Dexilant

Dexlansoprazole.

The active ingredient in DEXILANT (dexlansoprazole) delayed release capsules, a proton pump inhibitor, is (+)-2-[(R)-{[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl] methyl} sulfinyl]-1H-benzimidazole, a compound that inhibits gastric acid secretion. Dexlansoprazole is the R-enantiomer of lansoprazole (a racemic mixture of the R- and S-enantiomers). Its empirical formula is: C₁₆H₁₄F₃N₃O₂S, with a molecular weight of 369.36.
Dexlansoprazole is a white to nearly white crystalline powder which melts with decomposition at 140°C. Dexlansoprazole is freely soluble in dimethylformamide, methanol, dichloromethane, ethanol and ethyl acetate; and soluble in acetonitrile; slightly soluble in ether; and very slightly soluble in water; and practically insoluble in hexane.
Dexlansoprazole is stable when exposed to light. Dexlansoprazole is more stable in neutral and alkaline conditions than acidic conditions.
DEXILANT is supplied as a dual delayed-release formulation in capsules for oral administration. The capsules contain dexlansoprazole in a mixture of two types of enteric-coated granules with different pH-dependent dissolution profiles (see Pharmacology: Pharmacokinetics under Actions).
DEXILANT is available in two dosage strengths: 30 mg and 60 mg, per capsule. Each capsule contains enteric-coated granules consisting of dexlansoprazole (active ingredient).

Pharmacology: Pharmacodynamics: 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.
Antisecretory Activity: The effects of DEXILANT 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. (See Table 1).

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Serum Gastrin Effects: The effect of DEXILANT 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 DEXILANT 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.
Increased gastrin causes enterochromaffin-like cell hyperplasia and increased serum CgA levels. The increased CgA levels may cause false positive results in diagnostic investigations for neuroendocrine tumors (see Interactions with Investigations for Neuroendocrine Tumors under Precautions).
Enterochromaffin-Like Cell (ECL) Effects: There were no reports of ECL cell hyperplasia in gastric biopsy specimens obtained from 653 patients treated with DEXILANT 30, 60 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 (see Toxicology as follows).
Cardiac Electrophysiology: At a dose five times the maximum recommended dose, dexlansoprazole does not prolong the QT interval to any clinically relevant extent.
Clinical Studies: Healing of Erosive Esophagitis in Adults: Two multi-center, double-blind, active-controlled, randomized, 8-week studies were conducted in patients with endoscopically confirmed EE. Severity of the disease was classified based on the Los Angeles Classification Grading System (Grades A-D). Patients were randomized to one of the following three treatment groups: DEXILANT 60 mg capsules daily, DEXILANT 90 mg capsules daily or lansoprazole 30 mg daily. Patients who were H. pylori positive or who had Barrett's Esophagus and/or definite dysplastic changes at baseline were excluded from these studies. A total of 4092 patients were enrolled and ranged in age from 18 to 90 years (median age 48 years) with 54% male. Race was distributed as follows: 87% Caucasian, 5% Black and 8% other. Based on the Los Angeles Classification, 71% of patients had mild EE (Grades A and B) and 29% of patients had moderate to severe EE (Grades C and D) before treatment.
The studies were designed to test non-inferiority. If non-inferiority was demonstrated then superiority would be tested. Although non-inferiority was demonstrated in both studies, the finding of superiority in one study was not replicated in the other.
The proportion of patients with healed EE at Week 4 or 8 is presented as follows in Table 2. (See Table 2.)

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DEXILANT 90 mg capsules were studied and did not provide additional clinical benefit over DEXILANT 60 mg.
Maintenance of Healed Erosive Esophagitis and Relief of Heartburn in Adults: A multi-center, double-blind, placebo-controlled, randomized study was conducted in patients who successfully completed an EE study and showed endoscopically confirmed healed EE. Maintenance of healing and symptom resolution over a six month period were evaluated with DEXILANT 30 mg or 60 mg capsules once daily compared to placebo. A total of 445 patients were enrolled and ranged in age from 18 to 85 years (median age 49 years), with 52% female. Race was distributed as follows: 90% Caucasian, 5% Black and 5% other.
Sixty-six percent of patients treated with 30 mg of DEXILANT remained healed over the six-month time period as confirmed by endoscopy (see Table 3).

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DEXILANT 60 mg capsules were studied and did not provide additional clinical benefit over DEXILANT 30 mg daily.
The effect of DEXILANT 30 mg capsules on maintenance of relief of heartburn was also evaluated. Upon entry into the maintenance study, a majority of patients' baseline heartburn severity was rated as none. DEXILANT 30 mg capsules demonstrated a statistically significantly higher percent of 24-hour heartburn-free periods compared to placebo over the 6-month treatment period (see Table 4). The majority of patients treated with placebo discontinued due to relapse of EE between month two and month six.

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Treatment of Symptomatic Non-Erosive GERD in Adults: A multi-center, double-blind, placebo-controlled, randomized, four week study was conducted in patients with a diagnosis of symptomatic non-erosive GERD made primarily by presentation of symptoms. These patients who identified heartburn as their primary symptom, had a history of heartburn for six months or longer, had heartburn on at least four of seven days immediately prior to randomization and had no esophageal erosions as confirmed by endoscopy. However, patients with symptoms which were not acid-related may not have been excluded using these inclusion criteria. Patients were randomized to one of the following treatment groups: DEXILANT 30 mg daily, 60 mg daily, or placebo. A total of 947 patients were enrolled and ranged in age from 18 to 86 years (median age 48 years) with 71% female. Race was distributed as follows: 82% Caucasian,14% Black and 4% other.
DEXILANT 30 mg capsules provided statistically significantly greater percent of days with heartburn-free 24 hour periods over placebo as assessed by daily diary over four weeks (see Table 5). DEXILANT 60 mg capsules was studied and provided no additional clinical benefit over DEXILANT 30 mg capsules.

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A higher percentage of patients on DEXILANT 30 mg capsules had heartburn-free 24-hour periods compared to placebo as early as the first three days of treatment and this was sustained throughout the treatment period (percentage of patients on Day 3: DEXILANT 38% versus placebo 15%; on Day 28: DEXILANT 63% versus placebo 40%).
Pediatric GERD: Use of DEXILANT in patients 12 to 17 years of age is supported by evidence from adequate and well-controlled studies of DEXILANT in adults, with additional safety, efficacy, and pharmacokinetic data from studies performed in pediatric patients.
Healing of EE, Maintenance of Healed EE and Relief of Heartburn: In a multi-center, 36-week trial, 62 patients 12 to 17 years of age with a documented history of GERD for at least three months and endoscopically-proven erosive esophagitis (EE) were enrolled to evaluate the healing of EE, maintenance of healed EE and relief of heartburn, followed by an additional 12 weeks without treatment. The median age was 15 years, with males accounting for 61% of the patients. Based on the Los Angeles Classification Grading Scale, 97% of patients had mild EE (Grades A and B), and 3% of patients had moderate to severe EE (Grades C and D) before treatment.
In the first 8 weeks, 62 patients were treated with DEXILANT 60 mg capsules once daily to evaluate the healing of EE. Of the 62 patients, 58 patients completed the 8 week trial, and 51 (88%) patients achieved healing of EE, as confirmed by endoscopy, over 8 weeks of treatment (see Table 6).

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After the initial eight weeks of treatment, all 51 patients with healed EE were randomized to receive treatment with DEXILANT 30 mg capsules or placebo, once daily for an additional 16 weeks to evaluate maintenance of healing and symptom resolution. Maintenance of healing was assessed by endoscopy at week 24. Of the 51 patients randomized, 13 patients discontinued early. Of these, 5 patients did not undergo post-baseline endoscopy. Eighteen of 22 (82%) evaluable patients treated with DEXILANT 30 mg capsules remained healed over the 16 week treatment period as confirmed by endoscopy, compared with 14 of 24 (58%) in placebo (see Table 7).

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Relief of heartburn was assessed in randomized patients during the 16 week maintenance period. The median percentage of 24 hour heartburn-free periods was 87% for those receiving DEXILANT 30 mg capsules compared to 68% for those receiving placebo.
Out of the 32 patients who maintained healing of EE at the end of the 16 week maintenance period, 27 patients (16 treated with DEXILANT and 11 treated with placebo during the double-blind phase) were followed for an additional 12 weeks without therapy. Twenty-four of the 27 patients completed the 12-week follow-up period.
One patient required treatment with acid suppression therapy.
Treatment of Symptomatic Non-Erosive GERD: In a single-arm, open-label, multi-center trial, 104 pediatric patients 12 to 17 years of age with symptomatic non-erosive GERD were treated with DEXILANT 30 mg capsules once daily, for 4 weeks to evaluate safety and effectiveness. Patients had a documented history of GERD symptoms for at least three months prior to screening, reported heartburn on at least 3 out of 7 days during screening, and had no esophageal erosions as confirmed by endoscopy. The median age was 15 years, with females accounting for 70% of the patients.
During the 4 week treatment period, the median percentage of 24 hour heartburn free periods was 47%.
Pharmacokinetics: The dual delayed release formulation of DEXILANT results in a dexlansoprazole plasma concentration-time profile with two distinct peaks; the first peak occurs 1 to 2 hours after administration, followed by a second peak within 4 to 5 hours (see Figure). Dexlansoprazole is eliminated with a half-life of approximately 1 to 2 hours in healthy subjects and in patients with symptomatic GERD. No accumulation of dexlansoprazole occurs after multiple, once daily doses of DEXILANT 30 mg or 60 mg capsules although mean AUC_t and C_max values of dexlansoprazole were slightly higher (less than 10%) on day 5 than on day 1. (See Figure.)

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The pharmacokinetics of dexlansoprazole are highly variable, with percent coefficient of variation (CV%) values for C_max, AUC, and CL/F of greater than 30% (see Table 8).

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Absorption: After oral administration of DEXILANT 30 mg or 60 mg capsules to healthy subjects and symptomatic GERD patients, mean C_max and AUC values of dexlansoprazole increased approximately dose proportionally (see figure).
When granules of DEXILANT 60 mg capsules are mixed with water and dosed via NG tube or orally via syringe, the bioavailability (C_max and AUC) of dexlansoprazole was similar to that when DEXILANT 60 mg was administered as an intact capsule (see Dosage & Administration).
Effect on Food: In food-effect studies in healthy subjects receiving DEXILANT under various fed conditions compared to fasting, increase in C_max ranged from 12% to 55%, increase in AUC ranged from 9% to 37%, and T_max varied (ranging from a decrease of 0.7 hours to an increase of three hours) (see Dosage & Administration).
Distribution: Plasma protein binding of dexlansoprazole ranged from 96% to 99% in healthy subjects and was independent of concentration from 0.01 to 20 mcg per mL. The apparent volume of distribution (Vz/F) after multiple doses in symptomatic GERD patients was 40 L.
Elimination: Metabolism: Dexlansoprazole is extensively metabolized in the liver by oxidation, reduction, and subsequent formation of sulfate, glucuronide and glutathione conjugates to inactive metabolites. Oxidative metabolites are formed by the cytochrome P450 (CYP) enzyme system including hydroxylation mainly by CYP2C19, and oxidation to the sulfone by CYP3A4.
CYP2C19 is a polymorphic liver enzyme which exhibits three phenotypes in the metabolism of CYP2C19 substrates; extensive metabolizers (*1/*1), intermediate metabolizers (*1/mutant) and poor metabolizers (mutant/mutant). Dexlansoprazole is the major circulating component in plasma regardless of CYP2C19 metabolizer status. In CYP2C19 intermediate and extensive metabolizers, the major plasma metabolites are 5-hydroxy dexlansoprazole and its glucuronide conjugate, while in CYP2C19 poor metabolizers dexlansoprazole sulfone is the major plasma metabolite.
Excretion: Following the administration of DEXILANT, no unchanged dexlansoprazole is excreted in urine. Following the administration of [¹⁴C] dexlansoprazole to six healthy male subjects, approximately 50.7% (standard deviation (SD): 9.0%) of the administered radioactivity was excreted in urine and 47.6% (SD: 7.3%) in the feces. Apparent clearance (CL/F) in healthy subjects was 11.4 to 11.6 L/hour, respectively, after five days of 30 or 60 mg once daily administration.
Specific Populations: Age: Pediatric Population: The pharmacokinetics of dexlansoprazole in patients under the age of 12 years have not been studied.
Patients 12 to 17 Years of Age: The pharmacokinetics of dexlansoprazole were studied in 36 patients 12 to 17 years of age with symptomatic GERD in a multi-center trial. Patients were randomized to receive DEXILANT 30 mg or 60 mg capsules once daily for seven days. The dexlansoprazole mean C_max and AUC in patients 12 to 17 years of age were 105% and 88%, respectively, compared to those observed in adults at the 30 mg dose, and were 81% and 78%, respectively, at the 60 mg dose (see Tables 8 and 9).

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Age: Geriatric Population: The terminal elimination half-life of dexlansoprazole is significantly increased in geriatric subjects compared to younger subjects (2.2 and 1.5 hours, respectively). Dexlansoprazole exhibited higher systemic exposure (AUC) in geriatric subjects (34.5% higher) than younger subjects (see Hepatic Impairment under Precautions).
Sex: In a study of 12 male and 12 female healthy subjects who received a single oral dose of DEXILANT 60 mg capsules, females had higher systemic exposure (AUC) (43% higher) than males. This difference in exposure between males and female does not represent a significant safety concern.
Renal Impairment: 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. Therefore, the pharmacokinetics of dexlansoprazole are not expected to be altered in patients with renal impairment, and no studies were conducted in patients with renal impairment. In addition, the pharmacokinetics of lansoprazole were not clinically different in patients with mild, moderate or severe renal impairment; compared to healthy subjects with normal renal function. No dosage adjustment of DEXILANT is necessary in patients with renal impairment.
Hepatic Impairment: In a study of 12 patients with moderate hepatic impairment (Child-Pugh Class B) who received a single oral dose of 60 mg DEXILANT capsules the systemic exposure (AUC) of bound and unbound dexlansoprazole was approximately 2 times greater compared to subjects with normal hepatic function. This difference in exposure was not due to a difference in protein binding. No studies have been conducted in patients with severe hepatic impairment (Child-Pugh Class C) (see Dosage & Administration and Precautions).
Drug-drug Interactions: Effect of Dexlansoprazole on Other Drugs: Cytochrome P 450 Interactions: Dexlansoprazole is metabolized, in part, by CYP2C19 and CYP3A4 (see Pharmacology: Pharmacokinetics under Actions).
In vitro studies have shown that dexlansoprazole is not likely to inhibit CYP isoforms 1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2D6, 2E1 or 3A4. As such, no clinically relevant interactions with drugs metabolized by these CYP enzymes would be expected. Furthermore, in vivo studies showed that DEXILANT did not have an impact on the pharmacokinetics of coadministered phenytoin (CYP2C9 substrate) or theophylline (CYP1A2 substrate). The subjects' CYP1A2 genotypes in the drug-drug interaction study with theophylline were not determined. Although in vitro studies indicated that DEXILANT has the potential to inhibit CYP2C19 in vivo, an in vivo drug-drug interaction study in mainly CYP2C19 extensive and intermediate metabolizers has shown that DEXILANT does not affect the pharmacokinetics of diazepam (CYP2C19 substrate).
Clopidogrel: Clopidogrel is metabolized to its active metabolite in part by CYP2C19. A study of healthy subjects who were CYP2C19 extensive metabolizers, receiving once daily administration of clopidogrel 75 mg alone or concomitantly with DEXILANT 60 mg capsules (n=40), for nine days was conducted. The mean AUC of the active metabolite of clopidogrel was reduced by approximately 9% (mean AUC ratio was 91%, with 90% CI of 86-97%) when DEXILANT was coadministered compared to administration of clopidogrel alone. Pharmacodynamic parameters were also measured and demonstrated that the change in inhibition of platelet aggregation (induced by 5 mcM ADP) was related to the change in the exposure to clopidogrel active metabolite. The effect on exposure to the active metabolite of clopidogrel and on clopidogrel-induced platelet inhibition is not considered clinically important. No dose adjustment of clopidogrel is necessary when administered with an approved dose of DEXILANT.
Effect of Other Drugs on Dexlansoprazole: Because dexlansoprazole is metabolized by CYP2C19 and CYP3A4, inducers and inhibitors of these enzymes may potentially alter exposure of dexlansoprazole.
Pharmacogenomics: Effect of CYP2C19 Polymorphism on Systemic Exposure of Dexlansoprazole: Systemic exposure of dexlansoprazole is generally higher in intermediate and poor metabolizers. In male Japanese subjects who received a single dose of DEXILANT 30 mg or 60 mg (N=2 to 6 subjects/group), mean dexlansoprazole C_max and AUC values were up to 2 times higher in intermediate compared to extensive metabolizers; in poor metabolizers, mean C_max was up to four times higher and mean AUC was up to 12 times higher compared to extensive metabolizers. Though such study was not conducted in Caucasians and African Americans, it is expected dexlansoprazole exposure in these races will be affected by CYP2C19 phenotypes as well.
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 body surface area (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 (see Pharmacology: Pharmacodynamics under Actions).
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 human lansoprazole dose based on BSA) exceeded the low background incidence (range = 1.4 to 10%) for this strain of rat.
In a 24-month carcinogenicity study, CD-1 mice were treated orally with lansoprazole doses of 15 to 600 mg per kg per day, 2 to 80 times the recommended human lansoprazole 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 and 600 mg lansoprazole per kg per day (40 to 80 times the recommended human lansoprazole dose based on BSA) and female mice treated with 150 to 600 mg lansoprazole per kg per day (20 to 80 times the recommended human lansoprazole 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 human lansoprazole dose based on BSA).
A 26-week p53 (+/-) transgenic mouse carcinogenicity study of lansoprazole was not positive.
Lansoprazole was positive in the Ames test and the in vitro human lymphocyte chromosomal aberration assay. Lansoprazole was not genotoxic in the ex vivo rat hepatocyte unscheduled DNA synthesis (UDS) test, the in vivo mouse micronucleus test or the rat bone marrow cell chromosomal aberration test.
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 human lansoprazole dose based on BSA) was found to have no effect on fertility and reproductive performance of male and female rats.

Healing of Erosive Esophagitis: DEXILANT is indicated in patients 12 years of age and older for healing of all grades of erosive esophagitis (EE) for up to eight weeks.
Maintenance of Healed Erosive Esophagitis and Relief of Heartburn: DEXILANT is indicated in patients 12 years of age and older to maintain healing of EE and relief of heartburnfor up to six months in adults and up to 16 weeks in patients 12 to 17 years of age.
Treatment of Symptomatic Non-Erosive Gastroesophageal Reflux Disease: DEXILANT is 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.

Recommended Dosage in Patients 12 Years of Age and older: See Table 10.

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Dosage Adjustment in Patients with Hepatic Impairment for the Healing of EE: For patients with moderate hepatic impairment (Child-Pugh Class B), the recommended dosage is a 30 mg DEXILANT capsule once daily for up to 8 weeks. The use of DEXILANT is not recommended in patients with severe hepatic impairment (Child-Pugh Class C) (see Precautions).
Important Administration Information: 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.
DEXILANT Delayed Release Capsules: Take without regard to food.
Swallow whole; do not chew.
For patients who have trouble swallowing capsules, DEXILANT 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 granules on applesauce.
4. Swallow applesauce and granules immediately. Do not chew granules. Do not save the applesauce and granules 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 granules 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 granules from settling.
4. Administer the mixture immediately into the mouth. Do not save the water and granule 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 Nasogastric Tube (≥16 French): 1. Open the capsule and empty the granules 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 granules from settling, and immediately inject the mixture through the nasogastric tube into the stomach. Do not save the water and granule 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.

There have been no reports of significant overdose with DEXILANT. Multiple doses of DEXILANT 120 mg and a single dose of DEXILANT 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 DEXILANT 60 mg. Non-serious adverse reactions observed with twice daily doses of DEXILANT 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.

DEXILANT is contraindicated in patients with known hypersensitivity to any component of the formulation. Hypersensitivity reactions, including anaphylaxis have been reported (see Adverse Reactions). Acute interstitial nephritis (AIN) has been reported with other proton pump inhibitors (PPIs), including lansoprazole of which dexlansoprazole is the R-enantiomer.
PPIs, including DEXILANT, are contraindicated with rilpivirine-containing products (see Interactions).

Presence of Gastric Malignancy: In adults, symptomatic response to therapy with DEXILANT 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.
Acute Interstitial Nephritis: Acute interstitial nephritis has been observed in patients taking PPIs including lansoprazole. Acute interstitial nephritis may occur at any point during PPI therapy and is generally attributed to an idiopathic hypersensitivity reaction. Discontinue DEXILANT if acute interstitial nephritis develops (see Contraindications).
Cyanocobalamin (Vitamin B-12) Deficiency: Daily treatment with any acid-suppressing medications over a long period of time (e.g., longer than 3 years) may lead to malabsorption of cyanocobalamin (vitamin B-12) 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 obsereved in patients treated with DEXILANT.
Clostridium difficile-Associated Diarrhea: Published observational studies suggest that PPI therapy like DEXILANT 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).
Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.
Bone Fracture: Several published observational studies suggest that proton pump inhibitor (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 & Administration and Adverse Reactions).
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), health care professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically (see Adverse Reactions).
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 dexlansoprazole 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 Pharmacology under Actions and Interactions).
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 Interactions).
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 DEXILANT, discontinue the drug and refer the patient to the appropriate specialist for evaluation. Most patients improve with discontinuation of the PPI alone in 4 to 12 weeks.
Serological testing (e.g., ANA) may be positive and elevated serological test results may take longer to resolve than clinical manifestations.
Hepatic Impairment: No dosage adjustment for DEXILANT is necessary for patients with mild hepatic impairment (Child-Pugh Class A).
In a study of patients with moderate hepatic impairment (Child-Pugh Class B) who received a single 60 mg DEXILANT, there was a significant increase in systemic exposure of dexlansoprazole compared to healthy subjects with normal hepatic function (see Pharmacology under Actions). Therefore, for patients with moderate hepatic impairment (Child-Pugh Class B), dosage reduction is recommended for the healing of EE (see Dosage & Administration).
No studies have been conducted in patients with severe hepatic impairment (Child-Pugh Class C); the use of DEXILANT is not recommended for these patients (see Dosage & Administration).
Use in Children: The safety and effectiveness of DEXILANT have been established in pediatric patients 12 to 17 years of age for the healing of all grades of EE. The safety and effectiveness of DEXILANT ahave been established in pediatric patients 12 to 17 years of age for the maintenance of healed EE and relief of heartburn, and treatment of heartburn associated with symptomatic non-erosive GERD.
Use of DEXILANT in this age group is supported by evidence from adequate and well-controlled studies of DEXILANT in adults with additional safety, efficacy and pharmacokinetic data in pediatric patients 12 to 17 years of age (see Pharmacology under Actions, Dosage & Administration and Adverse Reactions).
The adverse reaction profile in patients 12 to 17 years of age was similar to adults.
The safety and effectiveness of DEXILANT have not been established in pediatric patients less than 12 years of age.
The use of DEXILANT is not recommended for symptomatic non-erosive GERD in pediatric patients less than 1 year of age because studies in this class of drugs have not demonstrated efficacy.
Use in Elderly: Of the total number of patients (n=4548) in clinical studies of DEXILANT, 11% of patients were aged 65 years and over, while 2% 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 Pharmacology under Actions).

Use in Pregnancy: Risk Summary: There are no studies with dexlansoprazole use in pregnant women to inform a drug-associated risk. In animal reproduction studies, no effects on embryo-fetal development were observed with the administration of oral dexlansoprazole into rabbits during organogenesis at doses up to 9 times the maximum recommended human dose (MRHD) (based on body surface area) or with administration of oral lansoprazole to rats and rabbits during organogenesis at doses up to 40 and 16 times the MRHD (based on body surface area), respectively (see Data as follows).
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Data: Animal Data: An embryo-fetal development study conducted in rabbits at oral dexlansoprazole doses up to 30 mg/kg/day (approximately 9 times the maximum recommended human dexlansoprazole dose (60 mg per 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.
Use in Lactation: Risk Summary: There is no information regarding the presence dexlansoprazole 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 (see Data as follows). The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for DEXILANT and any potential adverse effects on the breastfed child from DEXILANT or from the underlying maternal condition.
Data: When [¹⁴C] lansoprazole was administered orally at 2 mg/kg to lactating rats 14 days after parturition, milk collected at 0.5, 2 and 6 hours after the lansoprazole dose contained 2- to 6-fold higher concentrations of radioactivity than plasma. Almost all of the radioactivity was determined to be from lansoprazole metabolites.

The following serious adverse reactions are described as follows and elsewhere in monograph: Acute Interstitial Nephritis; Clostridium difficile-Associated Diarrhea; Bone Fracture; Cutaneous and Systemic Lupus Erythematosus; Cyanocobalamin (Vitamin B-12) Deficiency; Hypomagnesemia. (See Precautions).
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 DEXILANT were evaluated in 4548 adult 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 DEXILANT 30 mg, 2218 patients on DEXILANT 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 DEXILANT than placebo in the controlled studies are presented in Table 11. (See Table 11.)

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Adverse Reactions Resulting in Discontinuation: In controlled clinical studies, the most common adverse reaction leading to discontinuation from DEXILANT therapy 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 as follows 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 defecation, proctitis, paresthesia oral, rectal hemorrhage, retching.
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, dyspnea, hiccups, hyperventilation, respiratory tract congestion, sore throat.
Skin and Subcutaneous Tissue Disorders: acne, dermatitis, erythema, pruritus, rash, skin lesion, urticaria.
Vascular Disorders: deep vein thrombosis, hot flush, hypertension.
Additional adverse reactions that were reported in a long-term uncontrolled studiy and were considered related to DEXILANT by the treating physician included: anaphylaxis, auditory hallucination, B-cell lymphoma, bursitis, central obesity, cholecystitis acute, dehydration, diabetes mellitus, dysphonia, epistaxis, folliculitis, gout, herpes zoster, hyperlipidemia, hypothyroidism, increased neutrophils, MCHC decrease, neutropenia, rectal tenesmus, restless legs syndrome, somnolence, tonsillitis.
Pediatrics: The safety of DEXILANT capsules were evaluated in controlled and single-arm clinical trials including 166 pediatric patients, 12 to 17 years of age for the treatment of symptomatic non-erosive GERD, healing of EE, maintenance of healed EE and relief of heartburn (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions).
The adverse reaction profile was similar to that of adults. The most common adverse reactions that occurred in ≥ 5% of patients were headache, abdominal pain, diarrhea, nasopharyngitis and oropharyngeal pain.
Other Adverse Reactions: See the full prescribing information for lansoprazole for other adverse reactions not observed with DEXILANT.
Postmarketing Experience: The following adverse reactions have been identified during post-approval of DEXILANT. Because 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.
Blood and Lymphatic System Disorders: autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura.
Ear and Labyrinth Disorders: deafness.
Eye Disorders: blurred vision.
Gastrointestinal Disorders: oral edema, pancreatitis.
General Disorders and Administration Site Conditions: facial edema.
Hepatobiliary Disorders: drug-induced hepatitis.
Immune System Disorders: anaphylactic shock (requiring emergency intervention), exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis (some fatal).
Infections and Infestations: Clostridium difficile associated diarrhea.
Metabolism and Nutrition Disorders: hypomagnesemia, hyponatremia.
Musculoskeletal System Disorders: bone fracture.
Nervous System Disorders: cerebrovascular accident, transient ischemic attack.
Renal and Urinary Disorders: acute renal failure.
Respiratory, Thoracic and Mediastinal Disorders: pharyngeal edema, throat tightness.
Skin and Subcutaneous Tissue Disorders: generalized rash, leukocytoclastic vasculitis.

Tables 12 and 13 include drugs with clinically important drug interactions and interaction with diagnostics when administered concomitantly with DEXILANT and instructions for preventing or managing them.
Consult the labeling of concomitantly used drugs to obtain further information about interactions with PPIs. (See Tables 12 and 13.)

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Store below 30°C.

Antacids, Antireflux Agents & Antiulcerants

A02BC06 - dexlansoprazole ; Belongs to the class of proton pump inhibitors. Used in the treatment of peptic ulcer and gastro-oesophageal reflux disease (GERD).

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