Source: FDA, National Drug Code (US) Revision Year: 2020
Rabeprazole belongs to a class of antisecretory compounds (substituted benzimidazole proton-pump inhibitors) that do not exhibit anticholinergic or histamine H2-receptor antagonist properties, but suppress gastric acid secretion by inhibiting the gastric 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, rabeprazole has been characterized as a gastric proton-pump inhibitor. Rabeprazole blocks the final step of gastric acid secretion.
In gastric parietal cells, rabeprazole is protonated, accumulates, and is transformed to an active sulfenamide. When studied in vitro, rabeprazole is chemically activated at pH 1.2 with a half-life of 78 seconds. It inhibits acid transport in porcine gastric vesicles with a half-life of 90 seconds.
After oral administration to healthy adults of 10 mg ACIPHEX Sprinkle (delayed-release capsules opened and granules sprinkled on one tablespoon [15 mL] of applesauce) under fasting condition, median time (Tmax) to peak plasma concentrations (Cmax) of rabeprazole was 2.5 hours and ranged 1.0 to 6.5 hours. The plasma half-life of rabeprazole ranges from 1 to 2 hours.
In healthy adults, a concomitant high fat meal delayed the absorption of rabeprazole from ACIPHEX Sprinkle (granules sprinkled on one tablespoon (15 mL) of applesauce) resulting in the median Tmax of 4.5 hours and decreased the Cmax and AUClast on average by 55% and 33%, respectively [see Dosage and Administration (2.2)].
When 10 mg ACIPHEX Sprinkle (granules) administered under fasting conditions to healthy adults on one tablespoon (15 mL) of applesauce, one tablespoon (15 mL) of yogurt, or when mixed with a small amount (5 mL) of liquid infant formula; the type of soft food did not significantly affect Tmax, Cmax and AUC of rabeprazole.
Rabeprazole is 96.3% bound to human plasma proteins.
Rabeprazole is extensively metabolized. A significant portion of rabeprazole is metabolized via systemic nonenzymatic reduction to a thioether compound. Rabeprazole is also metabolized to sulphone and desmethyl compounds via cytochrome P450 in the liver. The thioether and sulphone are the primary metabolites measured in human plasma. These metabolites were not observed to have significant antisecretory activity. In vitro studies have demonstrated that rabeprazole is metabolized in the liver primarily by cytochromes P450 3A (CYP3A) to a sulphone metabolite and cytochrome P450 2C19 (CYP2C19) to desmethyl rabeprazole. CYP2C19 exhibits a known genetic polymorphism due to its deficiency in some sub-populations (e.g., 3 to 5% of Caucasians and 17 to 20% of Asians). Rabeprazole metabolism is slow in these sub-populations, therefore, they are referred to as poor metabolizers of the drug.
Following a single 20 mg oral dose of 14C-labeled rabeprazole, approximately 90% of the drug was eliminated in the urine, primarily as thioether carboxylic acid; its glucuronide, and mercapturic acid metabolites. The remainder of the dose was recovered in the feces. Total recovery of radioactivity was 99.8%. No unchanged rabeprazole was recovered in the urine or feces.
In patients with GERD 1 to 11 years of age, following once daily administration of ACIPHEX Sprinkle at doses from 0.14 to 1 mg/kg, the median time to peak plasma concentration ranged from 2 to 4 hours and the half-life was about 2.5 hours. No appreciable accumulation was noted following 5 days of dosing compared to exposure after a single dose.
Based on population pharmacokinetic analysis, over the body weight range from 7 to 77 kg, the apparent rabeprazole clearance increased from 8.0 to 13.5 L/hr, an increase of 69%.
The mean estimated total exposure i.e., AUC after a 10 mg dose of ACIPHEX Sprinkle in patients with GERD 1 to 11 years of age is comparable to AUC after 10 mg rabeprazole sodium delayed-release tablet in adults.
In analyses of adult data adjusted for body mass and height, rabeprazole pharmacokinetics showed no clinically significant differences between male and female subjects. In studies that used different formulations of rabeprazole, AUC0-∞ values for healthy Japanese men were approximately 50 to 60% greater than values derived from pooled data from healthy men in the United States.
In 10 adult patients with stable end-stage renal disease requiring maintenance hemodialysis (creatinine clearance ≤5 mL/min/1.73 m²), no clinically significant differences were observed in the pharmacokinetics of rabeprazole after administration of rabeprazole 20 mg delayed-release tablets when compared to 10 healthy adult subjects.
In a single dose study of 10 adult patients with chronic mild to moderate hepatic impairment (Child-Pugh Class A and B, respectively) who were administered a 20 mg dose of rabeprazole sodium delayed-release tablets, AUC0-24 was approximately doubled, the elimination half-life was 2- to 3-fold higher, and total body clearance was decreased to less than half compared to values in healthy adult men.
In a multiple dose study of 12 adult patients with mild to moderate hepatic impairment administered 20 mg rabeprazole sodium delayed-release tablets once daily for eight days, AUC0-∞ and Cmax values increased approximately 20% compared to values in healthy age- and gender-matched subjects. These increases were not statistically significant.
No information exists on rabeprazole disposition in patients with severe hepatic impairment (Child-Pugh Class C) [see Use in Specific Populations (8.6)].
Antacids: Co-administration of rabeprazole sodium delayed-release tablets and antacids produced no clinically relevant changes in plasma rabeprazole concentrations.
Studies in healthy adult subjects have shown that rabeprazole does not have clinically significant interactions with other drugs metabolized by the CYP450 system, such as theophylline (CYP1A2) given as single oral doses, diazepam (CYP2C9 and CYP3A4) as a single intravenous dose, and phenytoin (CYP2C9 and CYP2C19) given as a single intravenous dose (with supplemental oral dosing). Steady state interactions of rabeprazole and other drugs metabolized by this enzyme system have not been studied in patients.
Clopidogrel: Clopidogrel is metabolized to its active metabolite in part by CYP2C19. A study of healthy adult subjects including CYP2C19 extensive and intermediate metabolizers receiving once daily administration of clopidogrel 75 mg concomitantly with placebo or with 20 mg rabeprazole sodium delayed-release tablets (n=36), for 7 days was conducted. The mean AUC of the active metabolite of clopidogrel was reduced by approximately 12% (mean AUC ratio was 88%, with 90% CI of 81.7 to 95.5%) when rabeprazole sodium delayed-release tablets was co-administered compared to administration of clopidogrel with placebo [see Drug Interactions (7)].
Digoxin: In healthy adult subjects (n=16), co-administration of 20 mg rabeprazole sodium delayed-release tablets with 2.5 mg once daily doses of digoxin at steady state resulted in approximately 29% and 19% increase in mean Cmax and AUC(0-24) of digoxin [see Drug Interactions (7)].
Ketoconazole: In healthy adult subjects (n=19), co-administration of 20 mg rabeprazole sodium delayed-release tablets at steady state with a single 400 mg oral dose ketoconazole resulted in approximately an average of 31% reduction in both Cmax and AUC(0-inf) of ketoconazole [see Drug Interactions (7)].
Cyclosporine: In vitro incubations employing human liver microsomes indicated that rabeprazole inhibited cyclosporine metabolism with an IC50 of 62 micromolar, a concentration that is over 50 times higher than the Cmax in healthy volunteers following 14 days of dosing with 20 mg of ACIPHEX delayed-release tablets. This degree of inhibition is similar to that by omeprazole at equivalent concentrations.
In a clinical study in Japan evaluating rabeprazole sodium delayed-release tablets in Japanese adult patients categorized by CYP2C19 genotype (n=6 per genotype category), gastric acid suppression was higher in poor metabolizers as compared to extensive metabolizers. The clinical relevance of this is not known. This could be due to higher rabeprazole plasma levels in poor metabolizers. Whether or not interactions of rabeprazole sodium with other drugs metabolized by CYP2C19 would be different between extensive metabolizers and poor metabolizers has not been studied.
In an 88/104-week carcinogenicity study in CD-1 mice, rabeprazole at oral doses up to 100 mg/kg/day did not produce any increased tumor occurrence. The highest tested dose produced a systemic exposure to rabeprazole (AUC) of 1.40 µg•hr/mL which is 1.6 times the adult human exposure (plasma AUC0-∞ = 0.88 µg•hr/mL) at the recommended dose for GERD (20 mg of rabeprazole sodium delayed-release tablets per day). In a 28-week carcinogenicity study in p53+/- transgenic mice, rabeprazole at oral doses of 20, 60, and 200 mg/kg/day did not cause an increase in the incidence rates of tumors but produced gastric mucosal hyperplasia at all doses. The systemic exposure to rabeprazole at 200 mg/kg/day is about 17 to 24 times the adult human exposure at the recommended dose for GERD (20 mg of rabeprazole sodium delayed-release tablets per day). In a 104-week carcinogenicity study in Sprague-Dawley rats, males were treated with oral doses of 5, 15, 30, and 60 mg/kg/day and females with 5, 15, 30, 60, and 120 mg/kg/day. Rabeprazole produced gastric enterochromaffin-like (ECL) cell hyperplasia in male and female rats and ECL cell carcinoid tumors in female rats at all doses including the lowest tested dose. The lowest dose (5 mg/kg/day) produced a systemic exposure to rabeprazole (AUC) of about 0.1 µg•hr/mL which is about 0.1 times the adult human exposure at the recommended dose for GERD (20 mg of rabeprazole sodium delayed-release tablets per day). In male rats, no treatment-related tumors were observed at doses up to 60 mg/kg/day producing a rabeprazole plasma exposure (AUC) of about 0.2 µg•hr/mL (0.2 times the adult human exposure at the recommended dose for GERD).
Rabeprazole was positive in the Ames test, the Chinese hamster ovary cell (CHO/HGPRT) forward gene mutation test, and the mouse lymphoma cell (L5178Y/TK+/–) forward gene mutation test. Its demethylated-metabolite was also positive in the Ames test. Rabeprazole was negative in the in vitro Chinese hamster lung cell chromosome aberration test, the in vivo mouse micronucleus test, and the in vivo and ex vivo rat hepatocyte unscheduled DNA synthesis (UDS) tests.
Rabeprazole at intravenous doses up to 30 mg/kg/day (plasma AUC of 8.8 µg•hr/mL, about 10 times the adult human exposure at the recommended dose for GERD) was found to have no effect on fertility and reproductive performance of male and female rats. The recommended dose for GERD in adults is 20 mg per day (rabeprazole sodium delayed-release tablets).
The use of ACIPHEX Sprinkle in pediatric patients 1 to 11 years of age is supported by a two-part, multicenter, randomized, double-blind, parallel 2 dose arms clinical trial which was conducted in 127 pediatric patients with endoscopic and histologic evidence of GERD prior to study treatment.
Part 1 of the trial was 12 weeks in duration. Patients were randomized to one of two rabeprazole dose levels based on body weight. Patients weighing 6 to 14.9 kg received either 5 or 10 mg ACIPHEX Sprinkle, and those with body weight ≥15 kg received 10 mg ACIPHEX Sprinkle. Part 2 was a 24-week double-blinded extension of Part 1 (on same dose assigned in Part 1). Endoscopic evaluations were performed at 12 weeks (Part 1) and 36 weeks (Part 2) to assess esophageal healing. No prespecified formal hypothesis testing was conducted.
For Part 1, rates of endoscopic healing were calculated and are shown in Table 3.
Table 3. Short-Term (12-Week) Healing Rates In 1 To 11 Year Old Children (Part 1):
| Endoscopic Classification of GERD At Baseline | Healing Rate at 12 weeks | ||
|---|---|---|---|
| Body Weight Less than 15 kg | Body Weight 15 kg or Greater | ||
| 5 mg dose | 10 mg dose | 10 mg dose | |
| Erosivea | 88% (7/8) | 83% (5/6) | 71% (12/17) |
| Non-erosiveb | 78% (7/9) | 100% (10/10) | 81% (17/21) |
a Hetzel-Dent score ≥ 2
b Hetzel-Dent score = 1
Of the 87 patients with healing in Part 1, 64 patients were enrolled into Part 2. The absence of a placebo group does not allow assessment of sustained efficacy through 36 weeks. Of the 52 patients with available data, healing was observed in 47 (90%) patients at 36 weeks.
The recommended dosage of ACIPHEX Sprinkle is 5 mg once daily for 12 weeks in patients less than 15 kg with the option to increase to 10 mg once daily if there is an inadequate response. In patients 15 kg or greater, the recommended dosage is 10 mg once daily for 12 weeks.
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