Lansoprazole DR

Indications and Usage 1.1 Treatment of Active Duodenal Ulcer Lansoprazole delayed-release capsules are indicated in adults for short-term treatment (for four weeks ) for healing and symptom relief of active duodenal ulcer [see Clinical Studies ( 14.1]. 1.2 Eradication of H. pylori to Reduce the Risk of Duodenal Ulcer Recurrence Triple Therapy: Lansoprazole /amoxicillin /clarithromycin Lansoprazole delayed-release capsules in combination with amoxicillin plus clarithromycin as triple therapy is indicated in adults 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 ( 14.2)]. Please refer to the full prescribing information for amoxicillin and clarithromycin. Dual Therapy: Lansoprazole /amoxicillin Lansoprazole delayed-release capsules in combination with amoxicillin as dual therapy is indicated in adults for the treatment of patients with H. pylori infection and duodenal ulcer disease (active or one-year history of a duodenal ulcer) who are either allergic or intolerant to clarithromycin or in whom resistance to clarithromycin is known or suspected (see the clarithromycin prescribing information, Microbiology section). Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence [see Clinical Studies ( 14.2)]. Please refer to the full prescribing information for amoxicillin. 1.3 Maintenance of Healed Duodenal Ulcers Lansoprazole delayed-release capsules are indicated in adults to maintain healing of duodenal ulcers. Controlled studies do not extend beyond 12 months [see Clinical Studies ( 14.3)]. 1.4 Treatment of Active Benign Gastric Ulcer Lansoprazole delayed-release capsules are indicated in adults for short-term treatment (up to eight weeks) for healing and symptom relief of active benign gastric ulcer [see Clinical Studies ( 14.4)]. 1.5 Healing of NSAID-Associated Gastric Ulcer Lansoprazole delayed-release capsules are indicated in adults for the treatment of NSAID-associated gastric ulcer in patients who continue NSAID use. Controlled studies did not extend beyond eight weeks [see Clinical Studies ( 14.5)]. 1.6 Risk Reduction of NSAID-Associated Gastric Ulcer Lansoprazole delayed-release capsules are indicated in adults for reducing the risk of NSAID-associated gastric ulcers in patients with a history of a documented gastric ulcer who require the use of an NSAID. Controlled studies did not extend beyond 12 weeks [see Clinical Studies ( 14.6)]. 1.7 Treatment of Symptomatic Gastroesophageal Reflux Disease (GERD) Lansoprazole delayed-release capsules are indicated for short-term treatment in adults and pediatric patients 12 to 17 years of age (up to eight weeks) and pediatric patients one to 11 years of age (up to 12 weeks) for the treatment of heartburn and other symptoms associated with GERD [see Clinical Studies ( 14.7)]. 1.8 Treatment of Erosive Esophagitis (EE) Lansoprazole delayed-release capsules are indicated for short-term treatment in adults and pediatric patients 12 to 17 years of age (up to eight weeks) and pediatric patients one to 11 years of age (up to 12 weeks) for healing and symptom relief of all grades of EE. For adults who do not heal with lansoprazole delayed-release capsules for eight weeks (5 to 10%), it may be helpful to give an additional eight weeks of treatment. If there is a recurrence of erosive esophagitis an additional eight week course of lansoprazole delayed-release capsules may be considered. [see Clinical Studies ( 14.8)]. 1.9 Maintenance of Healing of EE Lansoprazole delayed-release capsules are indicated in adults to maintain healing of EE. Controlled studies did not extend beyond 12 months [see Clinical Studies ( 14.9)]. 1.10 Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome (ZES) Lansoprazole delayed-release capsules are indicated in adults for the long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison syndrome. [see Clinical Studies ( 14.10)].

Dosage and Administration 2.1 Recommended Adult Dosage by Indication Indication Recommended Dose Frequency Duodenal Ulcers Short-Term Treatment Maintenance of Healed 15 mg 15 mg Once daily for 4 weeks Once daily Eradication of H. pylori to Reduce the Risk of Duodenal Ulcer Recurrence * Triple Therapy: Lansoprazole Amoxicillin Clarithromycin Dual Therapy: Lansoprazole Amoxicillin 30 mg 1 gram 500 mg 30 mg 1 gram Twice daily for 10 or 14 days Twice daily for 10 or 14 days Twice daily for 10 or 14 days Three times daily for 14 days Three times daily for 14 days Benign Gastric Ulcer Short-Term Treatment 30 mg Once daily for up to 8 weeks NSAID-Associated Gastric Ulcer Healing Risk Reduction 30 mg 15 mg Once daily for 8 weeks † Once daily for up to 12 weeks † Gastroesophageal Reflux Disease (GERD) Short-Term Treatment of Symptomatic GERD Short -Term Treatment of Erosive Esophagitis 15 mg 30 mg Once daily for up to 8 weeks Once daily for up to 8 weeks ‡ Maintenance of Healing of Erosive Esophagitis 15 mg Once daily § Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome 60 mg Once daily ¶ * Please refer to the amoxicillin and clarithromycin full prescribing information, Contraindications and Warningsand Precautions sections, and for information regarding dosing in elderly and renally-impaired patients. † Controlled studies did not extend beyond indicated duration. ‡ For patients who do not heal with lansoprazole for eight weeks (5 to 10%), it may be helpful to give an additional eight weeks of treatment. If there is a recurrence of erosive esophagitis, an additional eight week course of lansoprazole may be considered. § Controlled studies did not extend beyond 12 months ¶ Varies with individual patient. Recommended adult starting dose is 60 mg once daily. Doses should be adjusted to individual patient needs and should continue for as long as clinically indicated. Dosages up to 90 mg twice daily have been administered. Daily dose of greater than 120 mg should be administered in divided doses. Some patients with Zollinger-Ellison syndrome have been treated continuously with lansoprazole for more than four years. 2.2 Recommended Pediatric Dosage by Indication Pediatric Patients 1 to 11 Years of Age In clinical studies, lansoprazole was not administered beyond 12 weeks in 1 to 11 year olds. It is not known if lansoprazole is safe and effective if used longer than the recommended duration. Do not exceed the recommended dose and duration of use in pediatric patients as outlined below [see Use in Specific Populations (8.4)]. Indication Recommended Dose Frequency Short-Term Treatment of Symptomatic GERD and Short-Term Treatment of Erosive Esophagitis ≤ 30 kg 15 mg Once daily for up to 12 weeks > 30 kg 30 mg Once daily for up to 12 weeks Pediatric Patients 12 to 17 Years of Age Indication Recommended Dose Frequency Short-Term Treatment of Symptomatic GERD Non-erosive GERD 15 mg Once daily for up to 8 weeks Erosive Esophagitis 30 mg Once daily for up to 8 weeks 2.3 Hepatic Impairment The recommended dosage is 15 mg orally daily in patients with severe liver impairment (Child-Pugh C) [see Use in Specific Populations ( 8.6) 2.4 Important Administration Information Take lansoprazole delayed-release capsules before meals . Do not crush or chew lansoprazole delayed-release capsules. Take lansoprazole delayed-release capsules at least 30 minutes prior to sucralfate [see Drug Interactions ( 7 )] Antacids may be used concomitantly with lansoprazole delayed-release capsules. Missed doses: If a dose is missed, administer as soon as possible. However, if the next scheduled dose is due, do not take the missed dose, and take the next dose on time. Do not take two doses at one time to make up for a missed dose. Lansoprazole delayed-release capsules Swallow whole; do not chew For patients who have difficulty swallowing capsules, lansoprazole delayed-release capsules can be opened and administered orally or via a nasogastric tube in the soft foods or liquids specified below. Administration of lansoprazole delayed-release capsules in foods or liquids other than those discussed below have not been studied clinically and therefore are not recommended. Administration in Soft Foods (applesauce, ENSURE pudding, cottage cheese, yogurt or strained pears ): Open capsule Sprinkle intact pellets on one tablespoon of either applesauce, ENSURE pudding, cottage cheese, yogurt or strained pears.. Swallow immediately. Administration in Liquids (apple juice, orange juice or tomato juice): Open capsule Sprinkle intact pellets into a small volume of either apple juice, orange juice or tomato juice (60 mL – approximately two ounces). Mix briefly. Swallow immediately. To ensure complete delivery of the dose, rinse the glass with two or more volumes of juice and swallow the contents immediately. Administration with Apple Juice Through a Nasogastric Tube (≥16 French) Open capsule Sprinkle intact pellets into 40 mL of apple juice. Mix briefly. Using a catheter tipped syringe, draw up the mixture. Inject through the nasogastric tube into the stomach Flush with additional apple juice to clear the tube.

Contraindications Lansoprazole is contraindicated in patients with known hypersensitivity to any component of the formulation. Hypersensitivity reactions may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, acute tubulointerstitial nephritis, and urticaria [see Warnings and Precautions (5.2), Adverse Reactions (6)]. Proton Pump Inhibitors (PPIs), including lansoprazole, are contraindicated with rilpivirine-containing products [see Drug Interactions (7)]. For information about contraindications of antibacterial agents (clarithromycin and amoxicillin) indicated in combination with lansoprazole, refer to the Contraindications section of their prescribing information.

Warnings and Precautions 5.1 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. 5.2 Acute Tubulointerstitial Nephritis Acute tubulointerstitial nephritis (TIN) has been observed in patients taking PPIs and 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 (e.g., malaise, nausea, anorexia). In reported case series, some patients were diagnosed on biopsy and in the absence of extra-renal manifestations (e.g., fever, rash or arthralgia). Discontinue lansoprazole and evaluate patients with suspected acute TIN [see Contraindications (4)]. 5.3 Clostridium difficile-Associated Diarrhea Published observational studies suggest that PPI therapy like lansoprazole may be associated with an increased risk of Clostridium difficile-associated diarrhea (CDAD), especially in hospitalized patients. This diagnosis should be considered for diarrhea that does not improve [see Adverse Reactions (6.2)]. Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. CDAD has been reported with use of nearly all antibacterial agents. For more information specific to antibacterial agents (clarithromycin and amoxicillin) indicated for use in combination with lansoprazole refer to Warnings and Precautions section of their prescribing information. 5.4 Bone Fracture Several published observational studies suggest that PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist or spine. The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long-term PPI therapy (a year or longer). Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the conditions being treated. Patients at risk for osteoporosis-related fractures should be managed according to established treatment guidelines [see Dosage and Administration ( 2),Adverse Reactions ( 6.2)]. 5.5 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, discontinue the drug and refer the patient to the appropriate specialist for evaluation. Most patients improve with discontinuation of the PPI alone in four to 12 weeks. Serological testing (e.g., ANA) may be positive and elevated serological test results may take longer to resolve than clinical manifestations. 5.6 Cyanocobalamin (Vitamin B12) Deficiency Daily treatment with any acid-suppressing medications over a long period of time (e.g., longer than three years) may lead to malabsorption of cyanocobalamin (Vitamin B12) caused by hypo- or achlorhydria. Rare reports of cyanocobalamin deficiency occurring with acid-suppressing therapy have been reported in the literature. This diagnosis should be considered if clinical symptoms consistent with cyanocobalamin deficiency are observed in patients treated with lansoprazole. 5.7 Hypomagnesemia Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuation of the PPI. For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), healthcare professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically [see Adverse Reactions ( 6.2)]. 5.8 Interactions with Investigations for Neuroendocrine Tumors 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. Healthcare providers should 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 [see Drug Interactions (7), Clinical Pharmacology (12.2)]. 5.9 Interaction with Methotrexate Literature suggests that 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. In high-dose methotrexate administration, a temporary withdrawal of the PPI may be considered in some patients [see Drug Interactions ( 7),Clinical Pharmacology ( 12.3)]. 5.11 Fundic Gland Polyps PPI use is associated with an increased risk of fundic gland polyps that increases with long-term use, especially beyond one year. Most PPI users who developed fundic gland polyps were asymptomatic and fundic gland polyps were identified incidentally on endoscopy. Use the shortest duration of PPI therapy appropriate to the condition being treated. 5.12 Risk of Heart Valve Thickening in Pediatric Patients Less Than One Year of Age Lansoprazole is not approved in pediatric patients less than one year of age. Nonclinical studies in juvenile rats with lansoprazole have demonstrated an adverse effect of heart valve thickening. The risk of heart valve injury does not appear to be relevant to patients one year of age and older [see Use in Specific Populations (8.4)].

Drug Interactions Tables 2 and 3 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 2. Clinically Relevant Interactions Affecting Drugs Co-Administered 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 (4)] . 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 and Precautions (5.8)] . 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 (12.3)] . 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): Co-administration 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 and MMF. Use lansoprazole 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 and 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 and Precautions (5.7), Clinical Pharmacology ( 12.2)] . 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 (12.2)]. 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 3. Clinically Relevant Interactions Affecting lansoprazole When Co-Administered with Other Drugs CYP2C19 OR CYP3A4 Inducers Clinical Impact: Decreased exposure of lansoprazole when used concomitantly with strong inducers [see Clinical Pharmacology (12.3)] . 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 (12.3)] . Intervention: Voriconazole : See prescribing information. Sucralfate Clinical Impact: Decreased and delayed absorption of lansoprazole [see Clinical Pharmacology (12.3)] . Intervention: Take lansoprazole at least 30 minutes prior to sucralfate [see Dosage and Administration (2.4)] .

Adverse Reactions The following serious adverse reactions are described below and elsewhere in labeling: Acute Tubulointerstitial Nephritis [see Warnings and Precautions ( 5.2)] Clostridium difficile-Associated Diarrhea [see Warnings and Precautions ( 5.3)] Bone Fracture [see Warnings and Precautions ( 5.4)] Cutaneous and Systemic Lupus Erythematosus [see Warnings and Precautions ( 5.5)] Cyanocobalamin (Vitamin B12) Deficiency [see Warnings and Precautions ( 5.6)] Hypomagnesemia [see Warnings and Precautions ( 5.7)] Fundic Gland Polyps [see Warnings and Precautions ( 5.11)] 6.1 Clinical Trials Experience 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. Worldwide, over 10,000 patients have been treated with lansoprazole in Phase 2 or Phase 3 clinical trials involving various dosages and durations of treatment. In general, lansoprazole treatment has been well-tolerated in both short-term and long-term trials. The following adverse reactions were reported by the treating physician to have a possible or probable relationship to drug in 1% or more of lansoprazole -treated patients and occurred at a greater rate in lansoprazole-treated patients than placebo-treated patients in Table 1. Table 1: Incidence of Possibly or Probably Treatment-Related Adverse Reactions in Short-Term, Placebo-Controlled Lansoprazole Studies Body System/Adverse Reaction Lansoprazole (N= 2768) % Placebo (N= 1023) % Body as a Whole Abdominal Pain 2.1 1.2 Digestive System Constipation Diarrhea Nausea 1.0 3.8 1.3 0.4 2.3 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 15 mg and 30 mg of lansoprazole, but higher in the patients who received 60 mg of lansoprazole (2.9%, 1.4%, 4.2%, and 7.4%, respectively). The most commonly reported possibly or probably treatment-related adverse event during maintenance therapy was diarrhea. In the risk reduction study of lansoprazole for NSAID-associated gastric ulcers, the incidence of diarrhea for patients treated with lansoprazole, misoprostol, and placebo was 5, 22,and 3%, respectively. Another study for the same indication, where patients took either a COX-2 inhibitor or lansoprazole and naproxen, demonstrated that the safety profile was similar to the prior study. Additional reactions from this study not previously observed in other clinical trials with lansoprazole included contusion, duodenitis, epigastric discomfort, esophageal disorder, fatigue, hunger, hiatal hernia, hoarseness, impaired gastric emptying, metaplasia, and renal impairment. Additional adverse experiences occurring in less than 1% of patients or subjects who received lansoprazole 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. 6.2 Postmarketing Experience Additional adverse experiences have been reported since lansoprazole have been marketed. The majority of these cases are foreign-sourced and a relationship to lansoprazole has not been established. Because these reactions 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; Musculoskeletal System – bone fracture, myositis; Skin and Appendages – severe dermatologic reactions including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (some fatal), cutaneous lupus erythematosus; Special Senses – speech disorder; Urogenital System – interstitial nephritis, urinary retention. 6.3 Combination Therapy with Amoxicillin and Clarithromycin In clinical trials using combination therapy with lansoprazole plus amoxicillin and clarithromycin, and lansoprazole plus amoxicillin, no adverse reactions peculiar to these drug combinations were observed. Adverse reactions that have occurred have been limited to those that had been previously reported with lansoprazole, amoxicillin, or clarithromycin. Triple Therapy: Lansoprazole/amoxicillin/ clarithromycin The most frequently reported adverse reactions for patients who received triple therapy for 14 days were diarrhea (7%), headache (6%), and taste perversion (5%). There were no statistically significant differences in the frequency of reported adverse reactions between the 10 and 14 day triple therapy regimens. No treatment-emergent adverse reactions were observed at significantly higher rates with triple therapy than with any dual therapy regimen. Dual Therapy: Lansoprazole/ amoxicillin The most frequently reported adverse reactions for patients who received lansoprazole three times daily plus amoxicillin three times daily dual therapy were diarrhea (8%) and headache (7%). No treatment-emergent adverse reactions were observed at significantly higher rates with lansoprazole three times daily plus amoxicillin three times daily dual therapy than with lansoprazole alone. For information about adverse reactions with antibacterial agents (amoxicillin and clarithromycin) indicated in combination with lansoprazole, refer to the ADVERSE REACTIONS section of their prescribing information 6.4 Laboratory Values The following changes in laboratory parameters in patients who received lansoprazole 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. Additional isolated laboratory abnormalities were 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, 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 reported jaundice at any time during the study. In clinical trials using combination therapy with lansoprazole plus amoxicillin and clarithromycin, and lansoprazole plus amoxicillin, no increased laboratory abnormalities particular to these drug combinations were observed. For information about laboratory value changes with antibacterial agents (amoxicillin and clarithromycin) indicated in combination with lansoprazole delayed-release capsules, refer to the ADVERSE REACTIONS section of their prescribing information.

Use In Specific Populations 8.1 Pregnancy Risk Summary Available data from published observational studies overall do not indicate an association of adverse pregnancy outcomes with lansoprazole treatment (See Data) . In animal reproduction studies, oral administration of lansoprazole to rats during organogenesis through lactation at 6.4 times the maximum recommended human dose produced reductions in the offspring in femur weight, femur length, crown-rump length and growth plate thickness (males only) on postnatal Day 21 ( See Data ). These effects were associated with reduction in body weight gain. Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. If lansoprazole is administered with clarithromycin, the pregnancy information for clarithromycin also applies to the combination regimen. Refer to the prescribing information for clarithromycin for more information on use in pregnancy. Data Human Data 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. In a prospective study by the European Network of Teratology Information Services, outcomes from a group of 62 pregnant women administered median daily doses of 30 mg of lansoprazole were compared to a control group of 868 pregnant women who did not take any PPIs. There was no difference in the rate of major malformations between women exposed to PPIs and the control group, corresponding to a Relative Risk (RR)=1.04, [95% Confidence Interval (CI) 0.25-4.21]. In a population-based retrospective cohort study covering all live births in Denmark from 1996 to 2008, there was no significant increase in major birth defects during analysis of first trimester exposure to lansoprazole in 794 live births. A meta-analysis that compared 1,530 pregnant women exposed to PPIs in at least the first trimester with 133,410 unexposed pregnant women showed no significant increases in risk for congenital malformations or spontaneous abortion with exposure to PPIs (for major malformations Odds Ratio (OR)=1.12, [95% CI 0.86-1.45] and for spontaneous abortions OR=1.29, [95% CI 0.84-1.97]). Animal Data 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. 8.2 Lactation Risk Summary There is no information regarding the presence of lansoprazole in human milk, the effects on the breastfed infant, or the effects on milk production. However, lansoprazole and its metabolites are present in rat milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for lansoprazole and any potential adverse effects on the breastfed child from lansoprazole or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of lansoprazole have been established in pediatric patients one year to 17 years of age for short-term treatment of symptomatic GERD and erosive esophagitis. In clinical studies of symptomatic GERD and erosive esophagitis, lansoprazole was not administered beyond 12 weeks in patients one year to 11 years of age. It is not known if lansoprazole is safe and effective if used longer than the recommended duration. Do not exceed the recommended dose and duration of use in pediatric patients (see Juvenile Animal Toxicity Data). Lansoprazole was not effective in pediatric patients with symptomatic GERD one month to less than one year of age in a multicenter, double-blind, placebo-controlled study. Therefore, safety and effectiveness have not been established in patients less than one year of age. Nonclinical studies in juvenile rats have demonstrated an adverse effect of heart valve thickening and bone changes at lansoprazole doses higher than the maximum recommended equivalent human dose. Neonate to less than one year of age The pharmacokinetics of lansoprazole were studied in pediatric patients with GERD aged less than 28 days and one to 11 months. Compared to healthy adults receiving 30 mg, neonates had higher exposure (mean weight-based normalized AUC values 2.04 and 1.88 fold higher at doses of 0.5 and 1 mg/kg/day, respectively). Infants aged ≤10 weeks had clearance and exposure values that were similar to neonates. Infants aged greater than 10 weeks who received 1 mg/kg/day had mean AUC values that were similar to adults who received a 30 mg dose. Lansoprazole was not found to be effective in a US and Polish four week, multicenter, double-blind, placebo-controlled, parallel-group study of 162 patients between one month and less than 12 months of age with symptomatic GERD based on a medical history of crying/fussing/irritability associated with feedings who had not responded to conservative GERD management (i.e., nonpharmacologic intervention) for seven to 14 days. Patients received lansoprazole as a suspension daily (0.2 to 0.3 mg/kg/day in infants ≤10 weeks of age or 1.0 to 1.5 mg/kg/day in infants greater than 10 weeks or placebo) for up to four weeks of double-blind treatment. The primary efficacy endpoint was assessed by greater than 50% reduction from baseline in either the percent of feedings with a crying/fussing/irritability episode or the duration (minutes) of a crying/fussing/irritability episode within one hour after feeding. There was no difference in the percentage of responders between the lansoprazole pediatric suspension group and placebo group (54% in both groups). There were no adverse events reported in pediatric clinical studies (one month to less than 12 months of age) that were not previously observed in adults. Based on the results of the Phase 3 efficacy study, lansoprazole was not shown to be effective. Therefore, these results do not support the use of lansoprazole in treating symptomatic GERD in infants. One year to 11 years of age In an uncontrolled, open-label, US multicenter study, 66 pediatric patients (one year to 11 years of age) with GERD were assigned, based on body weight, to receive an initial dose of either lansoprazole 15 mg daily if ≤30 kg or lansoprazole 30 mg daily if greater than 30 kg administered for eight to 12 weeks. The lansoprazole dose was increased (up to 30 mg twice daily) in 24 of 66 pediatric patients after two or more weeks of treatment if they remained symptomatic. At baseline 85% of patients had mild to moderate overall GERD symptoms (assessed by investigator interview), 58% had non-erosive GERD and 42% had erosive esophagitis (assessed by endoscopy). After eight to 12 weeks of lansoprazole treatment, the intent-to-treat analysis demonstrated an approximate 50% reduction in frequency and severity of GERD symptoms. Twenty one of 27 erosive esophagitis patients were healed at eight weeks and 100% of patients were healed at 12 weeks by endoscopy ( Table 4). Table 4: GERD Symptom Improvement and Erosive Esophagitis Healing Rates in Pediatric Patients Age 1 to 11 GERD Final Visit * % (n/N) Symptomatic GERD Improvement in Overall GERD Symptoms † 76% (47/62 ‡) Erosive Esophagitis Improvement in Overall GERD Symptoms † Healing Rate 81% (22/27) 100% (27/27) * At Week 8 or Week12 † Symptoms assessed by patients diary kept by caregiver. ‡ No data were available for four pediatric patients. In a study of 66 pediatric patients in the age group one year to 11 years old after treatment with lansoprazole given orally in doses of 15 mg daily to 30 mg twice daily, increases in serum gastrin levels were similar to those observed in adult studies. Median fasting serum gastrin levels increased 89% from 51 pg/mL at baseline to 97 pg/mL [interquartile range (25th to 75th percentile) of 71 to 130 pg/mL] at the final visit. The pediatric safety of lansoprazole delayed-release capsules has been assessed in 66 pediatric patients aged one to 11 years of age. Of the 66 patients with GERD, 85% (56/66) took lansoprazole for eight weeks and 15% (10/66) took it for 12 weeks. The most frequently reported (two or more patients) treatment-related adverse reactions in patients one to 11 years of age (N=66) were constipation (5%) and headache (3%). Twelve years to 17 years of age In an uncontrolled, open-label, US multicenter study, 87 adolescent patients (12 years to 17 years of age) with symptomatic GERD were treated with lansoprazole for eight to 12 weeks. Baseline upper endoscopies classified these patients into two groups: 64 (74%) non-erosive GERD and 23 (26%) erosive esophagitis (EE). The non-erosive GERD patients received lansoprazole 15 mg daily for eight weeks and the EE patients received lansoprazole 30 mg daily for eight to 12 weeks. At baseline, 89% of these patients had mild to moderate overall GERD symptoms (assessed by investigator interviews). During eight weeks of lansoprazole treatment, adolescent patients experienced a 63% reduction in frequency and a 69% reduction in severity of GERD symptoms based on diary results. Twenty one of 22 (95.5%) adolescent erosive esophagitis patients were healed after eight weeks of lansoprazole treatment. One patient remained unhealed after 12 weeks of treatment (Table 5). Table 5:GERD Symptom Improvement and Erosive Esophagitis Healing Rates in Pediatric Patients Age 12 to 17 GERD Final Visit % (n/N) Symptomatic GERD (All Patients) Improvement in Overall GERD Symptoms * 73.2%(60/82) † Non-erosive GERD Improvement in Overall GERD Symptoms * 71.2%(42/59) † Erosive Esophagitis Improvement in Overall GERD Symptoms * Healing rate ‡ 78.3%(18/23) 95.5%(21/22) ‡ * Symptoms assessed by patient diary (parents/caregivers as necessary). † No data available for five patients. ‡ Data from one healed patient was excluded from this analysis due to timing of final endoscopy. In these 87 adolescent patients, increases in serum gastrin levels were similar to those observed in adult studies, median fasting serum gastrin levels increased 42% from 45 pg/mL at baseline to 64 pg/mL [interquartile range (25 th to 75 th percentile) of 44 to 88 pg/mL] at the final visit. (Normal serum gastrin levels are 25 to 111 pg/mL). The safety of lansoprazole delayed-release capsules has been assessed in these 87 adolescent patients. Of the 87 adolescent patients with GERD, 6% (5/87) took lansoprazole for less than six weeks, 93% (81/87) for six to 10 weeks , and 1% (1/87) for greater than 10 weeks. The most frequently reported (at least 3%) treatment-related adverse reactions in these patients were headache (7%), abdominal pain (5%), nausea (3%) and dizziness (3%). Treatment-related dizziness, reported in this prescribing information as occurring in less than 1% of adult patients, was reported in this study by three adolescent patients with non-erosive GERD, who had dizziness concurrently with other reactions (such as migraine, dyspnea, and vomiting). Juvenile Animal Toxicity Data Heart Valve Thickening In two oral toxicity studies, thickening of the mitral heart valve occurred in juvenile rats treated with lansoprazole. Heart valve thickening was observed primarily with oral dosing initiated on postnatal Day 7 (age equivalent to neonatal humans) and postnatal Day 14 (human age equivalent of approximately one year) at doses of 250 mg/kg/day and higher (at postnatal Day 7 and postnatal Day 14, respectively 6.2 times and 4.2 times the daily pediatric dose of 15 mg in pediatric patients age one to 11 years weighing 30 kg or less, based on AUC). The treatment durations associated with heart valve thickening ranged from 5 days to 8 weeks. The findings reversed or trended towards reversibility after a 4-week drug-free recovery period. The incidence of heart valve thickening after initiation of dosing on postnatal Day 21 (human age equivalent of approximately two years) was limited to a single rat (1/24) in groups given 500 mg/kg/day for 4 or 8 weeks (approximately 5.2 times the daily pediatric dose of 15 mg in pediatric patients age one to 11 years weighing 30 kg or less, based on AUC). Based on exposure margins, the risk of heart valve injury does not appear to be relevant to patients one year of age and older. Bone Changes In an eight-week oral toxicity study in juvenile rats with dosing initiated on postnatal Day 7, doses equal to or greater than 100 mg/kg/day (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 four-week recovery period. Longer term data were not collected. 8.5 Geriatric Use Of the total number of patients (n=21,486) in clinical studies of lansoprazole 16% of patients were aged 65 years and over, while 4% were 75 years and over. No overall differences in safety or effectiveness were observed between these patients and younger patients and other reported clinical experience has not identified significant differences in responses between geriatric and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology ( 12.3)] 8.6 Hepatic Impairment In patients with various degrees of chronic hepatic impairment the exposure to lansoprazole was increased compared to healthy subjects with normal hepatic function [see Clinical Pharmacology ( 12.3)] . No dosage adjustment for lansoprazole is necessary for patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. The recommended dosage is 15 mg orally daily in patients with severe hepatic impairment(Child-Pugh Class C) [see Dosage and Administration ( 2.3)].