Aciphex (Rabeprazole Sodium) - Description and Clinical Pharmacology

DESCRIPTION

The active ingredient in ACIPHEX® Delayed-Release Tablets is rabeprazole sodium, a substituted benzimidazole that inhibits gastric acid secretion. Rabeprazole sodium is known chemically as 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]-methyl]sulfinyl]-1 H -benzimidazole sodium salt. It has an empirical formula of C₁₈H₂₀N₃NaO₃S and a molecular weight of 381.43. Rabeprazole sodium is a white to slightly yellowish-white solid. It is very soluble in water and methanol, freely soluble in ethanol, chloroform and ethyl acetate and insoluble in ether and n-hexane. The stability of rabeprazole sodium is a function of pH; it is rapidly degraded in acid media, and is more stable under alkaline conditions. The structural formula is:

ACIPHEX® is available for oral administration as delayed-release, enteric-coated tablets containing 20 mg of rabeprazole sodium. Inactive ingredients are carnauba wax, crospovidone, diacetylated monoglycerides, ethylcellulose, hydroxypropyl cellulose, hypromellose phthalate, magnesium stearate, mannitol, sodium hydroxide, sodium stearyl fumarate, talc, titanium dioxide, and yellow ferric oxide as a coloring agent.

CLINICAL PHARMACOLOGY

PHARMACOKINETICS AND METABOLISM

ACIPHEX® delayed-release tablets are enteric-coated to allow rabeprazole sodium, which is acid labile, to pass through the stomach relatively intact. After oral administration of 20 mg ACIPHEX®, peak plasma concentrations (C_max) of rabeprazole occur over a range of 2.0 to 5.0 hours (T_max). The rabeprazole C_max and AUC are linear over an oral dose range of 10 mg to 40 mg. There is no appreciable accumulation when doses of 10 mg to 40 mg are administered every 24 hours; the pharmacokinetics of rabeprazole are not altered by multiple dosing. The plasma half-life ranges from 1 to 2 hours.

Absorption: Absolute bioavailability for a 20 mg oral tablet of rabeprazole (compared to intravenous administration) is approximately 52%. When rabeprazole is administered with a high fat meal, its T_max is variable and may delay its absorption up to 4 hours or longer, however, the C_max and the extent of rabeprazole absorption (AUC) are not significantly altered. Thus rabeprazole may be taken without regard to timing of meals.

Distribution: Rabeprazole is 96.3% bound to human plasma proteins.

Metabolism: Rabeprazole is extensively metabolized. 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. The thioether metabolite is formed non-enzymatically by reduction of 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.

Elimination: Following a single 20 mg oral dose of¹⁴ C-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.

SPECIAL POPULATIONS

Geriatric: In 20 healthy elderly subjects administered 20 mg rabeprazole once daily for seven days, AUC values approximately doubled and the C_max increased by 60% compared to values in a parallel younger control group. There was no evidence of drug accumulation after once daily administration. (see PRECAUTIONS).

Pediatric: The pharmacokinetics of rabeprazole in pediatric patients under the age of 18 years have not been studied.

Gender and Race: In analyses 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, AUC_0-(infinity) values for healthy Japanese men were approximately 50-60% greater than values derived from pooled data from healthy men in the United States.

Renal Disease: In 10 patients with stable end-stage renal disease requiring maintenance hemodialysis (creatinine clearance 2), no clinically significant differences were observed in the pharmacokinetics of rabeprazole after a single 20 mg oral dose when compared to 10 healthy volunteers.

Hepatic Disease: In a single dose study of 10 patients with chronic mild to moderate compensated cirrhosis of the liver who were administered a 20 mg dose of rabeprazole, AUC_0-24 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 men.

In a multiple dose study of 12 patients with mild to moderate hepatic impairment administered 20 mg rabeprazole once daily for eight days, AUC_0-(infinity) and C_max 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. Please refer to the DOSAGE AND ADMINISTRATION section for information on dosage adjustment in patients with hepatic impairment.

Combined Administration with Antimicrobials: Sixteen healthy volunteers genotyped as extensive metabolizers with respect to CYP2C19 were given 20 mg rabeprazole sodium, 1000 mg amoxicillin, 500 mg clarithromycin, or all 3 drugs in a four-way crossover study. Each of the four regimens was administered twice daily for 6 days. The AUC and C_max for clarithromycin and amoxicillin were not different following combined administration compared to values following single administration. However, the rabeprazole AUC and C_max increased by 11% and 34%, respectively, following combined administration. The AUC and C_max for 14-hydroxyclarithromycin (active metabolite of clarithromycin) also increased by 42% and 46%, respectively. This increase in exposure to rabeprazole and 14-hydroxyclarithromycin is not expected to produce safety concerns.

PHARMACODYNAMICS

MECHANISM OF ACTION

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.

ANTISECRETORY ACTIVITY

The anti-secretory effect begins within one hour after oral administration of 20 mg ACIPHEX®. The median inhibitory effect of ACIPHEX® on 24 hour gastric acidity is 88% of maximal after the first dose. ACIPHEX® 20 mg inhibits basal and peptone mealstimulated acid secretion versus placebo by 86% and 95%, respectively, and increases the percent of a 24-hour period that the gastric pH>3 from 10% to 65% (see table below). This relatively prolonged pharmacodynamic action compared to the short pharmacokinetic half-life (1-2 hours) reflects the sustained inactivation of the H⁺, K⁺ATPase.

Compared to placebo, ACIPHEX®, 10 mg, 20 mg, and 40 mg, administered once daily for 7 days significantly decreased intragastric acidity with all doses for each of four meal-related intervals and the 24-hour time period overall. In this study, there were no statistically significant differences between doses; however, there was a significant dose-related decrease in intragastric acidity. The ability of rabeprazole to cause a dose-related decrease in mean intragastric acidity is illustrated below.

After administration of 20 mg ACIPHEX® once daily for eight days, the mean percent of time that gastric pH>3 or gastric pH>4 after a single dose (Day 1) and multiple doses (Day 8) was significantly greater than placebo (see table below). The decrease in gastric acidity and the increase in gastric pH observed with 20 mg ACIPHEX® administered once daily for eight days were compared to the same parameters for placebo, as illustrated below:

EFFECTS ON ESOPHAGEAL ACID EXPOSURE

In patients with gastroesophageal reflux disease (GERD) and moderate to severe esophageal acid exposure, ACIPHEX® 20 mg and 40 mg per day decreased 24-hour esophageal acid exposure. After seven days of treatment, the percentage of time that esophageal pH<4 decreased from baselines of 24.7% for 20 mg and 23.7% for 40 mg, to 5.1% and 2.0%, respectively. Normalization of 24-hour intraesophageal acid exposure was correlated to gastric pH>4 for at least 35% of the 24-hour period; this level was achieved in 90% of subjects receiving ACIPHEX® 20 mg and in 100% of subjects receiving ACIPHEX® 40 mg. With ACIPHEX® 20 mg and 40 mg per day, significant effects on gastric and esophageal pH were noted after one day of treatment, and more pronounced after seven days of treatment.

EFFECTS ON SERUM GASTRIN

In patients given daily doses of ACIPHEX® for up to eight weeks to treat ulcerative or erosive esophagitis and in patients treated for up to 52 weeks to prevent recurrence of disease the median fasting gastrin level increased in a dose-related manner. The group median values stayed within the normal range.

In a group of subjects treated daily with ACIPHEX® 20 mg for 4 weeks a doubling of mean serum gastrin concentrations were observed. Approximately 35% of these treated subjects developed serum gastrin concentrations above the upper limit of normal. In a study of CYP2C19 genotyped subjects in Japan, poor metabolizers developed statistically significantly higher serum gastrin concentrations than extensive metabolizers.

EFFECTS ON ENTEROCHROMAFFIN-LIKE (ECL) CELLS

Increased serum gastrin secondary to antisecretory agents stimulates proliferation of gastric ECL cells which, over time, may result in ECL cell hyperplasia in rats and mice and gastric carcinoids in rats, especially in females (see Carcinogenesis, Mutagenesis, Impairment of Fertility).

In over 400 patients treated with ACIPHEX® (10 or 20 mg/day) for up to one year, the incidence of ECL cell hyperplasia increased with time and dose, which is consistent with the pharmacological action of the proton-pump inhibitor. No patient developed the adenomatoid, dysplastic or neoplastic changes of ECL cells in the gastric mucosa. No patient developed the carcinoid tumors observed in rats.

ENDOCRINE EFFECTS

Studies in humans for up to one year have not revealed clinically significant effects on the endocrine system. In healthy male volunteers treated with ACIPHEX® for 13 days, no clinically relevant changes have been detected in the following endocrine parameters examined: 17 (beta)-estradiol, thyroid stimulating hormone, tri-iodothyronine, thyroxine, thyroxine-binding protein, parathyroid hormone, insulin, glucagon, renin, aldosterone, follicle-stimulating hormone, luteotrophic hormone, prolactin, somatotrophic hormone, dehydroepiandrosterone, cortisol-binding globulin, and urinary 6(beta)-hydroxycortisol, serum testosterone and circadian cortisol profile.

OTHER EFFECTS

In humans treated with ACIPHEX® for up to one year, no systemic effects have been observed on the central nervous, lymphoid, hematopoietic, renal, hepatic, cardiovascular, or respiratory systems. No data are available on long-term treatment with ACIPHEX® and ocular effects.

MICROBIOLOGY

Rabeprazole sodium, amoxicillin and clarithromycin as a three drug regimen has been shown to be active against most strains of Helicobacter pylori in vitro and in clinical infections as described in the CLINICAL STUDIES and INDICATIONS AND USAGE sections.

Helicobacter pylori

Susceptibility testing of H. pylori isolates was performed for amoxicillin and clarithromycin using agar dilution methodology¹, and minimum inhibitory concentrations (MICs) were determined. The clarithromycin and amoxicillin MIC values should be interpreted according to the following criteria:

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard clarithromycin and amoxicillin powders should provide the following MIC values:

INCIDENCE OF ANTIBIOTIC-RESISTANT ORGANISMS AMONG CLINICAL ISOLATES

Pretreatment Resistance: Clarithromycin pretreatment resistance rate (MIC >/= 1 µg/mL) to H. pylori was 9% (51/ 560) at baseline in all treatment groups combined. A total of > 99% (558/560) of patients had H. pylori isolates which were considered to be susceptible (MIC H. pylori isolates with an amoxicillin MIC of 0.5 µg/mL.

Clarithromycin Susceptibility Test Results and Clinical/Bacteriologic Outcomes: For the U.S. multicenter study, the baseline H. pylori clarithromycin susceptibility results and the H. pylori eradication results post-treatment are shown in the table below:

Patients with persistent H. pylori infection following rabeprazole, amoxicillin, and clarithromycin therapy will likely have clarithromycin resistant clinical isolates. Therefore, clarithromycin susceptibility testing should be done when possible. If resistance to clarithromycin is demonstrated or susceptibility testing is not possible, alternative antimicrobial therapy should be instituted.

Amoxicillin Susceptibility Test Results and Clinical/Bacteriological Outcomes: In the U.S. multicenter study, a total of >99% (558/560) of patients had H. pylori isolates which were considered to be susceptible (MIC H. pylori isolates with an amoxicillin MIC of 0.5 µg/mL, and both isolates were clarithromycin-resistant at baseline; in one case the H. pylori was eradicated. In the 7- and 10-day treatment groups 75% (107/145) and 79% (112/142), respectively, of the patients who had pretreatment amoxicillin susceptible MICs (H. pylori. No patients developed amoxicillin-resistant H. pylori during therapy.

CLINICAL STUDIES

HEALING OF EROSIVE OR ULCERATIVE GASTROESOPHAGEAL REFLUX DISEASE (GERD)

In a U.S., multicenter, randomized, double-blind, placebo-controlled study, 103 patients were treated for up to eight weeks with placebo, 10 mg, 20 mg or 40 mg ACIPHEX® QD. For this and all studies of GERD healing, only patients with GERD symptoms and at least grade 2 esophagitis (modified Hetzel-Dent grading scale) were eligible for entry. Endoscopic healing was defined as grade 0 or 1. Each rabeprazole dose was significantly superior to placebo in producing endoscopic healing after four and eight weeks of treatment. The percentage of patients demonstrating endoscopic healing was as follows:

In addition, there was a statistically significant difference in favor of the ACIPHEX® 10 mg, 20 mg, and 40 mg doses compared to placebo at Weeks 4 and 8 regarding complete resolution of GERD heartburn frequency (p In a North American multicenter, randomized, double-blind, active-controlled study of 336 patients, ACIPHEX® was statistically superior to ranitidine with respect to the percentage of patients healed at endoscopy after four and eight weeks of treatment (see table below):

ACIPHEX® 20 mg once daily was significantly more effective than ranitidine 150 mg QID in the percentage of patients with complete resolution of heartburn at Weeks 4 and 8 (p<0.001). ACIPHEX® 20 mg once daily was also more effective in complete resolution of daytime heartburn (p

LONG-TERM MAINTENANCE OF HEALING OF EROSIVE OR ULCERATIVE GASTROESOPHAGEAL REFLUX DISEASE (GERD MAINTENANCE)

The long-term maintenance of healing in patients with erosive or ulcerative GERD previously healed with gastric anti-secretory therapy was assessed in two U.S., multicenter, randomized, double-blind, placebo-controlled studies of identical design of 52 weeks duration. The two studies randomized 209 and 285 patients, respectively, to receive either 10 mg or 20 mg of ACIPHEX® QD or placebo. As demonstrated in the tables below, ACIPHEX® was significantly superior to placebo in both studies with respect to the maintenance of healing of GERD and the proportions of patients remaining free of heartburn symptoms at 52 weeks:

SYMPTOMATIC GASTROESOPHAGEAL REFLUX DISEASE (GERD)

Two U.S., multicenter, double-blind, placebo controlled studies were conducted in 316 patients with daytime and nighttime heartburn. Patients reported 5 or more periods of moderate to very severe heartburn during the placebo treatment phase the week prior to randomization. Patients were confirmed by endoscopy to have no esophageal erosions.

The percentage of heartburn free daytime and/or nighttime periods was greater with ACIPHEX® 20 mg compared to placebo over the 4 weeks of study in Study RAB-USA-2 (47% vs. 23%) and Study RAB-USA-3 (52% vs. 28%). The mean decreases from baseline in average daytime and nighttime heartburn scores were significantly greater for ACIPHEX® 20 mg as compared to placebo at week 4. Graphical displays depicting the daily mean daytime and nighttime scores are provided in Figures 1 to 4.

ACIPHEX® 20 mg also significantly reduced daily antacid consumption versus placebo over 4 weeks (p<0.001).

HEALING OF DUODENAL ULCERS

In a U.S., randomized, double-blind, multicenter study assessing the effectiveness of 20 mg and 40 mg of ACIPHEX® QD versus placebo for healing endoscopically defined duodenal ulcers, 100 patients were treated for up to four weeks. ACIPHEX® was significantly superior to placebo in producing healing of duodenal ulcers. The percentages of patients with endoscopic healing are presented below:

At Weeks 2 and 4, significantly more patients in the ACIPHEX® 20 and 40 mg groups reported complete resolution of ulcer pain frequency (p An international randomized, double-blind, active-controlled trial was conducted in 205 patients comparing 20 mg ACIPHEX® QD with 20 mg omeprazole QD. The study was designed to provide at least 80% power to exclude a difference of at least 10% between ACIPHEX® and omeprazole, assuming four-week healing response rates of 93% for both groups. In patients with endoscopically defined duodenal ulcers treated for up to four weeks, ACIPHEX® was comparable to omeprazole in producing healing of duodenal ulcers. The percentages of patients with endoscopic healing at two and four weeks are presented below:

ACIPHEX® and omeprazole were comparable in providing complete resolution of symptoms.

HELICOBACTER PYLORI ERADICATION IN PATIENTS WITH PEPTIC ULCER DISEASE OR SYMPTOMATIC NON-ULCER DISEASE

The U.S. multicenter study was a double blind, parallel group comparison of rabeprazole, amoxicillin, and clarithromycin for 3, 7, or 10 days vs. omeprazole, amoxicillin and clarithromycin for 10 days. Therapy consisted of rabeprazole 20 mg twice daily, amoxicillin 1000 mg twice daily, and clarithromycin 500 mg twice daily (RAC) or omeprazole 20 mg twice daily, amoxicillin 1000 mg twice daily, and clarithromycin 500 mg twice daily (OAC). Patients with H. pylori infection were stratified in a 1:1 ratio for those with peptic ulcer disease (active or a history of ulcer in the past five years) [PUD] and those who were symptomatic but without peptic ulcer disease [NPUD], as determined by upper gastrointestinal endoscopy. The overall H. pylori eradication rates, defined as negative¹³ C-UBT for H. pylori >/= 6 weeks from the end of the treatment are shown in the following table. The eradication rates in the 7-day and 10-day RAC regimens were found to be similar to 10-day OAC regimen using either the Intent-to-Treat (ITT) or Per-Protocol (PP) populations. Eradication rates in the RAC 3-day regimen were inferior to the other regimens.

PATHOLOGICAL HYPERSECRETORY CONDITIONS INCLUDING ZOLLINGER-ELLISON SYNDROME

Twelve patients with idiopathic gastric hypersecretion or Zollinger-Ellison syndrome have been treated successfully with ACIPHEX® at doses from 20 to 120 mg for up to 12 months. ACIPHEX® produced satisfactory inhibition of gastric acid secretion in all patients and complete resolution of signs and symptoms of acid-peptic disease where present. ACIPHEX® also prevented recurrence of gastric hypersecretion and manifestations of acid-peptic disease in all patients. The high doses of ACIPHEX® used to treat this small cohort of patients with gastric hypersecretion were well tolerated.