"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).
Kapidex Delayed Release Capsules
Kapidex Delayed Release Capsules
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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 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
|60 mg||30 mg|
|Mean Intragastric pH|
|% T ime Intragastric pH > 4 (hours)|
|(17 hours)||(14 hours)|
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 [see Nonclinical Toxicology].
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.
The dual delayed release formulation of KAPIDEX (dexlansoprazole delayed release capsules) 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 1). 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 KAPIDEX (dexlansoprazole delayed release capsules) 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 KAPIDEX (dexlansoprazole delayed release capsules) 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 KAPIDEX (dexlansoprazole delayed release capsules)
|30||658(40%)||3275 (47%)||11.4 (48%)|
|60||1397(51%)||6529 (60%)||11.6 (46%)|
After oral administration of KAPIDEX (dexlansoprazole delayed release capsules) 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).
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 per 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 5-hydroxy dexlansoprazole and its glucuronide conjugate, while in CYP2C19 poor metabolizers dexlansoprazole sulfone is the major plasma metabolite.
Following the administration of KAPIDEX (dexlansoprazole delayed release capsules) , no unchanged dexlansoprazole is excreted in urine. Following the administration of [14C]dexlansoprazole to 6 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 5-days of 30 or 60 mg once daily administration.
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 KAPIDEX (dexlansoprazole delayed release capsules) 30 mg or 60 mg (N=2 to 6 subjects/group), mean dexlansoprazole Cmax and AUC values were up to 2 times higher in intermediate compared to extensive metabolizers; in poor metabolizers, mean Cmax was up to 4 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.
Effect of Food on Pharmacokinetics and Pharmacodynamics
In food-effect studies in healthy subjects receiving KAPIDEX (dexlansoprazole delayed release capsules) 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 3 hours). No significant differences in mean intragastric pH were observed between fasted and various fed conditions. However, the percentage of time intragastric pH exceeded 4 over the 24-hour dosing interval decreased slightly when KAPIDEX (dexlansoprazole delayed release capsules) was administered after a meal (57%) relative to fasting (64%), primarily due to a decreased response in intragastric pH during the first 4 hours after dosing. Because of this, while KAPIDEX (dexlansoprazole delayed release capsules) 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 KAPIDEX (dexlansoprazole delayed release capsules) 60 mg, plasma exposure (AUC) of bound and unbound dexlansoprazole in the hepatic impairment group 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 between the two liver function groups. No 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) [see Use in Specific Populations].
In a study of 12 male and 12 female healthy subjects who received a single oral dose of KAPIDEX (dexlansoprazole delayed release capsules) 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 KAPIDEX (dexlansoprazole delayed release capsules) 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 KAPIDEX (dexlansoprazole delayed release capsules) is not likely to inhibit CYP isoforms 1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 or 3A4. As such, no clinically relevant interactions with drugs metabolized by these CYP enzymes would be expected. Furthermore, clinical drug-drug interaction studies in mainly CYP2C19 extensive and intermediate metabolizers have shown that KAPIDEX (dexlansoprazole delayed release capsules) does not affect the pharmacokinetics of diazepam, phenytoin, or theophylline. The subjects' CYP1A2 genotypes in the drug-drug interaction study with theophylline were not determined.
Healing of Erosive Esophagitis
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: KAPIDEX (dexlansoprazole delayed release capsules) 60 mg daily, KAPIDEX (dexlansoprazole delayed release capsules) 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 Ratesa: All Grades
|Study||Number of Patients (N) b||Treatment Group (daily)||Week 4
|Week 8 c
|(95% CI) for the Treatment Difference
(KAPIDEX – Lansoprazole) by Week 8
|1||657||KAPIDEX 60 mg||70||87||(-1.5, 6.1) d|
|648||Lansoprazole 30 mg||65||85|
|2||639||KAPIDEX 60 mg||66||85||(2.2, 10.5) d|
|656||Lansoprazole 30 mg||65||79|
|CI = Confidence interval
a Based on crude rate estimates, patients who did not have endoscopically documented healed EE and prematurely discontinued were considered not healed.
b Patients with at least one post baseline endoscopy
c Primary efficacy endpoint
d Demonstrated non-inferiority to lansoprazole
KAPIDEX (dexlansoprazole delayed release capsules) 90 mg was studied and did not provide additional clinical benefit over KAPIDEX (dexlansoprazole delayed release capsules) 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 KAPIDEX (dexlansoprazole delayed release capsules) 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 KAPIDEX (dexlansoprazole delayed release capsules) remained healed over the six-month time period as confirmed by endoscopy (see Table 6).
Table 6: Maintenance Ratesa of Healed EE at Month
|Number of Patients (N)b||Treatment Group(daily)||Maintenance Rate(%)|
|125||KAPIDEX 30 mg||66.4 c|
|a Based on crude rate estimates,
patients who did not have endoscopically documented relapse and prematurely
discontinued were considered to have relapsed.
b Patients with at least one post baseline endoscopy
c Statistically significant vs placebo
KAPIDEX (dexlansoprazole delayed release capsules) 60 mg was studied and did not provide additional clinical benefit over KAPIDEX (dexlansoprazole delayed release capsules) 30 mg.
KAPIDEX (dexlansoprazole delayed release capsules) 30 mg demonstrated a higher median percent of 24-hour heartburn-free days compared to placebo over the 6-month treatment period.
Symptomatic Non-Erosive GERD
A multi-center, double-blind, placebo-controlled, randomized, 4-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 4 of 7 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: KAPIDEX (dexlansoprazole delayed release capsules) 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.
KAPIDEX (dexlansoprazole delayed release capsules) 30 mg provided statistically significantly greater percent of days with heartburn-free 24-hour periods over placebo as assessed by daily diary over 4 weeks (see Table 7). KAPIDEX (dexlansoprazole delayed release capsules) 60 mg was studied and provided no additional clinical benefit over KAPIDEX (dexlansoprazole delayed release capsules) 30 mg.
Table 7: Median Percentages of 24-Hour Heartburn-Free Periods
During the 4 Week Treatment Period of the Symptomatic Non-Erosive GERD Study
|N||Treatment Group(daily)||Heartburn -Free 24 -hour Periods (%)|
|312||KAPIDEX 30 mg||54.9 a|
|a Statistically significant vs placebo|
A higher percentage of patients on KAPIDEX (dexlansoprazole delayed release capsules) 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: KAPIDEX 38% versus placebo 15%; on Day 28: KAPIDEX 63% versus placebo 40%).
Last reviewed on RxList: 4/14/2010
This monograph has been modified to include the generic and brand name in many instances.
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