventricular tachycardia, ventricular arrhythmia Ear and Labyrinth Disorders – Deafness was reported chiefly in elderly women and was usually reversible. Gastrointestinal Disorders – Pancreatitis acute, tongue discoloration, tooth discoloration was reported and was usually reversible with professional cleaning upon discontinuation of the drug. Hepatobiliary Disorders – Hepatic failure, jaundice hepatocellular. Adverse reactions related to hepatic dysfunction have been reported with clarithromycin (see WARNINGS , Hepatotoxicity ) Immune System Disorders – Anaphylactic reaction Infections and Infestations – Pseudomembranous colitis Investigations – Prothrombin time prolonged, white blood cell count decreased, international normalized ratio increased. Abnormal urine color has been reported, associated with hepatic failure. Metabolism and Nutrition Disorders – Hypoglycemia has been reported in patients taking oral hypoglycemic agents or insulin. Musculoskeletal and Connective Tissue Disorders – Myopathy, rhabdomyolysis was reported and in some of the reports, clarithromycin was administered concomitantly with statins, fibrates, colchicines or allopurinol (see CONTRAINDICATIONS and WARNINGS ). Nervous System Disorders – Convulsion, ageusia, parosmia, anosmia, paresthesia Psychiatric Disorders – Psychotic disorder, confusional state, depersonalization, depression, disorientation, manic behavior, hallucination, abnormal behavior, abnormal dreams. These disorders usually resolve upon discontinuation of the drug. There are no data on the effect of clarithromycin on the ability to drive or use machines. The potential for dizziness, vertigo, confusion and disorientation, which may occur with the medication, should be taken into account before patients drive or use machines. Renal and Urinary Disorders – Nephritis interstitial, renal failure Skin and Subcutaneous Tissue Disorders – Stevens-Johnson Syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS), Henoch-Schonlein purpura, acne Vascular Disorders – Hemorrhage There have been reports of colchicine toxicity with concomitant use of clarithromycin and colchicine, especially in the elderly, some of which occurred in patients with renal insufficiency. Deaths have been reported in some such patients (see WARNINGS and PRECAUTIONS ). Laboratory Values Lansoprazole Delayed-Release Capsules The following changes in laboratory parameters in patients who received lansoprazole delayed-release capsules were reported as adverse reactions: Abnormal liver function tests, increased SGOT (AST), increased SGPT (ALT), increased creatinine, increased alkaline phosphatase, increased globulins, increased GGTP, increased/decreased/abnormal WBC, abnormal AG ratio, abnormal RBC, bilirubinemia, blood potassium increased, blood urea increased, crystal urine present, eosinophilia, hemoglobin decreased, hyperlipemia, increased/decreased electrolytes, increased/decreased cholesterol, increased glucocorticoids, increased LDH, increased/decreased/abnormal platelets, increased gastrin levels and positive fecal occult blood. Urine abnormalities such as albuminuria, glycosuria, and hematuria were also reported. In the placebo-controlled studies, when SGOT (AST) and SGPT (ALT) were evaluated, 0.4% (4/978) and 0.4% (11/2677) patients, who received placebo and lansoprazole delayed-release capsules, respectively, had enzyme elevations greater than three times the upper limit of normal range at the final treatment visit. None of these patients who received lansoprazole delayed-release capsules reported jaundice at any time during the study.