Dexilant

Healing of Erosive Esophagitis

KAPIDEX (dexlansoprazole delayed release capsules) is indicated for healing of all grades of erosive esophagitis (EE) for up to 8 weeks.

Maintenance of Healed Erosive Esophagitis

KAPIDEX (dexlansoprazole delayed release capsules) is indicated to maintain healing of EE for up to 6 months.

Symptomatic Non-Erosive Gastroesophageal Reflux Disease

KAPIDEX (dexlansoprazole delayed release capsules) is indicated for the treatment of heartburn associated with non-erosive gastroesophageal reflux disease (GERD) for 4 weeks.

Recommended Dose

KAPIDEX (dexlansoprazole delayed release capsules) is available as capsules in 30 mg and 60 mg strengths for adult use. Directions for use in each indication are summarized in Table 1.

Table 1: KAPIDEX (dexlansoprazole delayed release capsules) Dosing Recommendations

Special Populations

No adjustment for KAPIDEX (dexlansoprazole delayed release capsules) is necessary for patients with mild hepatic impairment (Child-Pugh Class A). Consider a maximum daily dose of 30 mg for patients with moderate hepatic impairment (Child-Pugh Class B). No studies have been conducted in patients with severe hepatic impairment (Child-Pugh Class C).

No dosage adjustment is necessary for elderly patients or for patients with renal impairment.

Important Administration Information

KAPIDEX (dexlansoprazole delayed release capsules) can be taken without regard to food. KAPIDEX (dexlansoprazole delayed release capsules) should be swallowed whole.

• Alternatively, KAPIDEX (dexlansoprazole delayed release capsules) capsules can be opened and administered as follows:
  • Open capsule;
  • Sprinkle intact granules on one tablespoon of applesauce;
  • Swallow immediately.

KAPIDEX (dexlansoprazole delayed release capsules) is contraindicated in patients with known hypersensitivity to any component of the formulation. Hypersensitivity and anaphylaxis have been reported with KAPIDEX use.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Gastric Malignancy

Symptomatic response with KAPIDEX (dexlansoprazole delayed release capsules) does not preclude the presence of gastric malignancy.

Patient Counseling Information

Tell your patients to watch for signs of an allergic reaction as these could be serious and may require that KAPIDEX (dexlansoprazole delayed release capsules) be discontinued.

To ensure the safe and effective use of KAPIDEX (dexlansoprazole delayed release capsules) , this information and instructions provided in the FDA-approved patient labeling should be discussed with the patient. Inform patients of the following:

KAPIDEX (dexlansoprazole delayed release capsules) is available as a delayed release capsule. KAPIDEX (dexlansoprazole delayed release capsules) may be taken without regard to food. KAPIDEX (dexlansoprazole delayed release capsules) should be swallowed whole.

• Alternatively, KAPIDEX (dexlansoprazole delayed release capsules) capsules can be opened and administered as follows:
  • Open capsule;
  • Sprinkle intact granules on one tablespoon of applesauce;
  • Swallow immediately.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

The carcinogenic potential of dexlansoprazole was assessed using lansoprazole studies. In two 24-month carcinogenicity studies, Sprague-Dawley rats were treated orally with lansoprazole at doses of 5 to 150 mg per kg per day, about 1 to 40 times the exposure on a body surface (mg/m²) basis of a 50 kg person of average height (1.46 m² BSA) given the recommended human dose of lansoprazole 30 mg per day.

Lansoprazole produced dose-related gastric ECL cell hyperplasia and ECL cell carcinoids in both male and female rats.

In rats, lansoprazole also increased the incidence of intestinal metaplasia of the gastric epithelium in both sexes. In male rats, lansoprazole produced a dose-related increase of testicular interstitial cell adenomas. The incidence of these adenomas in rats receiving doses of 15 to 150 mg per kg per day (4 to 40 times the recommended lansoprazole human dose based on BSA) exceeded the low background incidence (range = 1.4 to 10%) for this strain of rat. Testicular interstitial cell adenoma also occurred in 1 of 30 rats treated with 50 mg lansoprazole per kg per day (13 times the recommended lansoprazole human dose based on BSA) in a 1-year toxicity study.

In a 24-month carcinogenicity study, CD-1 mice were treated orally with lansoprazole doses of 15 mg to 600 mg per kg per day, 2 to 80 times the recommended human dose based on BSA. Lansoprazole produced a dose-related increased incidence of gastric ECL cell hyperplasia. It also produced an increased incidence of liver tumors (hepatocellular adenoma plus carcinoma). The tumor incidences in male mice treated with 300 mg and 600 mg lansoprazole per kg per day (40 to 80 times the recommended lansoprazole human dose based on BSA) and female mice treated with 150 mg to 600 mg lansoprazole per kg per day (20 to 80 times the recommended human dose based on BSA) exceeded the ranges of background incidences in historical controls for this strain of mice. Lansoprazole treatment produced adenoma of rete testis in male mice receiving 75 to 600 mg per kg per day (10 to 80 times the recommended lansoprazole human dose based on BSA).

A 26-week p53 (+/-) transgenic mouse carcinogenicity study of lansoprazole was not positive.

Lansoprazole was negative in the Ames test, the ex vivo rat hepatocyte unscheduled DNA synthesis (UDS) test, the in vivo mouse micronucleus test and the rat bone marrow cell chromosomal aberration test. Lansoprazole was positive in in vitro human lymphocyte chromosomal aberration tests.

Dexlansoprazole was positive in the Ames test and in the in vitro chromosome aberration test using Chinese hamster lung cells. Dexlansoprazole was negative in the in vivo mouse micronucleus test.

The potential effects of dexlansoprazole on fertility and reproductive performance were assessed using lansoprazole studies. Lansoprazole at oral doses up to 150 mg per kg per day (40 times the recommended lansoprazole human dose based on BSA) was found to have no effect on fertility and reproductive performance of male and female rats.

Use In Specific Populations

Pregnancy

Teratogenic Effects

Pregnancy Category B. There are no adequate and well-controlled studies with dexlansoprazole in pregnant women. There were no adverse fetal effects in animal reproduction studies of dexlansoprazole in rabbits. Because animal reproduction studies are not always predictive of human response, KAPIDEX (dexlansoprazole delayed release capsules) should be used during pregnancy only if clearly needed.

A reproduction study conducted in rabbits at oral dexlansoprazole doses up to 30 mg per kg per day (approximately 9-fold the maximum recommended human dexlansoprazole dose [60 mg] based on body surface area [BSA]) revealed no evidence of harm to the fetus due to dexlansoprazole. In addition, reproduction studies performed in pregnant rats with oral lansoprazole at doses up to 150 mg per kg per day (40 times the recommended human dose based on BSA) and in pregnant rabbits at oral lansoprazole doses up to 30 mg per kg per day (16 times the recommended human dose based on BSA) revealed no evidence of impaired fertility or harm to the fetus due to lansoprazole.

Nursing Mothers

It is not known whether dexlansoprazole is excreted in human milk. However, lansoprazole and its metabolites are present in rat milk following the administration of lansoprazole. As many drugs are excreted in human milk, and because of the potential for tumorigenicity shown for lansoprazole in rat carcinogenicity studies , a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness of KAPIDEX (dexlansoprazole delayed release capsules) in pediatric patients (less than 18 years of age) have not been established.

Geriatric Use

In clinical studies of KAPIDEX (dexlansoprazole delayed release capsules) , 11% of patients were aged 65 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.

Renal Impairment

No dosage adjustment of KAPIDEX (dexlansoprazole delayed release capsules) is necessary in patients with renal impairment. The pharmacokinetics of dexlansoprazole in patients with renal impairment are not expected to be altered since dexlansoprazole is extensively metabolized in the liver to inactive metabolites, and no parent drug is recovered in the urine following an oral dose of dexlansoprazole.

Hepatic Impairment

No dosage adjustment for KAPIDEX (dexlansoprazole delayed release capsules) is necessary for patients with mild hepatic impairment (Child-Pugh Class A). KAPIDEX (dexlansoprazole delayed release capsules) 30 mg should be considered for patients with moderate hepatic impairment (Child-Pugh Class B). No studies have been conducted in patients with severe hepatic impairment (Child-Pugh Class C).

Clinical Trials Experience

The safety of KAPIDEX (dexlansoprazole delayed release capsules) was evaluated in 4548 patients in controlled and uncontrolled clinical studies, including 863 patients treated for at least 6 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 KAPIDEX (dexlansoprazole delayed release capsules) 30 mg, 2218 patients on KAPIDEX (dexlansoprazole delayed release capsules) 60 mg, and 1363 patients on lansoprazole 30 mg once daily.

As 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.

Most Commonly Reported Adverse Reactions

The most common adverse reactions ( ≥ 2%) that occurred at a higher incidence for KAPIDEX (dexlansoprazole delayed release capsules) than placebo in the controlled studies are presented in Table 2.

Table 2: Incidence of Treatment-Emergent Adverse Reactions in Controlled Studies

Adverse Reactions Resulting in Discontinuation

In controlled clinical studies, the most common adverse reaction leading to discontinuation from KAPIDEX (dexlansoprazole delayed release capsules) therapy was diarrhea (0.7%).

Other 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, nausea and vomiting, oral mucosal blistering, painful defecation, proctitis, paresthesia oral, rectal hemorrhage

General Disorders and Administration Site Conditions: adverse drug reaction, asthenia, chest pain, chills, feeling abnormal, inflammation, mucosal inflammation, nodule, pain, pyrexia

Hepatobiliary Disorders: biliary colic, cholelithiasis, hepatomegaly

Immune System Disorders: hypersensitivity

Infections and Infestations: candida infections, influenza, nasopharyngitis, oral herpes, pharyngitis, sinusitis, viral infection, vulvo-vaginal infection

Injury, Poisoning and Procedural Complications: falls, fractures, joint sprains, overdose, procedural pain, sunburn

Laboratory Investigations: ALP increased, ALT increased, AST increased, bilirubin decreased/increased, blood creatinine increased, blood gastrin increased, blood glucose increased, blood potassium increased, liver function test abnormal, platelet count decreased, total protein increased, weight increase

Metabolism and Nutrition Disorders: appetite changes, hypercalcemia, hypokalemia

Musculoskeletal and Connective Tissue Disorders: arthralgia, arthritis, muscle cramps, musculoskeletal pain, myalgia

Nervous System Disorders: altered taste, convulsion, dizziness, headaches, migraine, memory impairment, paresthesia, psychomotor hyperactivity, tremor, trigeminal neuralgia

Psychiatric Disorders: abnormal dreams, anxiety, depression, insomnia, libido changes

Renal and Urinary Disorders: dysuria, micturition urgency

Reproductive System and Breast Disorders: dysmenorrhea, dyspareunia, menorrhagia, menstrual disorder

Respiratory, Thoracic and Mediastinal Disorders: aspiration, asthma, bronchitis, cough, dyspnoea, hiccups, hyperventilation, respiratory tract congestion, sore throat

Skin and Subcutaneous Tissue Disorders: acne, dermatitis, erythema, pruritis, rash, skin lesion, urticaria

Vascular Disorders: deep vein thrombosis, hot flush, hypertension

Additional adverse reactions that were reported in a long-term uncontrolled study and were considered related to KAPIDEX (dexlansoprazole delayed release capsules) by the treating physician included: anaphylaxis, auditory hallucination, B-cell lymphoma, central obesity, cholecystitis acute, decreased hemoglobin, dehydration, diabetes mellitus, dysphonia, epistaxis, folliculitis, gastrointestinal pain, gout, herpes zoster, hyperglycemia, hyperlipidemia, hypothyroidism, increased neutrophils, MCHC decrease, neutropenia, oral soft tissue disorder, rectal tenesmus, restless legs syndrome, somnolence, thrombocythemia, tonsillitis.

Other adverse reactions not observed with KAPIDEX (dexlansoprazole delayed release capsules) , but occurring with the racemate lansoprazole can be found in the lansoprazole package insert, ADVERSE REACTIONS section.

Postmarketing Experience

Adverse reactions have been identified during post-approval of KAPIDEX (dexlansoprazole delayed release capsules). As these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Eye Disorders: blurred vision

Gastrointestinal Disorders: oral edema

General Disorders and Administration Site Conditions: facial edema

Immune System Disorders: anaphylactic shock (requiring emergency intervention),

Stevens-Johnsons syndrome, toxic epidermal necrolysis (some fatal)

Respiratory, Thoracic and Mediastinal Disorders: pharyngeal edema, throat tightness

Skin and Subcutaneous Tissue Disorders: generalized rash, leucocytoclastic vasculitis

There have been no reports of significant overdose of KAPIDEX (dexlansoprazole delayed release capsules). Multiple doses of KAPIDEX (dexlansoprazole delayed release capsules) 120 mg and a single dose of KAPIDEX (dexlansoprazole delayed release capsules) 300 mg did not result in death or other severe adverse events. Dexlansoprazole is not expected to be removed from the circulation by hemodialysis. If an overdose occurs, treatment should be symptomatic and supportive.

Antisecretory Activity

The effects of KAPIDEX (dexlansoprazole delayed release capsules) 60 mg (n=20) or lansoprazole 30 mg (n=23) once daily for five days on 24-hour intragastric pH were assessed in healthy subjects in a multiple-dose crossover study. The results are summarized in Table 3.

Table 3: Effect on 24-hour Intragastric pH on Day 5 After Administration of KAPIDEX (dexlansoprazole delayed release capsules) or Lansoprazole

Serum Gastrin Effects

The effect of KAPIDEX (dexlansoprazole delayed release capsules) on serum gastrin concentrations was evaluated in approximately 3460 patients in clinical trials up to 8 weeks and in 1023 patients for up to 6 to 12 months. The mean fasting gastrin concentrations increased from baseline during treatment with KAPIDEX (dexlansoprazole delayed release capsules) 30 mg and 60 mg doses. In patients treated for more than 6 months, mean serum gastrin levels increased during approximately the first 3 months of treatment and were stable for the remainder of treatment. Mean serum gastrin levels returned to pre-treatment levels within one month of discontinuation of treatment.

Enterochromaffin-Like Cell (ECL) Effects

There were no reports of ECL cell hyperplasia in gastric biopsy specimens obtained from 653 patients treated with KAPIDEX (dexlansoprazole delayed release capsules) 30 mg, 60 mg or 90 mg for up to 12 months.

During lifetime exposure of rats dosed daily with up to 150 mg per kg per day of lansoprazole, marked hypergastrinemia was observed followed by ECL cell proliferation and formation of carcinoid tumors, especially in female rats.

Effect on Cardiac Repolarization

A study was conducted to assess the potential of KAPIDEX (dexlansoprazole delayed release capsules) to prolong the QT/QTc interval in healthy adult subjects. KAPIDEX (dexlansoprazole delayed release capsules) doses of 90 mg or 300 mg did not delay cardiac repolarization compared to placebo. The positive control (moxifloxacin) produced statistically significantly greater mean maximum and time-averaged QT/QTc intervals compared to placebo.

KAPIDEX (dexlansoprazole delayed release capsules) causes inhibition of gastric acid secretion. KAPIDEX (dexlansoprazole delayed release capsules) is likely to substantially decrease the systemic concentrations of the HIV protease inhibitor atazanavir, which is dependent upon the presence of gastric acid for absorption, and may result in a loss of therapeutic effect of atazanavir and the development of HIV resistance. Therefore, KAPIDEX (dexlansoprazole delayed release capsules) should not be co-administered with atazanavir.

It is theoretically possible that KAPIDEX (dexlansoprazole delayed release capsules) may interfere with the absorption of other drugs where gastric pH is an important determinant of oral bioavailability (e.g., ampicillin esters, digoxin, iron salts, ketoconazole).