Lansoprazole, Amoxicillin, Clarithromycin

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.

Lansoprazole delayed-release capsules, amoxicillin capsules, and clarithromycin tablets are contraindicated in patients with known severe hypersensitivity to any component of the formulation of lansoprazole delayed-release capsules. Hypersensitivity reactions may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, acute interstitial nephritis, and urticaria (see ADVERSE REACTIONS ). Proton Pump Inhibitors (PPIs), including lansoprazole delayed-release capsules, are contraindicated with rilpivirine-containing products (see CLINICAL PHARMACOLOGY , Drug Interaction Studies ). A history of severe hypersensitivity reactions (e.g., anaphylaxis or Stevens-Johnson syndrome) to amoxicillin or other beta-lactam antibiotics (e.g., penicillins and cephalosporins) is a contraindication. Clarithromycin is contraindicated in patients with a known hypersensitivity to clarithromycin, erythromycin, or any of the macrolide antibiotics. Clarithromycin is contraindicated in patients with a history of cholestatic jaundice/hepatic dysfunction associated with prior use of clarithromycin. Clarithromycin is contraindicated with concomitant use of lurasidone due to the risk of an increase in lurasidone exposure and the potential for serious adverse reactions [(see PRECAUTIONS , Drug Interactions ) (7)]. Clarithromycin should not be given to patients with history of QT prolongation or ventricular cardiac arrhythmia, including torsades de pointes. Concomitant administration of clarithromycin, a component of lansoprazole delayed-release capsules, amoxicillin capsules, and clarithromycin tablets, and any of the following drugs is contraindicated: cisapride, pimozide, astemizole, terfenadine, ergotamine or dihydroergotamine (see PRECAUTIONS, Drug Interactions ). There have been post-marketing reports of drug interactions when clarithromycin and/or erythromycin are coadministered with cisapride, pimozide, astemizole, or terfenadine resulting in cardiac arrhythmias (QT prolongation, ventricular tachycardia, ventricular fibrillation, and torsades de pointes ) most likely due to inhibition of metabolism of these drugs by erythromycin and clarithromycin. Fatalities have been reported. Concomitant administration of clarithromycin and colchicine is contraindicated in patients with renal or hepatic impairment. Clarithromycin should not be used concomitantly with HMG-CoA reductase inhibitors (statins) that are extensively metabolized by CYP3A4 (lovastatin or simvastatin), due to the increase risk of myopathy, including rhabdomyolysis (see WARNINGS ).

Acute Hypersensitivity Reactions Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients on penicillin therapy, including amoxicillin. Although anaphylaxis is more frequent following parenteral therapy, it has occurred in patients on oral penicillins. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and/or a history of sensitivity to multiple allergens. There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe reactions when treated with cephalosporins. Before initiating therapy with lansoprazole delayed-release capsules, amoxicillin capsules, and clarithromycin tablets careful inquiry should be made regarding previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens. In the event of severe acute hypersensitivity reactions, such as anaphylaxis, and Henoch-Schonlein purpura lansoprazole delayed-release capsules, amoxicillin capsules, and clarithromycin tablets should be discontinued immediately and appropriate treatment should be urgently initiated. Severe Cutaneous Adverse Reactions Severe cutaneous adverse reactions (SCAR), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported with the components of lansoprazole delayed-release capsules, amoxicillin capsules, and clarithromycin tablets: lansoprazole, clarithromycin, and amoxicillin (see ADVERSE REACTIONS ). Monitor closely and discontinue lansoprazole delayed-release capsules, amoxicillin capsules, and clarithromycin tablets at the first signs of SCAR. Drug-induced enterocolitis syndrome (DIES) Drug-induced enterocolitis syndrome (DIES) has been reported with amoxicillin use (see ADVERSE REACTIONS ), with most cases occurring in pediatric patients ≤18 years of age. DIES is a non-IgE mediated hypersensitivity reaction characterized by protracted vomiting occurring 1 to 4 hours after drug ingestion in the absence of skin or respiratory symptoms. DIES may be associated with pallor, lethargy, hypotension, shock, diarrhea within 24 hours after ingesting amoxicillin, and leukocytosis with neutrophilia. If DIES occurs, discontinue lansoprazole delayed-release capsules, amoxicillin capsules, and clarithromycin tablets and institute appropriate therapy. Use in Pregnancy CLARITHROMYCIN SHOULD NOT BE USED IN PREGNANT WOMEN EXCEPT IN CLINICAL CIRCUMSTANCES WHERE NO ALTERNATIVE THERAPY IS APPROPRIATE. IF PREGNANCY OCCURS WHILE TAKING CLARITHROMYCIN, THE PATIENT SHOULD BE INFORMED OF THE POTENTIAL HAZARD TO THE FETUS. CLARITHROMYCIN HAS DEMONSTRATED ADVERSE EFFECTS OF PREGNANCY OUTCOME AND/OR EMBRYO-FETAL DEVELOPMENT IN MONKEYS, RATS, MICE, AND RABBITS AT DOSES THAT PRODUCED PLASMA LEVELS TWO TO 17 TIMES THE SERUM LEVELS ACHIEVED IN HUMANS TREATED AT THE MAXIMUM RECOMMENDED HUMAN DOSES (see PRECAUTIONS , Pregnancy ). Hepatotoxicity Hepatic dysfunction, including increased liver enzymes, and hepatocellular and/or cholestatic hepatitis, with or without jaundice, has been reported with clarithromycin. This hepatic dysfunction may be severe and is usually reversible. In some instances, hepatic failure with fatal outcome has been reported and generally has been 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. QT Prolongation Clarithromycin has been associated with prolongation of the QT interval and infrequent cases of arrhythmia. Cases of torsades de pointes have been spontaneously reported during postmarketing surveillance in patients receiving clarithromycin. Fatalities have been reported. Clarithromycin should be avoided in patients with ongoing proarrhythmic conditions such as uncorrected hypokalemia or hypomagnesemia, clinically significant bradycardia (see CONTRAINDICATIONS ) 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. Presence of Gastric Malignancy In adults, 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 an endoscopy. Acute Interstitial Nephritis Acute interstitial nephritis (AIN) has been 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 (see CONTRAINDICATIONS ). Cutaneous and Systemic Lupus Erythematosus Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) have been reported in patients taking PPIs, including lansoprazole. These events have occurred as both new onset and an exacerbation of existing autoimmune disease. The majority of PPI-induced lupus erythematosus cases were CLE. The most common form of CLE reported in patients treated with PPIs was subacute CLE (SCLE) and occurred within weeks to years after continuous drug therapy in patients ranging from infants to the elderly. Generally, histological findings were observed without organ involvement. Systemic lupus erythematosus (SLE) is less commonly reported than CLE in patients receiving PPIs. PPI associated SLE is usually milder than non-drug induced SLE. Onset of SLE typically occurred within days to years after initiating treatment primarily in patients ranging from young adults to the elderly. The majority of patients presented with rash; however, arthralgia and cytopenia were also reported. Avoid administration of PPIs for longer than medically indicated. If signs or symptoms consistent with CLE or SLE are noted in patients receiving Lansoprazole delayed-release capsules, amoxicillin capsules, and clarithromycin tablets, discontinue the drug and refer the patient to the appropriate specialist for evaluation. Most patients improve with discontinuation of the PPI alone in 4 to 12 weeks. Serological testing (e.g. ANA) may be positive and elevated serological test results may take longer to resolve than clinical manifestations Drug Interactions Serious adverse reactions have been reported in patients taking clarithromycin concomitantly with CYP3A4 substrates. These include colchicine toxicity with colchicine; rhabdomyolysis with simvastatin, lovastatin, and atorvastatin; hypoglycemia with disopyramide, toxicity with lurasidone, and hypotension and acute kidney injury with calcium channel blockers metabolized by CYP3A4 (e.g., 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 (see CONTRAINDICATIONS and PRECAUTIONS , Drug Interactions ). Clarithromycin should be used with caution when administered concurrently with medications that induce the cytochrome CYP3A4 enzyme (see PRECAUTIONS , Drug Interactions ). Colchicine Life-threatening and fatal drug interactions have been reported in patients treated with clarithromycin and colchicine. Clarithromycin is a strong CYP3A4 inhibitor and this interaction may occur while using both drugs at their recommended doses. If coadministration of clarithromycin and colchicine is necessary in patients with normal renal and hepatic function, the dose of colchicine should be reduced. Patients should be monitored for clinical symptoms of colchicine toxicity. […]

General The possibility of superinfections with fungal or bacterial pathogens should be considered during therapy. If superinfections occur, lansoprazole delayed-release capsules, amoxicillin capsules, and clarithromycin tablets should be discontinued and appropriate therapy instituted. Prescribing lansoprazole delayed-release capsules, amoxicillin capsules, and clarithromycin tablets either in the 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. Clarithromycin is principally excreted via the liver and kidney. Clarithromycin may be administered without dosage adjustment to patients with hepatic impairment and normal renal function. However, in the presence of severe renal impairment with or without coexisting hepatic impairment, decreased dosage or prolonged dosing intervals may be appropriate. Exacerbation of symptoms of myasthenia gravis and new onset of symptoms of myasthenic syndrome has been reported in patients receiving clarithromycin therapy. Information for Patients Each dose of lansoprazole delayed-release capsules, amoxicillin capsules, and clarithromycin tablets contain four pills: one dark blue and pink capsule (lansoprazole delayed-release capsules), two blue/pink hard gelatin capsules (amoxicillin) and one light yellow tablet (clarithromycin). Each dose should be taken twice per day before eating. Patients should be instructed to swallow each pill whole. Lansoprazole delayed-release capsules, amoxicillin capsules, and clarithromycin tablets may interact with some drugs; therefore patients should be advised to report to their doctor the use of any other medications. Patients should be counseled that antibacterial drugs including lansoprazole delayed-release capsules, amoxicillin capsules, and clarithromycin tablets should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When lansoprazole delayed-release capsules, amoxicillin capsules, and clarithromycin tablets are prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by lansoprazole delayed-release capsules, amoxicillin capsules, and clarithromycin tablets or other antibacterial drugs in the future. Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible. Patients should be advised to immediately report and seek care for diarrhea that does not improve. This may be a sign of Clostridium difficile associated diarrhea (see WARNINGS ). Patients should be advised to immediately report and seek care for any cardiovascular or neurological symptoms including palpitations, dizziness, seizures, and tetany as these may be signs of hypomagnesemia (see WARNINGS ). Advise patients to report any symptoms associated with cutaneous or systemic lupus erythematosus (see WARNINGS ). Advise patients to report to their healthcare provider if they are taking rilpivirine-containing products or high-dose methotrexate (see WARNINGS ). Advise patients about the signs and symptoms of serious skin manifestations. Instruct patients to stop taking lansoprazole delayed-release capsules, amoxicillin capsules, and clarithromycin tablets immediately and promptly report the first signs or symptoms of skin rash, mucosal lesions, or any other sign of hypersensitivity. Laboratory Tests Amoxicillin Periodic assessment of renal, hepatic, and hematopoietic function should be made during prolonged therapy. Drug Interactions No drug interaction studies have been conducted specifically with lansoprazole delayed-release capsules, amoxicillin capsules, and clarithromycin tablets. The following drug interactions are for the individual drug components: lansoprazole, amoxicillin, and clarithromycin. Therefore, the decision to adjust dosage should depend on the clinician’s assessment of among other things, the cumulative or net effect of the drug components of lansoprazole delayed-release capsules, amoxicillin capsules, and clarithromycin tablets. Lansoprazole Delayed-Release Capsules Tables 5 and 6 include drugs with clinically important drug interactions and interaction with diagnostics when administered concomitantly with lansoprazole delayed-release capsules and instructions for preventing or managing them. Consult the labeling of concomitantly used drugs to obtain further information about interactions with PPIs. Table 5. Clinically Relevant Interactions Affecting Drugs Coadministered with Lansoprazole Delayed-release Capsules and Interactions with Diagnostics Antiretrovirals Clinical Impact: The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir, and nelfinavir) when used concomitantly with lansoprazole may reduce antiviral effect and promote the development of drug resistance. Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with lansoprazole may increase toxicity of the antiretroviral drugs. There are other antiretroviral drugs which do not result in clinically relevant interactions with lansoprazole. Intervention: Rilpivirine-containing products: Concomitant use with lansoprazole is contraindicated (see CONTRAINDICATIONS ). See prescribing information. Atazanavir : See prescribing information for atazanavir for dosing information. Nelfinavir : Avoid concomitant use with lansoprazole. See prescribing information for nelfinavir. Saquinavir : See the prescribing information for saquinavir and monitor for potential saquinavir toxicities. Other antiretrovirals : See prescribing information. Warfarin Clinical Impact: Increased INR and prothrombin time in patients receiving PPIs and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Intervention: Monitor INR and prothrombin time. Dose adjustment of warfarin may be needed to maintain target INR range. See prescribing information for warfarin. Methotrexate Clinical Impact: Concomitant use of PPIs with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted (see WARNINGS ). Intervention: A temporary withdrawal of lansoprazole may be considered in some patients receiving high-dose methotrexate. Digoxin Clinical Impact: Potential for increased exposure of digoxin. Intervention: Monitor digoxin concentrations. Dose adjustment of digoxin may be needed to maintain therapeutic drug concentrations. See prescribing information for digoxin. Theophylline Clinical Impact: Increased clearance of theophylline (see CLINICAL PHARMACOLOGY ). Intervention: Individual patients may require additional titration of their theophylline dosage when lansoprazole is started or stopped to ensure clinically effective blood concentrations. […]

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. […]

No drug interaction studies have been conducted specifically with lansoprazole delayed-release capsules, amoxicillin capsules, and clarithromycin tablets. The following drug interactions are for the individual drug components: lansoprazole, amoxicillin, and clarithromycin. Therefore, the decision to adjust dosage should depend on the clinician’s assessment of among other things, the cumulative or net effect of the drug components of lansoprazole delayed-release capsules, amoxicillin capsules, and clarithromycin tablets. Lansoprazole Delayed-Release Capsules Tables 5 and 6 include drugs with clinically important drug interactions and interaction with diagnostics when administered concomitantly with lansoprazole delayed-release capsules and instructions for preventing or managing them. Consult the labeling of concomitantly used drugs to obtain further information about interactions with PPIs. Table 5. Clinically Relevant Interactions Affecting Drugs Coadministered with Lansoprazole Delayed-release Capsules and Interactions with Diagnostics Antiretrovirals Clinical Impact: The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir, and nelfinavir) when used concomitantly with lansoprazole may reduce antiviral effect and promote the development of drug resistance. Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with lansoprazole may increase toxicity of the antiretroviral drugs. There are other antiretroviral drugs which do not result in clinically relevant interactions with lansoprazole. Intervention: Rilpivirine-containing products: Concomitant use with lansoprazole is contraindicated (see CONTRAINDICATIONS ). See prescribing information. Atazanavir : See prescribing information for atazanavir for dosing information. Nelfinavir : Avoid concomitant use with lansoprazole. See prescribing information for nelfinavir. Saquinavir : See the prescribing information for saquinavir and monitor for potential saquinavir toxicities. Other antiretrovirals : See prescribing information. Warfarin Clinical Impact: Increased INR and prothrombin time in patients receiving PPIs and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Intervention: Monitor INR and prothrombin time. Dose adjustment of warfarin may be needed to maintain target INR range. See prescribing information for warfarin. Methotrexate Clinical Impact: Concomitant use of PPIs with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted (see WARNINGS ). Intervention: A temporary withdrawal of lansoprazole may be considered in some patients receiving high-dose methotrexate. Digoxin Clinical Impact: Potential for increased exposure of digoxin. Intervention: Monitor digoxin concentrations. Dose adjustment of digoxin may be needed to maintain therapeutic drug concentrations. See prescribing information for digoxin. Theophylline Clinical Impact: Increased clearance of theophylline (see CLINICAL PHARMACOLOGY ). Intervention: Individual patients may require additional titration of their theophylline dosage when lansoprazole is started or stopped to ensure clinically effective blood concentrations. Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole) Clinical Impact: Lansoprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity. Intervention: Mycophenolate mofetil (MMF): Coadministration of PPIs in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving lansoprazole delayed-release capsules and MMF. Use lansoprazole delayed-release capsules with caution in transplant patients receiving MMF. See the prescribing information for other drugs dependent on gastric pH for absorption. Combination Therapy with Clarithromycin and Amoxicillin Clinical Impact: Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions. Intervention: See CONTRAINDICATIONS , WARNINGS and PRECAUTIONS in prescribing information for clarithromycin. See Drug Interactions in prescribing information for amoxicillin. Tacrolimus Clinical Impact: Potentially increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19. Intervention: Monitor tacrolimus whole blood trough concentrations. Dose adjustment of tacrolimus may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus. Interactions with Investigations of Neuroendocrine Tumors Clinical Impact: CgA levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors (see WARNINGS , CLINICAL PHARMACOLOGY ). Intervention: Temporarily stop lansoprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary. Interaction with Secretin Stimulation Test Clinical Impact: Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma. Intervention: Temporarily stop lansoprazole treatment at least 28 days before assessing to allow gastrin levels to return to baseline (see CLINICAL PHARMACOLOGY ). False Positive Urine Tests for THC Clinical Impact: There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs. Intervention: An alternative confirmatory method should be considered to verify positive results. Table 6. Clinically Relevant Interactions Affecting Lansoprazole Delayed-release Capsules When Coadministered with Other Drugs CYP2C19 OR CYP3A4 Inducers Clinical Impact: Decreased exposure of lansoprazole when used concomitantly with strong inducers (see CLINICAL PHARMACOLOGY ). Intervention: St John's Wort, rifampin : Avoid concomitant use with lansoprazole. Ritonavir-containing products : See prescribing information. CYP2C19 or CYP3A4 Inhibitors Clinical Impact: Increased exposure of lansoprazole is expected when used concomitantly with strong inhibitors (see CLINICAL PHARMACOLOGY ). Intervention: Voriconazole : See prescribing information. Sucralfate Clinical Impact: Decreased and delayed absorption of lansoprazole (see CLINICAL PHARMACOLOGY ). Intervention: Take lansoprazole delayed-release capsules at least 30 minutes prior to sucralfate (see CLINICAL PHARMACOLOGY ). Amoxicillin Probenecid Probenecid decreases the renal tubular secretion of amoxicillin. Concurrent use of amoxicillin and probenecid may result in increased and prolonged blood levels of amoxicillin. Antibiotics Chloramphenicol, macrolides, sulfonamides, and tetracyclines may interfere with bactericidal effects of penicillin. This has been demonstrated in vitro ; however, the clinical significance of this interaction is not well documented. […]

Teratogenic Effects Pregnancy Category C Category C is based on the pregnancy category for clarithromycin. There are no adequate and well-controlled studies of lansoprazole, clarithromycin or amoxicillin (used separately or together) in pregnant women. Lansoprazole delayed-release capsules, amoxicillin capsules, and clarithromycin tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus and there is no appropriate alternative therapy (see WARNINGS ). Lansoprazole 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 30 mg/kg/day (16 times the recommended human dose based on body surface area) administered during organogenesis. A pre- and postnatal developmental toxicity study in rats with additional endpoints to evaluate bone development was performed with lansoprazole at oral doses of 10 to 100 mg/kg/day (0.7 to 6.4 times the maximum recommended human lansoprazole dose of 30 mg based on AUC [area under the plasma concentration-time curve]) administered during organogenesis through lactation. Maternal effects observed at 100 mg/kg/day (6.4 times the maximum recommended human lansoprazole dose of 30 mg based on AUC) included increased gestation period, decreased body weight gain during gestation, and decreased food consumption. The number of stillbirths was increased at this dose, which may have been secondary to maternal toxicity. Body weight of pups was reduced at 100 mg/kg/day starting on postnatal Day 11. Femur weight, femur length, and crown-rump length were reduced at 100 mg/kg/day on postnatal Day 21. Femur weight was still decreased in the 100 mg/kg/day group at age 17 to 18 weeks. Growth plate thickness was decreased in the 100 mg/kg/day males on postnatal Day 21, and was increased in the 30 and 100 mg/kg/day males at age 17 to 18 weeks. The effects on bone parameters were associated with reduction in body weight gain. Amoxicillin Reproduction studies with amoxicillin have been performed in mice and rats at doses up to ten times the human dose and revealed no evidence of impaired fertility or harm to the fetus. Clarithromycin Four teratogenicity studies in rats with clarithromycin (three with oral doses and one with intravenous doses up to 160 mg/kg/day administered during the period of major organogenesis) and two in rabbits at oral doses up to 125 mg/kg/day (approximately two times the recommended maximum human dose based on mg/m 2 ) or intravenous doses of 30 mg/kg/day administered during gestation days six to 18 failed to demonstrate any teratogenicity from clarithromycin. Two additional oral studies in a different rat strain at similar doses and similar conditions demonstrated a low incidence of cardiovascular anomalies at doses of 150 mg/kg/day administered during gestation days six to 15. Plasma levels after 150 mg/kg/day were two times the human serum levels. Four studies in mice revealed a variable incidence of cleft palate following oral doses of 1000 mg/kg/day (two and four times the recommended maximum human dose based on mg/m 2 , respectively) during gestation days six to 15. Cleft palate was also seen at 500 mg/kg/day. The 1000 mg/kg/day exposure resulted in plasma levels 17 times the human serum levels. In monkeys, an oral dose of 70 mg/kg/day (an approximate equidose of the recommended maximum human dose based on mg/m 2 ) produced fetal growth retardation at plasma levels that were two times the human serum levels.

Lansoprazole and its metabolites are excreted in the milk of rats. It is not known whether lansoprazole is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from lansoprazole delayed-release capsules, amoxicillin capsules, and clarithromycin tablets, and the potential for tumorigenicity shown for lansoprazole in rat carcinogenicity studies, a decision should be made whether to discontinue nursing or to discontinue lansoprazole delayed-release capsules, amoxicillin capsules, and clarithromycin tablets, taking into account the importance of the therapy to the mother. Penicillins have been shown to be excreted in human milk. Amoxicillin use by nursing mothers may lead to sensitization of infants. Caution should be exercised when amoxicillin is administered to a nursing woman. Clarithromycin and its active metabolite 14-hydroxy clarithromycin are excreted in human milk. Serum and milk samples were obtained after three days of treatment, at steady state, from one published study of 12 lactating women who were taking clarithromycin 250 mg orally twice daily. Based on the limited data from this study, and assuming milk consumption of 150 mL/kg/day, an exclusively human milk-fed infant would receive an estimated average of 136 mcg/kg/day of clarithromycin and its active metabolite, with this maternal dosage regimen. This is less than 2% of the maternal weight-adjusted dose (7.8 mg/kg/day, based on the average maternal weight of 64 kg), and less than 1% of the pediatric dose (15 mg/kg/day) for children greater than six months of age. A prospective observational study of 55 breastfed infants of mothers taking a macrolide antibiotic (six were exposed to clarithromycin) were compared to 36 breastfed infants of mothers taking amoxicillin. Adverse reactions were comparable in both groups. Adverse reactions occurred in 12.7% of infants exposed to macrolides and included rash, diarrhea, loss of appetite, and somnolence. 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 the human milk-fed child from the drug or from the underlying maternal condition.

The safety and effectiveness of lansoprazole delayed-release capsules, amoxicillin capsules, and clarithromycin tablets in pediatric patients infected with H. pylori have not been established. Juvenile Animal Toxicity Data In a juvenile rat study, adverse effects on bone growth and development and heart valves were observed at lansoprazole doses higher than the maximum recommended equivalent human dose. An eight-week oral toxicity study with a four-week recovery phase was conducted in juvenile rats, with lansoprazole administered from postnatal Day 7 (age equivalent to neonatal humans) through 62 (age equivalent to approximately 14 years in humans) at doses of 40 to 500 mg/kg/day (about 1.2 to 12 times the daily pediatric dose of 15 mg in children age one to 11 years weighing 30 kg or less, based on AUC). Heart valve thickening occurred at a dose of 500 mg/kg/day (approximately 12 times the daily dose of 15 mg in pediatric patients age one to 11 years weighing 30 kg or less, based on AUC). Heart valve thickening was not observed at the next lower dose (250 mg/kg/day) and below. The findings trended towards reversibility after a four-week drug-free recovery period. The relevance of heart valve thickening in this study to pediatric patients less than approximately 12 years of age is unknown. These findings are not relevant for patients 12 years of age and older. No effects on heart valves were observed in a 13-week intravenous toxicity study of lansoprazole in adolescent rats (approximately 12 years human age equivalence) at systemic exposures similar to those achieved in the eight-week oral toxicity study in juvenile (neonatal) rats. In the eight-week oral toxicity study, doses equal to or greater than 100 mg/kg/day (about 2.5 times the daily pediatric dose of 15 mg in children age one to 11 years weighing 30 kg or less, based on AUC) produced delayed growth, with impairment of weight gain observed as early as postnatal Day 10 (age equivalent to neonatal humans). At the end of treatment, the signs of impaired growth at 100 mg/kg/day and higher included reductions in body weight (14% to 44% compared to controls), absolute weight of multiple organs, femur weight, femur length, and crown-rump length. Femoral growth plate thickness was reduced only in males and only at the 500 mg/kg/day dose. The effects related to delayed growth persisted through the end of the 4- week recovery period. Longer term data were not collected.

Elderly patients may suffer from asymptomatic renal and hepatic dysfunction. Care should be taken when administering lansoprazole delayed-release capsules, amoxicillin capsules, and clarithromycin tablets to this patient population. An analysis of clinical studies of amoxicillin was conducted to determine whether subjects aged 65 and over respond differently from younger subjects. These analyses have not identified differences in responses between the elderly and younger patients, but a greater sensitivity of some older individuals cannot be ruled out. Amoxicillin is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. In a steady-state study in which healthy elderly subjects (age 65 to 81 years old) were given 500 mg of clarithromycin every 12 hours, the maximum serum concentrations and area under the curves of clarithromycin and 14-OH clarithromycin were increased compared to those achieved in healthy young adults. These changes in pharmacokinetics parallel known age-related decreases in renal function. In clinical trials of clarithromycin, elderly patients did not have an increased incidence of adverse events when compared to younger patients. Dosage adjustment should be considered in elderly patients with severe renal impairment. Elderly patients may be more susceptible to development of torsades de pointes arrhythmias than younger patients (see WARNINGS and PRECAUTIONS ). Most reports of acute kidney injury with calcium channel blockers metabolized by CYP3A4 (e.g., verapamil, amlodipine, diltiazem, nifedipine) involved elderly patients 65 years of age or older (see WARNINGS ).