"The U.S. Food and Drug Administration today approved the first generic versions of Aciphex (rabeprazole sodium) delayed-release tablets, used to treat gastroesophageal reflux disease (GERD) in adults and adolescents (ages 12 and up).
Mechanism of Action
Dexlansoprazole is a PPI that suppresses gastric acid secretion by specific inhibition of the (H+, K+)-ATPase in the gastric parietal cell. By acting specifically on the proton pump, dexlansoprazole blocks the final step of acid production.
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. The results are summarized in Table 3.
Table 3: Effect on 24 Hour Intragastric pH on Day 5
After Administration of DEXILANT or Lansoprazole
|DEXILANT 60 mg||Lansoprazole 30 mg|
|Mean Intragastric pH|
|% Time Intragastric pH > 4 (hours)|
|71 (17 hours)||60 (14 hours)|
Serum Gastrin Effects
The effect of DEXILANT on serum gastrin concentrations was evaluated in approximately 3460 patients in clinical trials up to eight weeks and in 1023 patients for up to six 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 six months, mean serum gastrin levels increased during approximately the first three 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 DEXILANT 30 mg, 60 mg or 90 mg for up to 12 months.
During lifetime exposure of rats dosed daily with up to 150 mg/kg/day of lansoprazole, marked hypergastrinemia was observed followed by ECL cell proliferation and formation of carcinoid tumors, especially in female rats [see Nonclinical Toxicology].
Effect on Cardiac Repolarization
A study was conducted to assess the potential of DEXILANT to prolong the QT/QTc interval in healthy adult subjects. DEXILANT 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.
The dual delayed release formulation of DEXILANT results in a dexlansoprazole plasma concentration-time profile with two distinct peaks; the first peak occurs one to two hours after administration, followed by a second peak within four to five hours (see Figure 1). Dexlansoprazole is eliminated with a half-life of approximately one to two 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, although mean AUCt and Cmax values of dexlansoprazole were slightly higher (less than 10%) on Day 5 than on Day 1.
Figure 1: Mean Plasma
Dexlansoprazole Concentration – Time Profile Following Oral Administration of
30 or 60 mg DEXILANT Once Daily for 5 Days in Healthy Subjects
The pharmacokinetics of dexlansoprazole are highly variable, with percent coefficient of variation (CV%) values for Cmax, AUC, and CL/F of greater than 30% (see Table 4).
Table 4: Mean (CV%) Pharmacokinetic Parameters for
Subjects on Day 5 After Administration of DEXILANT
|Dose (mg)||Cmax (ng/mL)||AUC24 (ng•h/mL)||CL/F (L/h)|
|30||658 (40%) (N=44)||3275 (47%) (N=43)||11.4 (48%) (N=43)|
|60||1397 (51%) (N=79)||6529 (60%) (N=73)||11.6 (46%) (N=41)|
After oral administration of DEXILANT 30 mg or 60 mg to healthy subjects and symptomatic GERD patients, mean Cmax and AUC values of dexlansoprazole increased approximately dose proportionally (see Figure 1).
When granules of DEXILANT 60 mg are mixed with water and dosed via NG tube or orally via syringe, the bioavailability (Cmax and AUC) of dexlansoprazole was similar to that when DEXILANT 60 mg was administered as an intact capsule.
Plasma protein binding of dexlansoprazole ranged from 96.1% to 98.8% in healthy subjects and was independent of concentration from 0.01 to 20 mcg/mL. The apparent volume of distribution (Vz/F) after multiple doses in symptomatic GERD patients was 40.3 L.
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 5hydroxy dexlansoprazole and its glucuronide conjugate, while in CYP2C19 poor metabolizers dexlansoprazole sulfone is the major plasma metabolite.
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/h, respectively, after five days of 30 or 60 mg once daily administration.
Effect of Food on Pharmacokinetics and Pharmacodynamics
In food-effect studies in healthy subjects receiving DEXILANT under various fed conditions compared to fasting, increases in Cmax ranged from 12% to 55%, increases in AUC ranged from 9% to 37%, and tmax varied (ranging from a decrease of 0.7 hours to an increase of three hours). No significant differences in mean intragastric pH were observed between fasted and various fed conditions. However, the percentage of time intragastric pH exceeded four over the 24 hour dosing interval decreased slightly when DEXILANT was administered after a meal (57%) relative to fasting (64%), primarily due to a decreased response in intragastric pH during the first four hours after dosing. Because of this, while DEXILANT can be taken without regard to food, some patients may benefit from administering the dose prior to a meal if post-meal symptoms do not resolve under post-fed conditions.
The pharmacokinetics of dexlansoprazole in patients under the age of 18 years have not been studied.
The terminal elimination half-life of dexlansoprazole is significantly increased in geriatric subjects compared to younger subjects (2.23 and 1.5 hours, respectively); this difference is not clinically relevant. Dexlansoprazole exhibited higher systemic exposure (AUC) in geriatric subjects (34.5% higher) than younger subjects. No dosage adjustment is needed in geriatric patients [see Use In Specific Populations].
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 subjects with renal impairment [see Use in Specific Populations]. In addition, the pharmacokinetics of lansoprazole were studied in patients with mild, moderate or severe renal impairment; results demonstrated no need for a dose adjustment for this patient population.
In a study of 12 patients with moderately impaired hepatic function who received a single oral dose of DEXILANT 60 mg, plasma exposure (AUC) of bound and unbound dexlansoprazole in the hepatic impairment group was approximately two times greater compared to subjects with normal hepatic function. This difference in exposure was not due to a difference in protein binding between the two liver function groups. No adjustment for DEXILANT is necessary for patients with mild hepatic impairment (Child-Pugh Class A). DEXILANT 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) [see Use in Specific Populations].
In a study of 12 male and 12 female healthy subjects who received a single oral dose of DEXILANT 60 mg, females had higher systemic exposure (AUC) (42.8% higher) than males. No dosage adjustment is necessary in patients based on gender.
In a study of 20 healthy subjects, co-administration of DEXILANT 90 mg once daily for 11 days with a single 25 mg oral dose of warfarin on Day 6 did not result in any significant differences in the pharmacokinetics of warfarin or INR compared to administration of warfarin with placebo. However, there have been reports of increased INR and prothrombin time in patients receiving PPIs and warfarin concomitantly [see DRUG INTERACTIONS].
Cytochrome P 450 Interactions
Dexlansoprazole is metabolized, in part, by CYP2C19 and CYP3A4.
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 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 (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 8697%) 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 clinical significance of this finding is not clear.
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 Cmax and AUC values were up to two times higher in intermediate compared to extensive metabolizers; in poor metabolizers, mean Cmax 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.
Animal Toxicology and/or Pharmacology
Reproductive Toxicology Studies
A reproduction 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 BSA) revealed no evidence of impaired fertility or harm to the fetus due to dexlansoprazole. In addition, reproduction studies performed in pregnant rats with oral lansoprazole at doses up to 150 mg/kg/day (40 times the recommended human lansoprazole dose based on BSA) and in pregnant rabbits at oral lansoprazole doses up to 30 mg/kg/day (16 times the recommended human lansoprazole dose based on BSA) revealed no evidence of impaired fertility or harm to the fetus due to lansoprazole.
Healing of Erosive Esophagitis
Two multi-center, double-blind, active-controlled, randomized, eight 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 daily, DEXILANT 90 mg 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 below in Table 5.
Table 5: EE Healing Rates*: All Grades
|Study||Number of Patients (N)†||Treatment Group (daily)||Week 4 % Healed||Week 8‡ % Healed||(95% CI) for the Treatment Difference (DEXILANT–Lansoprazole) by Week 8|
|1||657||DEXILANT 60 mg||70||87||(-1.5, 6.1)§|
|648||Lansoprazole 30 mg||65||85|
|2||639||DEXILANT 60 mg||66||85||(2.2, 10.5)§|
|656||Lansoprazole 30 mg||65||79|
|CI = Confidence interval
*Based on crude rate estimates, patients who did not have endoscopically documented healed EE and prematurely discontinued were considered not healed.
†Patients with at least one post baseline endoscopy
‡Primary efficacy endpoint
§Demonstrated non-inferiority to lansoprazole
DEXILANT 90 mg was studied and did not provide additional clinical benefit over DEXILANT 60 mg.
Maintenance of Healed Erosive Esophagitis
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 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 6).
Table 6: Maintenance Rates* of Healed EE at Month 6
|Number of Patients (N)†||Treatment Group (daily)||Maintenance Rate (%)|
|125||DEXILANT 30 mg||66.4‡|
|*Based on crude rate estimates, patients who did not have
endoscopically documented relapse and prematurely discontinued were considered
to have relapsed.
†Patients with at least one post baseline endoscopy
‡Statistically significant vs placebo
DEXILANT 60 mg was studied and did not provide additional clinical benefit over DEXILANT 30 mg.
The effect of DEXILANT 30 mg 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 demonstrated a statistically significantly higher percent of 24 hour heartburn-free periods compared to placebo over the six month treatment period (see Table 7). The majority of patients treated with placebo discontinued due to relapse of EE between month two and month six.
Table 7: Median Percentage of 24 Hour Heartburn-Free
Periods of the Maintenance of Healed EE Study
|Treatment Group (daily)||Overall Treatment*||Month 1||Month 6|
|N||Heartburn-Free 24-hour Periods (%)||N||Heartburn-Free 24-hour Periods (%)||N||Heartburn-Free 24-hour Periods (%)|
|DEXILANT 30 mg||132||96.1†||126||96.7||80||98.3|
|*Secondary efficacy endpoint
†Statistically significant vs placebo
Symptomatic Non-Erosive GERD
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 6 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 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 8). DEXILANT 60 mg was studied and provided no additional clinical benefit over DEXILANT 30 mg
Table 8: Median Percentages of 24 Hour Heartburn-Free
Periods During the 4 Week Treatment Period of the Symptomatic Non-Erosive GERD
|N||Treatment Group (daily)||Heartburn-Free 24-hour Periods (%)|
|312||DEXILANT 30 mg||54.9*|
|*Statistically significant vs placebo|
A higher percentage of patients on DEXILANT 30 mg 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%).
Last reviewed on RxList: 9/4/2013
This monograph has been modified to include the generic and brand name in many instances.
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