Dexlansoprazole

1 INDICATIONS AND USAGE Dexlansoprazole delayed-release capsules are a proton pump inhibitor (PPI) indicated in patients 12 years of age and older for: • Healing of all grades of erosive esophagitis (EE). ( 1.1 ) • Maintenance of healed EE and relief of heartburn. ( 1.2 ) • Treatment of symptomatic non-erosive gastroesophageal reflux disease (GERD). ( 1.3 ) 1.1 Healing of Erosive Esophagitis Dexlansoprazole delayed-release capsules are indicated in patients 12 years of age and older for healing of all grades of erosive esophagitis (EE) for up to eight weeks. 1.2 Maintenance of Healed Erosive Esophagitis and Relief of Heartburn Dexlansoprazole delayed-release capsules are indicated in patients 12 years of age and older to maintain healing of EE and relief of heartburn for up to six months in adults and 16 weeks in patients 12 to 17 years of age. 1.3 Treatment of Symptomatic Non-Erosive Gastroesophageal Reflux Disease Dexlansoprazole delayed-release capsules are indicated in patients 12 years of age and older for the treatment of heartburn associated with symptomatic non-erosive gastroesophageal reflux disease (GERD) for four weeks.

12.1 Mechanism of Action Dexlansoprazole belongs to a class of antisecretory compounds, the substituted benzimidazoles, that suppress gastric acid secretion by specific inhibition of the (H + , K + )-ATPase at the secretory surface of the gastric parietal cell. Because this enzyme is regarded as the acid (proton) pump within the parietal cell, dexlansoprazole has been characterized as a gastric proton-pump inhibitor, in that it blocks the final step of acid production.

2 DOSAGE AND ADMINISTRATION Recommended dosage in patients 12 years of age and older: • See full prescribing information for complete dosing information for dexlansoprazole delayed-release capsules by indication and age group and dosage adjustment in patients with hepatic impairment. ( 2.1 , 2.2 ) Administration Instructions ( 2.3 ): • Take without regard to food. • Swallow whole; do not chew. • See full prescribing information for alternative administration options. 2.1 Recommended Dosage in Patients 12 Years of Age and Older Table 1. Recommended Dexlansoprazole Delayed-Release Capsules Dosage Regimen by Indication in Patients 12 Years of Age and Older Indication Dosage of Dexlansoprazole Delayed-Release Capsules Duration Healing of EE One 60 mg capsule once daily. Up to 8 weeks. Maintenance of Healed EE and Relief of Heartburn One 30 mg capsule once daily. Controlled studies did not extend beyond 6 months in adults and 16 weeks in patients 12 to 17 years of age. Symptomatic Non-Erosive GERD One 30 mg capsule once daily. 4 weeks. 2.2 Dosage Adjustment in Patients with Hepatic Impairment for the Healing of Erosive Esophagitis For patients with moderate hepatic impairment (Child-Pugh Class B), the recommended dosage is 30 mg dexlansoprazole delayed-release capsules once daily for up to eight weeks. Dexlansoprazole delayed-release capsule is not recommended in patients with severe hepatic impairment (Child-Pugh Class C) [see Use in Specific Populations (8.6)]. 2.3 Important Administration Information • Take without regard to food. • 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. • Swallow whole; do not chew. • For patients who have trouble swallowing capsules, dexlansoprazole delayed-release capsules can be opened and administered with applesauce as follows: 1. Place one tablespoonful of applesauce into a clean container. 2. Open capsule. 3. Sprinkle intact pellets on applesauce. 4. Swallow applesauce and pellets immediately. Do not chew pellets. Do not save the applesauce and pellets for later use. • Alternatively, the capsule can be administered with water via oral syringe or nasogastric (NG) tube. Administration with Water in an Oral Syringe 1. Open the capsule and empty the pellets into a clean container with 20 mL of water. 2. Withdraw the entire mixture into a syringe. 3. Gently swirl the syringe in order to keep pellets from settling. 4. Administer the mixture immediately into the mouth. Do not save the water and pellet mixture for later use. 5. Refill the syringe with 10 mL of water, swirl gently, and administer. 6. Refill the syringe again with 10 mL of water, swirl gently, and administer. Administration with Water via a NG Tube (≥16 French) 1. Open the capsule and empty the pellets into a clean container with 20 mL of water. 2. Withdraw the entire mixture into a catheter-tip syringe. 3. Swirl the catheter-tip syringe gently in order to keep the pellets from settling, and immediately inject the mixture through the NG tube into the stomach. Do not save the water and pellet mixture for later use. 4. Refill the catheter-tip syringe with 10 mL of water, swirl gently, and flush the tube. 5. Refill the catheter-tip syringe again with 10 mL of water, swirl gently, and administer.

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 B12) Deficiency [see Warnings and Precautions (5.7)] • Hypomagnesemia and Mineral Metabolism [see Warnings and Precautions (5.8)] • Fundic Gland Polyps [see Warnings and Precautions (5.11)] • Risk of Heart Valve Thickening in Pediatric Patients Less than Two Years of Age [see Warnings and Precautions (5.12)] The most common adverse reactions are: • Adults (≥2%): diarrhea, abdominal pain, nausea, upper respiratory tract infection, vomiting, and flatulence. ( 6.1 ) • Patients 12 to 17 years of age (≥5%): headache, abdominal pain, diarrhea, nasopharyngitis, and oropharyngeal pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact FDA at 1-800-FDA-1088 or 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 practice. Adults The safety of dexlansoprazole was evaluated in 4548 adult patients in controlled and single-arm clinical trials, including 863 patients treated for at least six months and 203 patients treated for one year. Patients ranged in age from 18 to 90 years (median age 48 years), with 54% female, 85% Caucasian, 8% Black, 4% Asian, and 3% Other races. Six randomized controlled clinical trials were conducted for the treatment of EE, maintenance of healed EE, and symptomatic GERD, which included 896 patients on placebo, 455 patients on dexlansoprazole 30 mg, 2218 patients on dexlansoprazole 60 mg, and 1363 patients on lansoprazole 30 mg once daily. Common Adverse Reactions The most common adverse reactions (>2%) that occurred at a higher incidence for dexlansoprazole than placebo in the controlled studies are presented in Table 2 . Table 2. Common Adverse Reactions in Controlled Studies in Adults Adverse Reaction Placebo (N=896) % Dexlansoprazole 30 mg (N=455) % Dexlansoprazole 60 mg (N=2218) % Dexlansoprazole Total (N=2621) % Lansoprazole 30 mg (N=1363) % Diarrhea 2.9 5.1 4.7 4.8 3.2 Abdominal Pain 3.5 3.5 4 4 2.6 Nausea 2.6 3.3 2.8 2.9 1.8 Upper Respiratory Tract Infection 0.8 2.9 1.7 1.9 0.8 Vomiting 0.8 2.2 1.4 1.6 1.1 Flatulence 0.6 2.6 1.4 1.6 1.2 Adverse Reactions Resulting in Discontinuation In controlled clinical studies, the most common adverse reaction leading to discontinuation from dexlansoprazole was diarrhea (0.7%). Less Common Adverse Reactions Other adverse reactions that were reported in controlled studies at an incidence of less than 2% are listed below by body system: Blood and Lymphatic System Disorders : anemia, lymphadenopathy Cardiac Disorders : angina, arrhythmia, bradycardia, chest pain, edema, myocardial infarction, palpitation, tachycardia Ear and Labyrinth Disorders : ear pain, tinnitus, vertigo Endocrine Disorders : goiter Eye Disorders : eye irritation, eye swelling Gastrointestinal Disorders : abdominal discomfort, abdominal tenderness, abnormal feces, anal discomfort, Barrett’s esophagus, bezoar, bowel sounds abnormal, breath odor, colitis microscopic, colonic polyp, constipation, dry mouth, duodenitis, dyspepsia, dysphagia, enteritis, eructation, esophagitis, gastric polyp, gastritis, gastroenteritis, gastrointestinal disorders, gastrointestinal hypermotility disorders, GERD, GI ulcers and perforation, hematemesis, hematochezia, hemorrhoids, impaired gastric emptying, irritable bowel syndrome, mucus stools, oral mucosal blistering, painful defeca

5 WARNINGS AND PRECAUTIONS • Gastric Malignancy: In adults, symptomatic response with dexlansoprazole 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. ( 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 dexlansoprazole and refer to specialist for evaluation. ( 5.6 ) • Cyanocobalamin (Vitamin B12) 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: 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 dexlansoprazole. ( 5.10 , 7 ) • Fundic Gland Polyps: Risk increases with long-term use, especially beyond 1 year. Use the shortest duration of therapy. ( 5.11 ) • Risk of Heart Valve Thickening in Pediatric Patients Less than Two Years of Age: Dexlansoprazole is not recommended in pediatric patients less than 2 years of age. ( 5.12 , 8.4 ) 5.1 Presence of Gastric Malignancy In adults, symptomatic response to therapy with dexlansoprazole 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 dexlansoprazole and evaluate patients with suspected acute TIN [see Contraindications (4)]. 5.3 Clostridium difficile-Associated Diarrhea Published observational studies suggest that PPI therapy like dexlansoprazole may be associated with an increased risk of Clostridium difficile -associated diarrhea, 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. 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 con

4 CONTRAINDICATIONS • Dexlansoprazole delayed-release capsules are contraindicated in patients with known hypersensitivity to any component of the formulation [see Description (11)] . Hypersensitivity reactions may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, acute tubulointerstitial nephritis and urticaria [see Warnings and Precautions (5.2), Adverse Reactions (6)]. • PPIs, including dexlansoprazole delayed-release capsules, are contraindicated with rilpivirine-containing products [see Drug Interactions (7)]. • Patients with known hypersensitivity to any component of the formulation. ( 4 ) • Patients receiving rilpivirine-containing products. ( 4 , 7 )

10 OVERDOSAGE There have been no reports of significant overdose with dexlansoprazole. Multiple doses of dexlansoprazole 120 mg and a single dose of dexlansoprazole 300 mg did not result in death or other severe adverse events. However, serious adverse events of hypertension have been reported in association with twice daily doses of dexlansoprazole 60 mg. Nonserious adverse reactions observed with twice daily doses of dexlansoprazole 60 mg include hot flashes, contusion, oropharyngeal pain, and weight loss. Dexlansoprazole is not expected to be removed from the circulation by hemodialysis. 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.