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 once daily. 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.
If over-exposure occurs, call your Poison Control Center at 1-800-222-1222 for current information on the management of poisoning or overdosage.
The following serious adverse reactions are described below and elsewhere in labeling:
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.
AdultsThe data described below reflect exposure to %medicine_name% delayed-release tablets in 1064 adult patients exposed for up to 8 weeks. The studies were primarily placebo- and active-controlled trials in adult 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 per day of %medicine_name% delayed-release tablets.
An analysis of adverse reactions appearing in ≥2% of patients treated with %medicine_name% delayed-release tablets (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%).
Three long-term maintenance studies consisted of a total of 740 adult patients; at least 54% of adult patients were exposed to %medicine_name% delayed-release tablets for 6 months and at least 33% were exposed for 12 months. Of the 740 adult patients, 247 (33%) and 241 (33%) patients received 10 mg and 20 mg of %medicine_name% delayed-release tablets, respectively, while 169 (23%) patients received placebo and 83 (11%) received omeprazole.
The safety profile of rabeprazole in the maintenance studies in adults was consistent with what was observed in the acute studies.
Less common adverse reactions seen in controlled clinical trials (<2% of patients treated with %medicine_name% delayed-release tablets and greater than 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.
Combination Treatment With Amoxicillin And ClarithromycinIn 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 prescribing information, Adverse Reactions section.
PediatricsIn a multicenter, open-label study of adolescent patients 12 to 16 years of age 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 %medicine_name% delayed-release tablets 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 this study that were not previously observed in adults.
Postmarketing ExperienceThe following adverse reactions have been identified during post approval use of rabeprazole. 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:
Blood and Lymphatic System Disorders: agranulocytosis, hemolytic anemia, leukopenia, pancytopenia, thrombocytopenia
Ear and Labyrinth Disorders: vertigo
Eye Disorders: blurred vision
General Disorders and Administration Site Conditions: sudden death
Hepatobiliary Disorders: jaundice
Immune System Disorders: anaphylaxis, angioedema, systemic lupus erythematosus, Stevens-Johnson syndrome, toxic epidermal necrolysis (some fatal)
Infections and Infestations: Clostridium difficile-associated diarrhea
Investigations: Increases in prothrombin time/INR (in patients treated with concomitant warfarin), TSH elevations
Metabolism and Nutrition Disorders: hyperammonemia, hypomagnesemia
Musculoskeletal System Disorders: bone fracture, rhabdomyolysis
Nervous System Disorders: coma
Psychiatric Disorders: delirium, disorientation
Renal and Urinary Disorders: interstitial nephritis
Respiratory, Thoracic and Mediastinal Disorders: interstitial pneumonia
Skin and Subcutaneous Tissue Disorders: severe dermatologic reactions including bullous and other drug eruptions of the skin, cutaneous lupus erythematosus, erythema multiforme
%medicine_name% delayed-release tablets are 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 %medicine_name% may be considered.
Maintenance Of Healing Of Erosive Or Ulcerative GERD In Adults%medicine_name% delayed-release tablets are 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 In Adults%medicine_name% delayed-release tablets are indicated for the treatment of daytime and nighttime heartburn and other symptoms associated with GERD in adults for up to 4 weeks.
Healing Of Duodenal Ulcers In Adults%medicine_name% delayed-release tablets are 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 In Adults%medicine_name% delayed-release tablets, in combination with amoxicillin and clarithromycin as a three drug regimen, are 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.
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.
Treatment Of Pathological Hypersecretory Conditions, Including Zollinger-Ellison Syndrome In Adults%medicine_name% delayed-release tablets are indicated for the long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison syndrome.
Treatment Of Symptomatic GERD In Adolescent Patients 12 Years Of Age And Older%medicine_name% delayed-release tablets are indicated for the treatment of symptomatic GERD in adolescents 12 years of age and above for up to 8 weeks.
The antisecretory effect begins within one hour after oral administration of 20 mg %medicine_name% delayed-release tablets. The median inhibitory effect of rabeprazole on 24 hour gastric acidity is 88% of maximal after the first dose. A 20 mg dose of %medicine_name% delayed-release tablets 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 to 2 hours) reflects the sustained inactivation of the H+, K+ATPase.
Table 3: Gastric Acid Parameters: %medicine_name%
Delayed-Release Tablets versus Placebo After 7 Days of Once Daily Dosing
| Parameter | %medicine_name% delayed-release tablets (20 mg once daily) | 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 |
| *(p<0.01 versus placebo) |
Compared to placebo, 10 mg, 20 mg, and 40 mg of %medicine_name% delayed-release tablets, 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.
Table 4: AUC Acidity (Mmol•Hr/L): %medicine_name%
Delayed-Release Tablets versus Placebo on Day 7 of Once Daily Dosing (Mean ± SD)
| AUC interval (hrs) | %medicine_name% delayed-release tablets | Placebo (N=24) |
||
| 10 mg (N=24) | 20 mg (N=24) |
40 mg (N=24) |
||
| 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 |
| *(p<0.001 versus placebo) |
After administration of 20 mg %medicine_name% delayed-release tablets once daily for eight days, the mean percent of time that gastric pH greater than 3 or gastric pH greater than 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 %medicine_name% delayed-release tablets administered once daily for eight days were compared to the same parameters for placebo, as illustrated below:
Table 5: Gastric Acid Parameters %medicine_name%
Delayed-Release Tablets Once Daily Dosing versus Placebo on Day 1 and Day 8
| Parameter | %medicine_name% delayed-release tablets 20 mg once daily | Placebo | ||
| 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 greater than 3b | 54.6* | 68.7* | 19.1 | 21.7 |
| % Time Gastric pH greater than 4b | 44.1* | 60.3* | 7.6 | 11.0 |
| a No inferential statistics conducted for this
parameter. b Gastric pH was measured every hour over a 24-hour period. * (p<0.001 versus placebo) |
In patients with GERD and moderate to severe esophageal acid exposure, a dose of 20 mg and 40 mg per day of %medicine_name% delayed-release tablets decreased 24-hour esophageal acid exposure. After seven days of treatment, the percentage of time that the esophageal pH was less than 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 greater than 4 for at least 35% of the 24-hour period; this level was achieved in 90% of subjects receiving %medicine_name% 20 mg and in 100% of subjects receiving %medicine_name% 40 mg. With %medicine_name% 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 GastrinThe median fasting gastrin level increased in a dose-related manner in patients treated once daily with %medicine_name% delayed-release tablets for up to eight weeks for ulcerative or erosive esophagitis and in patients treated for up to 52 weeks to prevent recurrence of disease. The group median values stayed within the normal range.
In a group of subjects treated with 20 mg %medicine_name% delayed-release tablets for 4 weeks a doubling of mean serum gastrin concentrations was observed. Approximately 35% of these treated subjects developed serum gastrin concentrations above the upper limit of normal.
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.
In over 400 patients treated with %medicine_name% delayed-release tablets (10 or 20 mg) once daily 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 EffectsStudies in humans for up to one year have not revealed clinically significant effects on the endocrine system. In healthy male subjects treated with %medicine_name% delayed-release tablets 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 EffectsIn humans treated with %medicine_name% delayed-release tablets 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 %medicine_name% delayed-release tablets and ocular effects.
After oral administration of 20 mg %medicine_name% delayed-release tablets, peak plasma concentrations (Cmax) of rabeprazole occur over a range of 2 to 5 hours (Tmax). The rabeprazole Cmax 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 is not altered by multiple dosing.
AbsorptionAbsolute bioavailability for a 20 mg oral tablet of rabeprazole (compared to intravenous administration) is approximately 52%. When %medicine_name% delayed-release tablets are administered with a high fat meal, Tmax is variable; which concomitant food intake may delay the absorption up to 4 hours or longer. However, the Cmax and the extent of rabeprazole absorption (AUC) are not significantly altered. Thus %medicine_name% delayed-release tablets may be taken without regard to timing of meals.
DistributionRabeprazole is 96.3% bound to human plasma proteins.
EliminationMetabolism
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.
Excretion
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.
There are no available human data on %medicine_name% use in pregnant women to inform the drug associated risk. The background risk of major birth defects and miscarriage for the indicated populations are unknown. However, the background risk in the U.S. general population of major birth defects is 2 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies. No evidence of adverse developmental effects were seen in animal reproduction studies with rabeprazole administered during organogenesis at 13 and 8 times the human area under the plasma concentration-time curve (AUC) at the recommended dose for GERD, in rats and rabbits, respectively.
Changes in bone morphology were observed in offspring of rats treated with oral doses of a different PPI through most of pregnancy and lactation. When maternal administration was confined to gestation only, there were no effects on bone physeal morphology in the offspring at any age.
DataAnimal Data
Embryo-fetal developmental studies have been performed in rats during organogenesis at intravenous doses of rabeprazole up to 50 mg/kg/day (plasma AUC of 11.8 μg•hr/mL, about 13 times the human exposure at the recommended oral 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 oral dose for GERD) and have revealed no evidence of harm to the fetus due to rabeprazole.
Administration of rabeprazole to rats in late gestation and during lactation at an oral dose of 400 mg/kg/day (about 195-times the human oral dose based on mg/m²) resulted in decreases in body weight gain of the pups.
A pre- and postnatal developmental toxicity study in rats with additional endpoints to evaluate bone development was performed with a different PPI at about 3.4 to 57 times an oral human dose on a body surface area basis. Decreased femur length, width and thickness of cortical bone, decreased thickness of the tibial growth plate, and minimal to mild bone marrow hypocellularity were noted at doses of this PPI equal to or greater than 3.4 times an oral human dose on a body surface area basis. Physeal dysplasia in the femur was also observed in offspring after in utero and lactational exposure to the PPI at doses equal to or greater than 33.6 times an oral human dose on a body surface area basis. Effects on maternal bone were observed in pregnant and lactating rats in a pre- and postnatal toxicity study when the PPI was administered at oral doses of 3.4 to 57 times an oral human dose on a body surface area basis. When rats were dosed from gestational day 7 through weaning on postnatal day 21, a statistically significant decrease in maternal femur weight of up to 14% (as compared to placebo treatment) was observed at doses equal to or greater than 33.6 times an oral human dose on a body surface area basis.
A follow-up developmental toxicity study in rats with further time points to evaluate pup bone development from postnatal day 2 to adulthood was performed with a different PPI at oral doses of 280 mg/kg/day (about 68 times an oral human dose on a body surface area basis) where drug administration was from either gestational day 7 or gestational day 16 until parturition. When maternal administration was confined to gestation only, there were no effects on bone physeal morphology in the offspring at any age.
Included as part of the PRECAUTIONS section.
PRECAUTIONS Presence Of Gastric MalignancyIn adults, symptomatic response to therapy with %medicine_name% does not preclude the presence of gastric malignancy. Consider additional follow-up and diagnostic testing in adult patients who have a suboptimal response or an early symptomatic relapse after completing treatment with a PPI.
Interaction With WarfarinSteady 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 %medicine_name% delayed-release tablets and warfarin concomitantly may need to be monitored for increases in INR and prothrombin time.
Acute Interstitial NephritisAcute interstitial nephritis has been observed in patients taking PPIs including %medicine_name%. Acute interstitial nephritis may occur at any point during PPI therapy and is generally attributed to an idiopathic hypersensitivity reaction. Discontinue %medicine_name% if acute interstitial nephritis develops.
Clostridium Difficile-Associated DiarrheaPublished observational studies suggest that PPI therapy like %medicine_name% may be associated with an increased risk of Clostridium difficile-associated diarrhea, especially in hospitalized patients. This diagnosis should be considered for diarrhea that does not improve.
Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.
Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents. For more information specific to antibacterial agents (clarithromycin and amoxicillin) indicated for use in combination with %medicine_name%, refer to Warnings and Precautions sections of the corresponding prescribing information.
Bone FractureSeveral published observational studies in adults suggest that 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.
Cutaneous And Systemic Lupus ErythematosusCutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) have been reported in patients taking PPIs, including rabeprazole. These events have occurred as both new onset and an exacerbation of existing autoimmune disease. The majority of PPI-induced lupus erythematosus cases were CLE.
The most common form of CLE reported in patients treated with PPIs was subacute CLE (SCLE) and occurred within weeks to years after continuous drug therapy in patients ranging from infants to the elderly. Generally, histological findings were observed without organ involvement.
Systemic lupus erythematosus (SLE) is less commonly reported than CLE in patients receiving PPIs. PPI associated SLE is usually milder than non-drug induced SLE. Onset of SLE typically occurred within days to years after initiating treatment primarily in patients ranging from young adults to the elderly. The majority of patients presented with rash; however, arthralgia and cytopenia were also reported.
Avoid administration of PPIs for longer than medically indicated. If signs or symptoms consistent with CLE or SLE are noted in patients receiving %medicine_name%, discontinue the drug and refer the patient to the appropriate specialist for evaluation. Most patients improve with discontinuation of the PPI alone in 4 to 12 weeks. Serological testing (e.g. ANA) may be positive and elevated serological test results may take longer to resolve than clinical manifestations.
Cyanocobalamin (Vitamin B-12) DeficiencyDaily treatment with any acid-suppressing medications over a long period of time (e.g., longer than 3 years) may lead to malabsorption of cyanocobalamin (vitamin B-12) caused by hypo- or achlorhydria. Rare reports of cyanocobalamin deficiency occurring with acid-suppressing therapy have been reported in the literature. This diagnosis should be considered if clinical symptoms consistent with cyanocobalamin deficiency are observed in patients treated with %medicine_name%.
HypomagnesemiaHypomagnesemia, 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.
Interaction With MethotrexateLiterature suggests that concomitant use of PPIs with methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum concentrations of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities. In high-dose methotrexate administration, a temporary withdrawal of the PPI may be considered in some patients.
Patient Counseling InformationAdvise the patient to read the FDA-approved patient labeling (Medication Guide).
Acute Interstitial NephritisAdvise the patient or caregiver to call the patient's healthcare provider immediately if they experience signs and/or symptoms associated with acute interstitial nephritis.
Clostridium Difficile-Associated DiarrheaAdvise the patient or caregiver to immediately call the patient's healthcare provider if they experience diarrhea that does not improve .
Bone FractureAdvise the patient or caregiver to report any fractures, especially of the hip, wrist or spine, to the patient's healthcare provider .
Cutaneous And Systemic Lupus ErythematosusAdvise the patient or caregiver to immediately call the patient's healthcare provider for any new or worsening of symptoms associated with cutaneous or systemic lupus erythematosus.
Cyanocobalamin (Vitamin B-12) DeficiencyAdvise the patient or caregiver to report any clinical symptoms that may be associated with cyanocobalamin deficiency to the patient's healthcare provider if they have been receiving %medicine_name% for longer than 3 years .
HypomagnesemiaAdvise the patient or caregiver to report any clinical symptoms that may be associated with hypomagnesemia to the patient's healthcare provider, if they have been receiving %medicine_name% for at least 3 months.
Drug InteractionsAdvise patients to report to their healthcare provider if they are taking rilpivirine-containing products , warfarin, digoxin or high-dose methotrexate.
AdministrationIn 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 human exposure (plasma AUC0-∞ = 0.88 μg•hr/mL) at the recommended dose for GERD (20 mg/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 human exposure at the recommended dose for GERD. 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 human exposure at the recommended dose for GERD. 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 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 human exposure at the recommended dose for GERD) was found to have no effect on fertility and reproductive performance of male and female rats.
Use In Specific Populations Pregnancy Risk SummaryThere are no available human data on %medicine_name% use in pregnant women to inform the drug associated risk. The background risk of major birth defects and miscarriage for the indicated populations are unknown. However, the background risk in the U.S. general population of major birth defects is 2 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies. No evidence of adverse developmental effects were seen in animal reproduction studies with rabeprazole administered during organogenesis at 13 and 8 times the human area under the plasma concentration-time curve (AUC) at the recommended dose for GERD, in rats and rabbits, respectively.
Changes in bone morphology were observed in offspring of rats treated with oral doses of a different PPI through most of pregnancy and lactation. When maternal administration was confined to gestation only, there were no effects on bone physeal morphology in the offspring at any age.
DataAnimal Data
Embryo-fetal developmental studies have been performed in rats during organogenesis at intravenous doses of rabeprazole up to 50 mg/kg/day (plasma AUC of 11.8 μg•hr/mL, about 13 times the human exposure at the recommended oral 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 oral dose for GERD) and have revealed no evidence of harm to the fetus due to rabeprazole.
Administration of rabeprazole to rats in late gestation and during lactation at an oral dose of 400 mg/kg/day (about 195-times the human oral dose based on mg/m²) resulted in decreases in body weight gain of the pups.
A pre- and postnatal developmental toxicity study in rats with additional endpoints to evaluate bone development was performed with a different PPI at about 3.4 to 57 times an oral human dose on a body surface area basis. Decreased femur length, width and thickness of cortical bone, decreased thickness of the tibial growth plate, and minimal to mild bone marrow hypocellularity were noted at doses of this PPI equal to or greater than 3.4 times an oral human dose on a body surface area basis. Physeal dysplasia in the femur was also observed in offspring after in utero and lactational exposure to the PPI at doses equal to or greater than 33.6 times an oral human dose on a body surface area basis. Effects on maternal bone were observed in pregnant and lactating rats in a pre- and postnatal toxicity study when the PPI was administered at oral doses of 3.4 to 57 times an oral human dose on a body surface area basis. When rats were dosed from gestational day 7 through weaning on postnatal day 21, a statistically significant decrease in maternal femur weight of up to 14% (as compared to placebo treatment) was observed at doses equal to or greater than 33.6 times an oral human dose on a body surface area basis.
A follow-up developmental toxicity study in rats with further time points to evaluate pup bone development from postnatal day 2 to adulthood was performed with a different PPI at oral doses of 280 mg/kg/day (about 68 times an oral human dose on a body surface area basis) where drug administration was from either gestational day 7 or gestational day 16 until parturition. When maternal administration was confined to gestation only, there were no effects on bone physeal morphology in the offspring at any age.
Lactation Risk SummaryLactation studies have not been conducted to assess the presence of rabeprazole in human milk, the effects of rabeprazole on the breastfed infant, or the effects of rabeprazole on milk production. Rabeprazole is present in rat milk. The development and health benefits of breastfeeding should be considered along with the mother's clinical need for %medicine_name% and any potential adverse effects on the breastfed infant from %medicine_name% or from the underlying maternal condition.
Pediatric UseThe safety and effectiveness of %medicine_name% delayed-release tablets have been established in pediatric patients for adolescent patients 12 years of age and older for the treatment of symptomatic GERD. Use of %medicine_name% delayed-release tablets in this age group is supported by adequate and well controlled studies in adults and a multicenter, randomized, open-label, parallel-group study in 111 adolescent patients 12 to 16 years of age. Patients had a clinical diagnosis of symptomatic GERD, or suspected or endoscopically proven GERD and were randomized to either 10 mg or 20 mg once daily for up to 8 weeks for the evaluation of safety and efficacy. The adverse reaction profile in adolescent patients was similar to that of adults. The related reported adverse reactions that occurred in ≥2% of patients were headache (5%) and nausea (2%). There were no adverse reactions reported in these studies that were not previously observed in adults.
The safety and effectiveness of %medicine_name% delayed-release tablets have not been established in pediatric patients for:
%medicine_name% delayed-release 20 mg tablets are not recommended for use in pediatric patients less than 12 years of age because the tablet strength exceeds the recommended dose for these patients. For pediatric patients 1 year to less than 12 years of age consider another rabeprazole formulation. The safety and effectiveness of a different dosage form and dosage strength of rabeprazole has been established in pediatric patients 1 to 11 years for the treatment of GERD.
Juvenile Animal DataStudies in juvenile and young adult rats and dogs were performed. In juvenile animal studies rabeprazole sodium was administered orally to rats for up to 5 weeks and to dogs for up to 13 weeks, each commencing on Day 7 post-partum and followed by a 13-week recovery period. Rats were dosed at 5, 25, or 150 mg/kg/day and dogs were dosed at 3, 10, or 30 mg/kg/day. The data from these studies were comparable to those reported for young adult animals. Pharmacologically mediated changes, including increased serum gastrin levels and stomach changes, were observed at all dose levels in both rats and dogs. These observations were reversible over the 13-week recovery periods. Although body weights and/or crown-rump lengths were minimally decreased during dosing, no effects on the development parameters were noted in either juvenile rats or dogs.
When juvenile animals were treated for 28 days with a different PPI at doses equal to or greater than 34 times the daily oral human dose on a body surface area basis, overall growth was affected and treatment-related decreases in body weight (approximately 14%) and body weight gain, and decreases in femur weight and femur length were observed.
Geriatric UseOf the total number of subjects (n=2009) in clinical studies of %medicine_name% delayed-release tablets, 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.
Hepatic ImpairmentAdministration of %medicine_name% delayed-release tablets to patients with mild to moderate hepatic impairment (Child-Pugh Class A and B, respectively) resulted in increased exposure and decreased elimination. No dosage adjustment is necessary in patients with mild to moderate hepatic impairment. There is no information in patients with severe hepatic impairment (Child-Pugh Class C). Avoid use of %medicine_name% delayed-release tablets in patients with severe hepatic impairment; however, if treatment is necessary, monitor patients for adverse reactions.
Table 1 shows the recommended dosage of %medicine_name% delayed-release tablets in adults and adolescent patients 12 years of age and older. The use of %medicine_name% delayed-release tablets is not recommended for use in pediatric patients 1 year to less than 12 years of age because the lowest available tablet strength (20 mg) exceeds the recommended dose for these patients. Use another rabeprazole formulation for pediatric patients 1 year to less than 12 years of age.
Table 1: Recommended Dosage and Duration of %medicine_name%
Delayed-Release Tablets in Adults and Adolescents 12 Years of Age and Older
| Indication | Dosage of %medicine_name% delayed-release tablets | Treatment Duration |
| Adults | ||
| Healing of Erosive or Ulcerative Gastroesophageal Reflux Disease (GERD) | 20 mg once daily | 4 to 8 weeks* |
| Maintenance of Healing of Erosive or Ulcerative GERD | 20 mg once daily | Controlled studies do not extend beyond 12 months |
| Symptomatic GERD in Adults | 20 mg once daily | Up to 4 weeks** |
| Healing of Duodenal Ulcers | 20 mg once daily after the morning meal | Up to 4 weeks*** |
| Helicobacter pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence | %medicine_name% 20 mg Amoxicillin 1000 mg Clarithromycin 500 mg Take all three medications twice daily with morning and evening meals; it is important that patients comply with the full 7-day regimen | 7 days |
| Pathological Hypersecretory Conditions, Including Zollinger-Ellison Syndrome | Starting dose 60 mg once daily then adjust to patient needs; some patients require divided doses Dosages of 100 mg once daily and 60 mg twice daily have been administered |
As long as clinically indicated Some patients with Zollinger-Ellison syndrome have been treated continuously for up to one year |
| Adolescents 12 Years of Age and Older | ||
| Symptomatic GERD | 20 mg once daily | Up to 8 weeks |
| * For those patients who have not healed after 8 weeks of
treatment, an additional 8-week course of %medicine_name% may be considered. ** If symptoms do not resolve completely after 4 weeks, an additional course of treatment may be considered. *** Most patients heal within 4 weeks; some patients may require additional therapy to achieve healing. |
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The following serious adverse reactions are described below and elsewhere in labeling:
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.
AdultsThe data described below reflect exposure to %medicine_name% delayed-release tablets in 1064 adult patients exposed for up to 8 weeks. The studies were primarily placebo- and active-controlled trials in adult 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 per day of %medicine_name% delayed-release tablets.
An analysis of adverse reactions appearing in ≥2% of patients treated with %medicine_name% delayed-release tablets (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%).
Three long-term maintenance studies consisted of a total of 740 adult patients; at least 54% of adult patients were exposed to %medicine_name% delayed-release tablets for 6 months and at least 33% were exposed for 12 months. Of the 740 adult patients, 247 (33%) and 241 (33%) patients received 10 mg and 20 mg of %medicine_name% delayed-release tablets, respectively, while 169 (23%) patients received placebo and 83 (11%) received omeprazole.
The safety profile of rabeprazole in the maintenance studies in adults was consistent with what was observed in the acute studies.
Less common adverse reactions seen in controlled clinical trials (<2% of patients treated with %medicine_name% delayed-release tablets and greater than 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.
Combination Treatment With Amoxicillin And ClarithromycinIn 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 prescribing information, Adverse Reactions section.
PediatricsIn a multicenter, open-label study of adolescent patients 12 to 16 years of age 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 %medicine_name% delayed-release tablets 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 this study that were not previously observed in adults.
Postmarketing ExperienceThe following adverse reactions have been identified during post approval use of rabeprazole. 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:
Blood and Lymphatic System Disorders: agranulocytosis, hemolytic anemia, leukopenia, pancytopenia, thrombocytopenia
Ear and Labyrinth Disorders: vertigo
Eye Disorders: blurred vision
General Disorders and Administration Site Conditions: sudden death
Hepatobiliary Disorders: jaundice
Immune System Disorders: anaphylaxis, angioedema, systemic lupus erythematosus, Stevens-Johnson syndrome, toxic epidermal necrolysis (some fatal)
Infections and Infestations: Clostridium difficile-associated diarrhea
Investigations: Increases in prothrombin time/INR (in patients treated with concomitant warfarin), TSH elevations
Metabolism and Nutrition Disorders: hyperammonemia, hypomagnesemia
Musculoskeletal System Disorders: bone fracture, rhabdomyolysis
Nervous System Disorders: coma
Psychiatric Disorders: delirium, disorientation
Renal and Urinary Disorders: interstitial nephritis
Respiratory, Thoracic and Mediastinal Disorders: interstitial pneumonia
Skin and Subcutaneous Tissue Disorders: severe dermatologic reactions including bullous and other drug eruptions of the skin, cutaneous lupus erythematosus, erythema multiforme
DRUG INTERACTIONSTable 2 includes drugs with clinically important drug interactions and interaction with diagnostics when administered concomitantly with %medicine_name% delayed-release tablets and instructions for preventing or managing them.
Consult the labeling of concomitantly used drugs to obtain further information about interactions with PPIs.
Table 2: Clinically Relevant Interactions Affecting
Drugs Co-Administered with %medicine_name% Delayed-Release Tablets and Interactions with
Diagnostics
| Antiretrovirals | |
| Clinical Impact: | The effect of PPI on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known.
|
| Intervention: | Rilpivirine-containing products: Concomitant use with %medicine_name% delayed-release tablets is contraindicated. See prescribing information. Atazanavir: See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with %medicine_name% delayed-release tablets. See prescribing information for nelfinavir. Saquinavir: See the prescribing information for saquinavir and monitor for potential saquinavir toxicities. Other antiretrovirals: See prescribing information. |
| Warfarin | |
| Clinical Impact: | Increased INR and prothrombin time in patients receiving PPIs, including rabeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. |
| Intervention: | Monitor INR and prothrombin time. Dose adjustment of warfarin may be needed to maintain target INR range. See prescribing information for warfarin. |
| Methotrexate | |
| Clinical Impact: | Concomitant use of rabeprazole with methotrexate (primarily at high dose) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of methotrexate with PPIs have been conducted. |
| Intervention: | A temporary withdrawal of %medicine_name% delayed-release tablets may be considered in some patients receiving high dose methotrexate administration. |
| Digoxin | |
| Clinical Impact: | Potential for increased exposure of digoxin. |
| Intervention: | Monitor digoxin concentrations. Dose adjustment of digoxin may be needed to maintain therapeutic drug concentrations. See prescribing information for digoxin. |
| Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole, itraconazole) | |
| Clinical Impact: | Rabeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity. |
| Intervention: | Mycophenolate mofetil (MMF): Co-administration of PPIs in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving %medicine_name% delayed-release tablets and MMF. Use %medicine_name% delayed-release tablets with caution in transplant patients receiving MMF. See the prescribing information for other drugs dependent on gastric pH for absorption. |
| Combination Therapy with Clarithromycin and Amoxicillin | |
| Clinical Impact: | Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions. |
| Intervention: | See CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS in prescribing information for clarithromycin. See Drug Interactions in prescribing information for amoxicillin. |
| Tacrolimus | |
| Clinical Impact: | Potentially increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19. |
| Intervention: | Monitor tacrolimus whole blood trough concentrations. Dose adjustment of tacrolimus may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus. |
| Interactions with Investigations of Neuroendocrine Tumors | |
| Clinical Impact: | Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors. |
| Intervention: | Temporarily stop %medicine_name% delayed-release tablets treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g. for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary. |
| Interaction with Secretin Stimulation Test | |
| Clinical Impact: | Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma. |
| Intervention: | Temporarily stop treatment with %medicine_name% delayed-release tablets at least 14 days before assessing to allow gastrin levels to return to baseline. |
| False Positive Urine Tests for THC | |
| Clinical Impact: | There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs. |
| Intervention: | An alternative confirmatory method should be considered to verify positive results. |
