Generic Name: rabeprazole sodium
Dosage Form: tablet, coated
FULL PRESCRIBING INFORMATION
1. INDICATIONS AND USAGE
. Healing of Erosive or Ulcerative GERD
Aciphex is indicated for short-term (4 to 8 weeks) treatment in the healing and symptomatic relief of erosive or ulcerative gastroesophageal reflux disease (GERD). For those patients who have not healed after 8 weeks of treatment, an additional 8-week course of Aciphex may be considered.
. Maintenance of Healing of Erosive or Ulcerative GERD
Aciphex is indicated for maintaining healing and reduction in relapse rates of heartburn symptoms in patients with erosive or ulcerative gastroesophageal reflux disease (GERD Maintenance). Controlled studies do not extend beyond 12 months.
. Treatment of Symptomatic GERD
Aciphex is indicated for the treatment of daytime and nighttime heartburn and other symptoms associated with GERD in adults and adolescents 12 years of age and above.
. Healing of Duodenal Ulcers
Aciphex is indicated for short-term (up to four weeks) treatment in the healing and symptomatic relief of duodenal ulcers. Most patients heal within four weeks.
. Helicobacter pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence
Aciphex in combination with amoxicillin and clarithromycin as a three drug regimen, is indicated for the treatment of patients with H. pylori infection and duodenal ulcer disease (active or history within the past 5 years) to eradicate H. pylori. Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence. {See CLINICAL STUDIES (14.5) and DOSAGE AND ADMINISTRATION (2.5)}.
In patients who fail therapy, susceptibility testing should be done. If resistance to clarithromycin is demonstrated or susceptibility testing is not possible, alternative antimicrobial therapy should be instituted. {See CLINICAL PHARMACOLOGY, Microbiology (12.2) and the clarithromycin package insert, CLINICAL PHARMACOLOGY, Microbiology.}
. Treatment of Pathological Hypersecretory Conditions, Including Zollinger-Ellison Syndrome
Aciphex is indicated for the long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison syndrome.
2. DOSAGE AND ADMINISTRATION
Aciphex tablets should be swallowed whole. The tablets should not be chewed, crushed, or split. Aciphex can be taken with or without food.
. Healing of Erosive or Ulcerative GERD
The recommended adult oral dose is one Aciphex 20 mg delayed-release tablet to be taken once daily for four to eight weeks. {See INDICATIONS AND USAGE (1.1)}. For those patients who have not healed after 8 weeks of treatment, an additional 8-week course of Aciphex may be considered.
. Maintenance of Healing of Erosive or Ulcerative GERD
The recommended adult oral dose is one Aciphex 20 mg delayed-release tablet to be taken once daily. {See INDICATIONS AND USAGE (1.2)}.
. Treatment of Symptomatic GERD
The recommended adult oral dose is one Aciphex 20 mg delayed-release tablet to be taken once daily for 4 weeks. {See INDICATIONS AND USAGE (1.3)}. If symptoms do not resolve completely after 4 weeks, an additional course of treatment may be considered. The recommended adolescent dosing is listed in Section 2.7.
. Healing of Duodenal Ulcers
The recommended adult oral dose is one Aciphex 20 mg delayed-release tablet to be taken once daily after the morning meal for a period up to four weeks. {See INDICATIONS AND USAGE (1.4)}. Most patients with duodenal ulcer heal within four weeks. A few patients may require additional therapy to achieve healing.
. Helicobacter pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence
| All three medications should be taken twice daily with the morning and evening meals. a It is important that patients comply with the full 7-day regimen. {See CLINICAL STUDIES section (14.5)}. | ||
| Aciphex | 20 mg | Twice Daily for 7 Days |
| Amoxicillin | 1000 mg | Twice Daily for 7 Days |
| Clarithromycin | 500 mg | Twice Daily for 7 Days |
. Treatment of Pathological Hypersecretory Conditions, Including Zollinger-Ellison Syndrome
The dosage of Aciphex in patients with pathologic hypersecretory conditions varies with the individual patient. The recommended adult oral starting dose is 60 mg once a day. Doses should be adjusted to individual patient needs and should continue for as long as clinically indicated. Some patients may require divided doses. Doses up to 100 mg QD and 60 mg BID have been administered. Some patients with Zollinger-Ellison syndrome have been treated continuously with Aciphex for up to one year.
. Short-term Treatment of GERD in Adolescent Patients 12 Years of Age and Above
The recommended oral dose for adolescents 12 years of age and above is 20 mg once daily for up to 8 weeks {See Pediatric Use (8.4)}.
. Elderly, Renal and Hepatic Impaired Patients
No dosage adjustment is necessary in elderly patients, in patients with renal disease or in patients with mild to moderate hepatic impairment. Administration of rabeprazole to patients with mild to moderate liver impairment resulted in increased exposure and decreased elimination. Due to the lack of clinical data on rabeprazole in patients with severe hepatic impairment, caution should be exercised in those patients.
3. DOSAGE FORMS AND STRENGTHS
20 mg light yellow enteric-coated delayed-release tablets. The name and strength, in mg, (Aciphex 20) is imprinted on one side.
4. CONTRAINDICATIONS
. Hypersensitivity to rabeprazole
Rabeprazole is contraindicated in patients with known hypersensitivity to rabeprazole, substituted benzimidazoles or to any component of the formulation.
. Use of Clarithromycin and hypersensitivity to macrolide antibiotics
Clarithromycin is contraindicated in patients with known hypersensitivity to any macrolide antibiotic.
. Concomitant use of Clarithromycin with pimozide and cisapride
Concomitant administration of clarithromycin with pimozide and cisapride is contraindicated. There have been post-marketing reports of drug interactions when clarithromycin and/or erythromycin are co-administered with pimozide resulting in cardiac arrhythmias (QT prolongation, ventricular tachycardia, ventricular fibrillation, and torsade de pointes) most likely due to inhibition of hepatic metabolism of pimozide by erythromycin and clarithromycin. Fatalities have been reported. (Please refer to full prescribing information for clarithromycin.)
. Amoxicillin and hypersensitivity to penicillin
Amoxicillin is contraindicated in patients with a known hypersensitivity to any penicillin. (Please refer to full prescribing information for amoxicillin.)
5. WARNINGS AND PRECAUTIONS
. Clarithromycin use in pregnant women
CLARITHROMYCIN SHOULD NOT BE USED IN PREGNANT WOMEN EXCEPT IN CLINICAL CIRCUMSTANCES WHERE NO ALTERNATIVE THERAPY IS APPROPRIATE. If pregnancy occurs while taking clarithromycin, the patient should be apprised of the potential hazard to the fetus. (See WARNINGS in prescribing information for clarithromycin.)
. Anaphylactic reactions associated with antibiotic use
Amoxicillin:
Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients on penicillin therapy. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and/or a history of sensitivity to multiple allergens.
There have been well-documented reports of individuals with a history of penicillin hypersensitivity reactions that have experienced severe hypersensitivity reactions when treated with a cephalosporin. Before initiating therapy with any penicillin, careful inquiry should be made concerning previous hypersensitivity reactions to penicillin, cephalosporin, and other allergens. If an allergic reaction occurs, amoxicillin should be discontinued and the appropriate therapy instituted. (See WARNINGS in prescribing information for amoxicillin.)
SERIOUS ANAPHYLACTIC REACTIONS REQUIRE IMMEDIATE EMERGENCY TREATMENT WITH EPINEPHRINE. OXYGEN, INTRAVENOUS STEROIDS, AND AIRWAY MANAGEMENT, INCLUDING INTUBATION, SHOULD ALSO BE ADMINISTERED AS INDICATED.
. Pseudomembranous colitis associated with antibiotic use
Pseudomembranous colitis has been reported with nearly all antibacterial agents, including clarithromycin and amoxicillin, and may range in severity from mild to life threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.
Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is a primary cause of "antibiotic-associated colitis".
After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to discontinuation of the drug alone. In moderate to severe cases, consideration should be given to management with fluid and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against Clostridium difficile colitis.
. Presence of gastric malignancy
Symptomatic response to therapy with rabeprazole does not preclude the presence of gastric malignancy.
Patients with healed GERD were treated for up to 40 months with rabeprazole and monitored with serial gastric biopsies. Patients without H. pylori infection (221 of 326 patients) had no clinically important pathologic changes in the gastric mucosa. Patients with H. pylori infection at baseline (105 of 326 patients) had mild or moderate inflammation in the gastric body or mild inflammation in the gastric antrum. Patients with mild grades of infection or inflammation in the gastric body tended to change to moderate, whereas those graded moderate at baseline tended to remain stable. Patients with mild grades of infection or inflammation in the gastric antrum tended to remain stable. At baseline 8% of patients had atrophy of glands in the gastric body and 15% had atrophy in the gastric antrum. At endpoint, 15% of patients had atrophy of glands in the gastric body and 11% had atrophy in the gastric antrum. Approximately 4% of patients had intestinal metaplasia at some point during follow-up, but no consistent changes were seen.
. Concomitant use with warfarin
Steady state interactions of rabeprazole and warfarin have not been adequately evaluated in patients. There have been reports of increased INR and prothrombin time in patients receiving a proton pump inhibitor and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with a proton pump inhibitor and warfarin concomitantly may need to be monitored for increases in INR and prothrombin time.
. 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 condition being treated. Patients at risk for osteoporosis-related fractures should be managed according to established treatment guidelines. {see DOSAGE AND ADMINISTRATION (2) and ADVERSE REACTIONS (6.2)}
. 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), healthcare professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically {see Adverse Reactions (6.2)}.
6. ADVERSE REACTIONS
Worldwide, over 2900 patients have been treated with rabeprazole in Phase II-III clinical trials involving various dosages and durations of treatment.
Because clinical trials are conducted under 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.
. Clinical Studies Experience
The data described below reflect exposure to Aciphex in 1064 patients exposed for up to 8 weeks. The studies were primarily placebo- and active-controlled trials in patients with Erosive or Ulcerative Gastroesophageal Reflux Disease (GERD), Duodenal Ulcers and Gastric Ulcers. The population had a mean age of 53 years (range 18-89 years) and had a ratio of approximately 60% male/ 40% female. The racial distribution was 86% Caucasian, 8% African American, 2% Asian and 5% other. Most patients received either 10 mg, 20 mg or 40 mg/day of Aciphex.
An analysis of adverse reactions appearing in ≥ 2% of Aciphex patients (n=1064) and with a greater frequency than placebo (n=89) in controlled North American and European acute treatment trials, revealed the following adverse reactions: pain (3% vs. 1%), pharyngitis (3% vs. 2%), flatulence (3% vs. 1%), infection (2% vs. 1%), and constipation (2% vs. 1%).
The 3 long-term maintenance studies consisted of a total of 740 patients; at least 54% of patients were exposed to rabeprazole for 6 months while at least 33% were exposed for 12 months. Of the 740 patients, 247 (33%) and 241 (33%) patients received 10 mg and 20 mg of Aciphex, respectively, while 169 (23%) patients received placebo and 83 (11%) received omeprazole.
The safety profile of rabeprazole in the maintenance studies was consistent with what was observed in the acute studies.
Other adverse reactions that were seen in controlled clinical trials which do not meet the above criteria (≥ 2% of Aciphex treated patients and > placebo) and for which there is a possibility of a causal relationship to rabeprazole include the following: headache, abdominal pain, diarrhea, dry mouth, dizziness, peripheral edema, hepatic enzyme increase, hepatitis, hepatic encephalopathy, myalgia, and arthralgia.
In a multicenter, open-label study of adolescent patients aged 12 to 16 years with a clinical diagnosis of symptomatic GERD or endoscopically proven GERD, the adverse event profile was similar to that of adults. The adverse reactions reported without regard to relationship to ACIHPEX that occurred in ≥ 2% of 111 patients were headache (9.9%), diarrhea (4.5%), nausea (4.5%), vomiting (3.6%), and abdominal pain (3.6%). The related reported adverse reactions that occurred in ≥ 2% of patients were headache (5.4%) and nausea (1.8%). There were no adverse reactions reported in these studies that were not previously observed in adults.
Combination Treatment with Amoxicillin and Clarithromycin: In clinical trials using combination therapy with rabeprazole plus amoxicillin and clarithromycin (RAC), no adverse reactions unique to this drug combination were observed. In the U.S. multicenter study, the most frequently reported drug related adverse reactions for patients who received RAC therapy for 7 or 10 days were diarrhea (8% and 7%) and taste perversion (6% and 10%), respectively.
No clinically significant laboratory abnormalities particular to the drug combinations were observed.
For more information on adverse reactions or laboratory changes with amoxicillin or clarithromycin, refer to their respective package prescribing information, ADVERSE REACTIONS section.
. Postmarketing Experience
The following adverse reactions have been identified during postapproval use of Aciphex. 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: sudden death; coma, hyperammonemia; jaundice; rhabdomyolysis; disorientation and delirium; anaphylaxis; angioedema; bullous and other drug eruptions of the skin; severe dermatologic reactions, including toxic epidermal necrolysis (some fatal), Stevens-Johnson syndrome, and erythema multiforme; interstitial pneumonia; interstitial nephritis; TSH elevations: bone fractures and hypomagnesemia. In addition, agranulocytosis, hemolytic anemia, leukopenia, pancytopenia, and thrombocytopenia have been reported. Increases in prothrombin time/INR in patients treated with concomitant warfarin have been reported.
7. DRUG INTERACTIONS
. Drugs metabolized by CYP450
Rabeprazole is metabolized by the cytochrome P450 (CYP450) drug metabolizing enzyme system. Studies in healthy subjects have shown that rabeprazole does not have clinically significant interactions with other drugs metabolized by the CYP450 system, such as warfarin and theophylline given as single oral doses, diazepam as a single intravenous dose, and phenytoin 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.
. Warfarin
There have been reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including rabeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.{See WARNINGS AND PRECAUTIONS (5.5)}.
. 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 rabeprazole. This degree of inhibition is similar to that by omeprazole at equivalent concentrations.
. Compounds dependent on gastric pH for absorption
Rabeprazole produces sustained inhibition of gastric acid secretion. An interaction with compounds which are dependent on gastric pH for absorption may occur due to the magnitude of acid suppression observed with rabeprazole. For example, in normal subjects, co-administration of rabeprazole 20 mg QD resulted in an approximately 30% decrease in the bioavailability of ketoconazole and increases in the AUC and Cmax for digoxin of 19% and 29%, respectively. Therefore, patients may need to be monitored when such drugs are taken concomitantly with rabeprazole. Co-administration of rabeprazole and antacids produced no clinically relevant changes in plasma rabeprazole concentrations.
Concomitant use of atazanavir and proton pump inhibitors is not recommended. Co-administration of atazanavir with proton pump inhibitors is expected to substantially decrease atazanavir plasma concentrations and thereby reduce its therapeutic effect.
. Drugs metabolized by CYP2C19
In a clinical study in Japan evaluating rabeprazole in patients categorized by CYP2C19 genotype (n=6 per genotype category), gastric acid suppression was higher in poor metabolizers as compared to extensive metabolizers. 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.
. Combined Administration with Clarithromycin
Combined administration consisting of rabeprazole, amoxicillin, and clarithromycin resulted in increases in plasma concentrations of rabeprazole and 14-hydroxyclarithromycin. {See CLINICAL PHARMACOLOGY, Combination Therapy with Antimicrobials (12.3)}.
Concomitant administration of clarithromycin with pimozide and cisapride is contraindicated. (See PRECAUTIONS in prescribing information for clarithromycin.) (See PRECAUTIONS in prescribing information for amoxicillin.)
8. USE IN SPECIFIC POPULATIONS
. Pregnancy
Teratogenic Effects. Pregnancy Category B: Teratology studies have been performed in rats at intravenous doses up to 50 mg/kg/day (plasma AUC of 11.8 μg•hr/mL, about 13 times the human exposure at the recommended dose for GERD) and rabbits at intravenous doses up to 30 mg/kg/day (plasma AUC of 7.3 μg•hr/mL, about 8 times the human exposure at the recommended dose for GERD) and have revealed no evidence of impaired fertility or harm to the fetus due to rabeprazole. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
. Nursing Mothers
Following intravenous administration of 14C-labeled rabeprazole to lactating rats, radioactivity in milk reached levels that were 2- to 7-fold higher than levels in the blood. It is not known if unmetabolized rabeprazole is excreted in human breast milk. Administration of rabeprazole to rats in late gestation and during lactation at doses of 400 mg/kg/day (about 195-times the human dose based on mg/m2) resulted in decreases in body weight gain of the pups. Since many drugs are excreted in milk, and because of the potential for adverse reactions to nursing infants from rabeprazole, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
. Pediatric Use
Use of Aciphex in adolescent patients 12 years of age and above for short-term treatment of GERD is supported by a) extrapolation of results from adequate and well-controlled studies that supported the approval of Aciphex for adults {see CLINICAL STUDIES (14.1, 14.2, 14.3) and INDICATIONS AND USAGE (1.1, 1.2, 1.3)}; b) safety and pharmacokinetic studies performed in adolescent patients {see Pharmacokinetics, Pediatric (12.3)}. The safety and effectiveness of Aciphex for the treatment of GERD patients <12 years of age have not been established. The safety and effectiveness of Aciphex for other uses have not been established in pediatric patients.
In a multicenter, randomized, open-label, parallel-group study, 111 adolescent patients 12 to 16 years of age with a clinical diagnosis of symptomatic GERD or suspected or endoscopically proven GERD were randomized and treated with either Aciphex 10 mg or Aciphex 20 mg once daily for up to 8 weeks for the evaluation of safety and efficacy. The adverse event profile in adolescent patients was similar to that of adults. The related reported adverse reactions that occurred in ≥ 2% of patients were headache (5.4%) and nausea (1.8%). There were no adverse reactions reported in these studies that were not previously observed in adults.
. Geriatric Use
Of the total number of subjects in clinical studies of Aciphex, 19% were 65 years and over, while 4% were 75 years and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
. Gender
Duodenal ulcer and erosive esophagitis healing rates in women are similar to those in men. Adverse reactions and laboratory test abnormalities in women occurred at rates similar to those in men.
10. OVERDOSAGE
Because strategies for the management of overdose are continually evolving, it is advisable to contact a Poison Control Center to determine the latest recommendations for the management of an overdose of any drug. There has been no experience with large overdoses with rabeprazole. Seven reports of accidental overdosage with rabeprazole have been received. The maximum reported overdose was 80 mg. There were no clinical signs or symptoms associated with any reported overdose. Patients with Zollinger-Ellison syndrome have been treated with up to 120 mg rabeprazole QD. No specific antidote for rabeprazole is known. Rabeprazole is extensively protein bound and is not readily dialyzable. In the event of overdosage, treatment should be symptomatic and supportive.
Single oral doses of rabeprazole at 786 mg/kg and 1024 mg/kg were lethal to mice and rats, respectively. The single oral dose of 2000 mg/kg was not lethal to dogs. The major symptoms of acute toxicity were hypoactivity, labored respiration, lateral or prone position and convulsion in mice and rats and watery diarrhea, tremor, convulsion and coma in dogs.
11. 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]-1H-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:
FIGURE 1
Aciphex is available for oral administration as delayed-release, enteric-coated tablets containing 20 mg of rabeprazole sodium.
Inactive ingredients of the 20 mg tablet are carnauba wax, crospovidone, diacetylated monoglycerides, ethylcellulose, hydroxypropyl cellulose, hypromellose phthalate, magnesium stearate, mannitol, propylene glycol, sodium hydroxide, sodium stearyl fumarate, talc, and titanium dioxide. Iron oxide yellow is the coloring agent for the tablet coating. Iron oxide red is the ink pigment.
12. CLINICAL PHARMACOLOGY
. 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.
. Pharmacodynamics
Antisecretory Activity
The antisecretory 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 meal-stimulated 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.
| *(p<0.01 versus placebo) | ||
| Parameter | Aciphex (20 mg QD) | Placebo |
| Basal Acid Output (mmol/hr) | 0.4* | 2.8 |
| Stimulated Acid Output (mmol/hr) | 0.6* | 13.3 |
| % Time Gastric pH>3 | 65* | 10 |
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.
| Treatment | ||||
|---|---|---|---|---|
| AUC interval (hrs) | 10 mg RBP (N=24) | 20 mg RBP (N=24) | 40 mg RBP (N=24) | Placebo (N=24) |
| *(p<0.001 versus placebo) | ||||
| 08:00 - 13:00 | 19.6±21.5* | 12.9±23* | 7.6±14.7* | 91.1±39.7 |
| 13:00 - 19:00 | 5.6±9.7* | 8.3±29.8* | 1.3±5.2* | 95.5±48.7 |
| 19:00 - 22:00 | 0.1±0.1* | 0.1±0.06* | 0.0±0.02* | 11.9±12.5 |
| 22:00 - 08:00 | 129.2±84* | 109.6±67.2* | 76.9±58.4* | 479.9±165 |
| AUC 0-24 hours | 155.5±90.6* | 130.9±81* | 85.8±64.3* | 678.5±216 |
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:
| a No inferential statistics conducted for this parameter. * (p<0.001 versus placebo) b Gastric pH was measured every hour over a 24-hour period. | ||||
| Aciphex 20 mg QD | Placebo | |||
| Parameter | Day 1 | Day 8 | Day 1 | Day 8 |
| Mean AUC0-24 Acidity | 340.8* | 176.9* | 925.5 | 862.4 |
| Median trough pH (23-hr)a | 3.77 | 3.51 | 1.27 | 1.38 |
| % Time Gastric pH>3b | 54.6* | 68.7* | 19.1 | 21.7 |
| % Time Gastric pH>4b | 44.1* | 60.3* | 7.6 | 11.0 |
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 (13.1)}.
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 β-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 6β-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
The following in vitro data are available but the clinical significance is unknown.
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 (14) and INDICATIONS AND USAGE (1) 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:
| a These are breakpoints for the agar dilution methodology and they should not be used to interpret results using alternative methods. b There were not enough organisms with MICs > 0.25 μg/mL to determine a resistance breakpoint. | |
| Clarithromycin MIC (μg/mL) a | Interpretation |
| ≤ 0.25 0.5 ≥ 1.0 | Susceptible (S) Intermediate (I) Resistant (R) |
| Amoxicillin MIC (μg/mL) a,b | Interpretation |
| ≤ 0.25 | Susceptible (S) |
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:
| a These are quality control ranges for the agar dilution methodology and they should not be used to control test results obtained using alternative methods. | ||
| Microorganism | Antimicrobial Agent | MIC (μg/mL) a |
| H. pylori ATCC 43504 | Clarithromycin | 0.015 - 0.12 μg/mL |
| H. pylori ATCC 43504 | Amoxicillin | 0.015 - 0.12 μg/mL |
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 ≤ 0.25 μg/mL) to amoxicillin at baseline. Two patients had baseline 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:
| a Includes only patients with pretreatment and post-treatment clarithromycin susceptibility test results. b Susceptible (S) MIC ≤ 0.25 μg/mL, Intermediate (I) MIC = 0.5 μg/mL, Resistant (R) MIC ≥ 1 μg/mL | |||||||
| Days of RAC Therapy | Clarithromycin Pretreatment Results | Total Number | H. pylori Negative (Eradicated) | H. pylori Positive (Persistent) Post-Treatment Susceptibility Results | |||
| S b | I b | R b | No MIC | ||||
| 7 | Susceptible b | 129 | 103 | 2 | 0 | 1 | 23 |
| 7 | Intermediate b | 0 | 0 | 0 | 0 | 0 | 0 |
| 7 | Resistant b | 16 | 5 | 2 | 1 | 4 | 4 |
| 10 | Susceptible b | 133 | 111 | 3 | 1 | 2 | 16 |
| 10 | Intermediate b | 0 | 0 | 0 | 0 | 0 | 0 |
| 10 | Resistant b | 9 | 1 | 0 | 0 | 5 | 3 |
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 sus
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