Lansoprazole

1 INDICATIONS AND USAGE Lansoprazole delayed-release capsules are a proton pump inhibitor (PPI) indicated for the: Treatment of active duodenal ulcer in adults ( 1.1 ) Eradication of H. pylori to reduce the risk of duodenal ulcer recurrence in adults ( 1.2 ) Maintenance of healed duodenal ulcers in adults ( 1.3 ) Treatment of active benign gastric ulcer in adults ( 1.4 ) Healing of nonsteroidal anti-inflammatory drugs (NSAID)-associated gastric ulcer in adults ( 1.5 ) Risk reduction of NSAID-associated gastric ulcer in adults ( 1.6 ) Treatment of symptomatic gastroesophageal reflux disease (GERD) in adults and pediatric patients 1 year of age and older. ( 1.7 ) Treatment of erosive esophagitis (EE) in adults and pediatric patients 1 year of age and older. ( 1.8 ) Maintenance of healing of EE in adults ( 1.9 ) Pathological hypersecretory conditions, including Zollinger-Ellison Syndrome (ZES) in adults ( 1.10 ) 1.1 Treatment of Active Duodenal Ulcer Lansoprazole delayed-release capsules are indicated 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 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 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 years to 17 years of age (up to eight weeks) and pediatric patients one year 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

12.1 Mechanism of Action Lansoprazole belongs to a class of antisecretory compounds, the substituted benzimidazoles, that suppress gastric acid secretion by specific inhibition of the (H + , K + )-ATPase enzyme system at the secretory surface of the gastric parietal cell. Because this enzyme system is regarded as the acid (proton) pump within the parietal cell, lansoprazole has been characterized as a gastric acid-pump inhibitor, in that it blocks the final step of acid production. This effect is dose-related and leads to inhibition of both basal and stimulated gastric acid secretion irrespective of the stimulus. Lansoprazole does not exhibit anticholinergic or histamine type-2 antagonist activity.

2 DOSAGE AND ADMINISTRATION Recommended Dosage: See full prescribing information for complete dosing information for lansoprazole delayed-release capsules by indication and age group and dosage adjustment in patients with severe hepatic impairment. ( 2.1 , 2.2 , 2.3 ) Administration Instructions ( 2.4 ) Lansoprazole delayed-release capsules Should be swallowed whole. See full prescribing information for alternative administration options 2.1 Recommended Adult Dosage by Indication Indication Recommended Dose Frequency Duodenal Ulcers Short-Term Treatment 15 mg Once daily for 4 weeks Maintenance of Healed 15 mg Once daily Eradication of H. pylori to Reduce the Risk of Duodenal Ulcer Recurrence* Triple Therapy: Lansoprazole 30 mg Twice daily for 10 or 14 days Amoxicillin 1 gram Twice daily for 10 or 14 days Clarithromycin 500 mg Twice daily for 10 or 14 days Dual Therapy: Lansoprazole 30 mg Three times daily for 14 days Amoxicillin 1 gram 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 30 mg Once daily for 8 weeks † Risk Reduction 15 mg Once daily for up to 12 weeks † Gastroesophageal Reflux Disease (GERD) Short-Term Treatment of Symptomatic GERD 15 mg Once daily for up to 8 weeks Short-Term Treatment of Erosive Esophagitis 30 mg 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 WARNINGS and 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. ¶ 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. # Controlled studies did not extend beyond 12 months 2.2 Recommended Pediatric Dosage by Indication Pediatric Patients 1 to 11 Years of Age In clinical studies, Lansoprazole delayed-release capsules was not administered beyond 12 weeks in 1 to 11 year olds. It is not known if Lansoprazole delayed-release capsules are 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 cap

6 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 )] Severe Cutaneous Adverse Reactions [see Warnings and Precautions ( 5.5 )] Cutaneous and Systemic Lupus Erythematosus [see Warnings and Precautions ( 5.6 )] Cyanocobalamin (Vitamin B-12) Deficiency [see Warnings and Precautions ( 5.7 )] Hypomagnesemia and Mineral Metabolism [see Warnings and Precautions ( 5.8 )] Fundic Gland Polyps [see Warnings and Precautions ( 5.12 )] Most commonly reported adverse reactions (≥1%): diarrhea, abdominal pain, nausea and constipation. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Xiromed LLC at 844-XIROMED (844-947-6633) or FDA at 1-800-FDA-1088 o r www.fda.gov/medwatch. 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 delayed-release capsule-treated patients and occurred at a greater rate in lansoprazole delayed-release capsule-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 Event Lansoprazole (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 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,

5 WARNINGS AND PRECAUTIONS Gastric Malignancy : In adults, symptomatic response with lansoprazole does not preclude the presence of gastric malignancy. Consider additional follow-up and diagnostic testing ( 5.1 ) Acute Tubulointerstitial Nephritis : Discontinue treatment and evaluate patients. ( 5.2 ) Clostridium difficile Associated Diarrhea : PPI therapy may be associated with increased risk of Clostridium difficile associated diarrhea. ( 5.3 ) Bone Fracture : Long-term and multiple daily dose PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist or spine. ( 5.4 ) Severe Cutaneous Adverse Reactions: Discontinue at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation. ( 5.5) Cutaneous and Systemic Lupus Erythematosus : Mostly cutaneous; new onset or exacerbation of existing disease; discontinue lansoprazole and refer to specialist for evaluation. ( 5.6 ) Cyanocobalamin (Vitamin B-12) Deficiency : Daily long-term use (e.g., longer than 3 years) may lead to malabsorption or a deficiency of cyanocobalamin. ( 5.7 ) Hypomagnesemia and Mineral Metabolism : Hypomagnesemia has been reported rarely with prolonged treatment with PPIs. ( 5.8 ) Interactions with Investigations for Neuroendocrine Tumors : Increases in intragastric pH may result in hypergastrinemia and enterochromaffin-like cell hyperplasia and increased chromogranin A levels which may interfere with diagnostic investigations for neuroendocrine tumors. ( 5.9 , 7 ) Interaction with Methotrexate : Concomitant use with PPIs may elevate and/or prolong serum concentrations of methotrexate and/or its metabolite, possibly leading to toxicity. With high-dose methotrexate administration, consider a temporary withdrawal of lansoprazole. (5.10 , 7 ) Fundic Gland Polyps : Risk increases with long-term use, especially beyond 1 year. Use the shortest duration of therapy. ( 5.12 ) Risk of Heart Valve Thickening in Pediatric Patients Less than One Year of Age : lansoprazole delayed-release capsules are not recommended in pediatric patients less than 1 year of age. ( 5.13 , 8.4) 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 delayed-release capsules and evaluate patients with suspected acute TIN [see Contraindications ( 4 )] . 5.3 Clostridium difficile -Associated Diarrhea Published observational studies suggest that proton pump inhibitor (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 sections of their prescribing information. 5.4 Bone Fracture Several publish

4 CONTRAINDICATIONS Lansoprazole delayed-release capsules are 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. Contraindicated in patients with known hypersensitivity to any component of the lansoprazole delayed-release capsules formulation. ( 4 ) Patients receiving rilpivirine-containing products. ( 4 , 7 )

10 OVERDOSAGE Lansoprazole is not removed from the circulation by hemodialysis. In one reported overdose, a patient consumed 600 mg of lansoprazole with no adverse reaction. Oral lansoprazole doses up to 5000 mg/kg in rats [approximately 1300 times the 30 mg human dose based on body surface area (BSA)] and in mice (about 675.7 times the 30 mg human dose based on BSA) did not produce deaths or any clinical signs. In the event of over-exposure, treatment should be symptomatic and supportive. If over-exposure occurs, call your poison control center at 1-800-222-1222 for current information on the management of poisoning or over-exposure.