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.

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 capsules are 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.

3 DOSAGE FORMS AND STRENGTHS Dexlansoprazole Delayed-Release Capsules are available containing 30 mg or 60 mg of dexlansoprazole sesquihydrate as enteric-coated pellets. • The 30 mg capsules are cellulose capsules with a light blue opaque cap and white opaque body filled with creamish yellow to brownish yellow pellets. The capsules are axially printed with MYLAN over DX 30 in black ink on cap and body. • The 60 mg capsules are cellulose capsules with a light blue opaque cap and light blue opaque body filled with creamish yellow to brownish yellow pellets. The capsules are axially printed with MYLAN over DX 60 in black ink on cap and body. Delayed-release capsules: 30 mg and 60 mg. ( 3 )

4 CONTRAINDICATIONS • Dexlansoprazole extended-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 )

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 Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or 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 4.0 4.0 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 bowe …

7 DRUG INTERACTIONS Tables 3 and 4 include drugs with clinically important drug interactions and interaction with diagnostics when administered concomitantly with dexlansoprazole and instructions for preventing or managing them. Consult the labeling of concomitantly used drugs to obtain further information about interactions with PPIs. Table 3. Clinically Relevant Interactions Affecting Drugs Coadministered with Dexlansoprazole 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 dexlansoprazole may reduce antiviral effect and promote the development of drug resistance. • Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with dexlansoprazole may increase toxicity of the antiretroviral drugs. • There are other antiretroviral drugs which do not result in clinically relevant interactions with dexlansoprazole. Intervention: Rilpivirine-containing products : Concomitant use with dexlansoprazole is contraindicated [see Contraindications (4) ] . See prescribing information. Atazanavir : See prescribing information for atazanavir for dosing information. Nelfinavir : Avoid concomitant use with dexlansoprazole. 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 (5.10) ] . Intervention: A temporary withdrawal of dexlansoprazole 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. Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole) Clinical Impact: Dexlansoprazole 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 dexlansoprazole and MMF. Use dexlansoprazole with caution in transplant patients receiving MMF. See the prescribing information for other drugs dependent on gastric pH for absorption. 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. …

8 USE IN SPECIFIC POPULATIONS • Pregnancy : Based on animal data, may cause adverse effects on fetal bone growth and development. ( 8.1 ) • Pediatrics : Based on data with lansoprazole, dexlansoprazole is not effective in patients with symptomatic GERD 1 month to less than 1 year of age and nonclinical studies have demonstrated adverse effects in juvenile rats. ( 8.4 ) 8.1 Pregnancy Risk Summary There are no studies with dexlansoprazole use in pregnant women to inform a drug-associated risk. Dexlansoprazole is the R-enantiomer of lansoprazole, and published observational studies of lansoprazole use during pregnancy did not demonstrate an association of adverse pregnancy-related outcomes with lansoprazole (see Data ) . In animal reproduction studies, oral administration of lansoprazole to rats during organogenesis through lactation at 1.8 times the maximum recommended human dexlansoprazole 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 the fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is 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. Data Human Data Dexlansoprazole is the R-enantiomer of lansoprazole. 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 An embryo-fetal development study conducted in rabbits at oral dexlansoprazole doses up to 30 mg/kg/day (approximately nine times the maximum recommended human dexlansoprazole dose [60 mg/day] based on body surface area) during organogenesis showed no effects on fetuses due to dexlansoprazole. In addition, embryo-fetal development studies performed in rats with oral lansoprazole at doses up to 150 mg/kg/day (40 times the recommended human lansoprazole dose based on body surface area) during organogenesis and in rabbits with oral lansoprazole at doses up to 30 mg/kg/day (16 times the recommended human lansoprazole dose based on body surface area) during organogenesis revealed no effects on fetuses due to lansoprazole. 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 (0.2 to 1.8 times the maximum recommended human dexlansoprazole d …

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.

11 DESCRIPTION The active ingredient in dexlansoprazole delayed-release capsules, a proton pump inhibitor, is 2-[( R )-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2- pyridinyl]methyl]sulfinyl]-1 H -benzimidazole Sesquihydrate, a compound that inhibits gastric acid secretion. Dexlansoprazole is the R -enantiomer of lansoprazole (a racemic mixture of the R - and S -enantiomers). Dexlansoprazole sesquihydrate’s molecular formula is: C 16 H 14 F 3 N 3 O 2 S•11⁄2 H 2 O, with a molecular weight of 396.39. Dexlansoprazole sesquihydrate has the following chemical structure: Dexlansoprazole sesquihydrate is a white to brown color powder which melts with decomposition at 85.5°C. Dexlansoprazole sesquihydrate is freely soluble in N,N-dimethylformamide and practically insoluble in water. Dexlansoprazole sesquihydrate is not stable when exposed to light. Dexlansoprazole sesquihydrate is not stable in alkaline or acidic conditions. Dexlansoprazole is supplied for oral administration as a dual delayed-release formulation in capsules. The capsules contain dexlansoprazole sesquihydrate in a single type of enteric-coated pellets [see Clinical Pharmacology (12.3) ] . Dexlansoprazole delayed-release capsules are available in two dosage strengths: 30 and 60 mg, per capsule. Each capsule contains enteric-coated pellets consisting of dexlansoprazole sesquihydrate (active ingredient) and the following inactive ingredients: colloidal silicon dioxide, ethyl cellulose dispersion type B, hypromellose, methacrylic acid - ethyl acrylate copolymer (1:1) type A, mono- and di-glycerides, polysorbate 80, potassium hydroxide, povidone, sucrose, sugar spheres (corn starch and sucrose), talc and triethyl citrate. The components of the capsule shells include the following inactive ingredients: carrageenan, FD&C Blue No. 2, hypromellose, potassium chloride and titanium dioxide. The black imprinting ink contains black iron oxide, potassium hydroxide and shellac. Dexlansoprazole Structural Formula

10 OVERDOSAGE There have been no reports of significant overdose with dexlansoprazole delayed-release capsules. Multiple doses of dexlansoprazole delayed-release capsules 120 mg and a single dose of dexlansoprazole delayed-release capsules 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 delayed-release capsules 60 mg. Nonserious adverse reactions observed with twice daily doses of dexlansoprazole delayed-release capsules 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.

16 HOW SUPPLIED/STORAGE AND HANDLING Dexlansoprazole Delayed-Release Capsules are available containing 30 mg or 60 mg of dexlansoprazole sesquihydrate as enteric-coated pellets. The 30 mg capsules are cellulose capsules with a light blue opaque cap and white opaque body filled with creamish yellow to brownish yellow pellets. The capsules are axially printed with MYLAN over DX 30 in black ink on cap and body. They are available as follows: NDC 0378-2085-93 bottles of 30 capsules NDC 0378-2085-77 bottles of 90 capsules NDC 0378-2085-05 bottles of 500 capsules The 60 mg capsules are cellulose capsules with a light blue opaque cap and light blue opaque body filled with creamish yellow to brownish yellow pellets. The capsules are axially printed with MYLAN over DX 60 in black ink on cap and body. They are available as follows: NDC 0378-2086-93 bottles of 30 capsules NDC 0378-2086-77 bottles of 90 capsules NDC 0378-2086-05 bottles of 500 capsules Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. PHARMACIST: Dispense a Medication Guide with each prescription.