1 INDICATIONS AND USAGE ACIPHEX delayed-release tablets is a proton-pump inhibitor (PPI) indicated in adults for: Healing of Erosive or Ulcerative Gastroesophageal Reflux Disease (GERD) (1.1). Maintenance of Healing of Erosive or Ulcerative GERD (1.2). Treatment of Symptomatic GERD (1.3). Healing of Duodenal Ulcers (1.4). Helicobacter pylori Eradication to Reduce Risk of Duodenal Ulcer Recurrence (1.5). Treatment of Pathological Hypersecretory Conditions, Including Zollinger-Ellison Syndrome (1.6). In adolescent patients 12 years of age and older for: Short-term Treatment of Symptomatic GERD (1.7). 1.1 Healing of Erosive or Ulcerative GERD in Adults ACIPHEX 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 ACIPHEX may be considered. 1.2 Maintenance of Healing of Erosive or Ulcerative GERD in Adults ACIPHEX 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. 1.3 Treatment of Symptomatic GERD in Adults ACIPHEX 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. 1.4 Healing of Duodenal Ulcers in Adults ACIPHEX 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. 1.5 Helicobacter pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence in Adults ACIPHEX 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 [ see Clinical Pharmacology (12.2) and the full prescribing information for clarithromycin]. 1.6 Treatment of Pathological Hypersecretory Conditio ns, Including Zollinger-Ellison Syndrome in Adults ACIPHEX delayed-release tablets are indicated for the long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison syndrome. 1.7 Treatment of Symptomatic GERD in Adolescent Patients 12 Years of Age and Older ACIPHEX delayed-release tablets are indicated for the treatment of symptomatic GERD in adolescents 12 years of age and above for up to 8 weeks.
Table 1: Recommended Dosage and Duration of ACIPHEX Delayed-Release Tablets in Adults and Adolescents 12 Years of Age and Older
| Indication || Dosage of ACIPHEX 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 ||ACIPHEX 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 [see Clinical Studies (14.5) ] ||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 |
3 DOSAGE FORMS AND STRENGTHS ACIPHEX delayed-release tablets are provided in one strength, 20 mg. The tablets are round, light yellow, enteric coated, biconvex tablets. “ACIPHEX 20” is imprinted in red on one side of the tablet. Delayed-Release Tablets: 20 mg (3).
4 CONTRAINDICATIONS • ACIPHEX is contraindicated in patients with known hypersensitivity to rabeprazole, substituted benzimidazoles, or to any component of the formulation. Hypersensitivity reactions may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, acute interstitial nephritis, and urticaria [see Adverse Reactions (6) ]. • PPIs, including ACIPHEX, are contraindicated with rilpivirine-containing products [see Drug Interactions (7) ]. • For information about contraindications of antibacterial agents (clarithromycin and amoxicillin) indicated in combination with ACIPHEX delayed-release tablets, refer to the Contraindications section of their package inserts. Patients with a history of hypersensitivity to rabeprazole (4). Patients receiving rilpivirine-containing products (4, 7). Refer to the Contraindications section of the prescribing information for clarithromycin and amoxicillin, when administered in combination with ACIPHEX (4).
5 WARNINGS AND PRECAUTIONS Gastric Malignancy: Symptomatic response to therapy with rabeprazole does not preclude the presence of gastric malignancy (5.1). Use with Warfarin: Monitor for increases in INR and prothombin time (5.2, 7). Acute Interstitial Nephritis: Observed in patients taking PPIs (5.3). Cyanocobalamin (vitamin B-12) Deficiency: Daily long-term use (e.g., longer than 3 years) may lead to malabsorption or a deficiency of cyanocobalamin (5.4). Clostridium difficile Associated Diarrhea: PPI therapy may be associated with increased risk of (5.5). Bone Fracture: Long-term and multiple daily dose PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine (5.6). Hypomagnesemia: Reported rarely with prolonged treatment with PPIs (5.7). Interaction with Methotrexate: Concomitant use with PPIs may elevate and/or prolong serum concentrations of methotrexate and/or its metabolite, possibly leading to toxicity. With high dose methotrexate administration, consider a temporary withdrawal of ACIPHEX delayed-release tablets (5.8, 7). 5.1 Presence of G astric M alignancy Symptomatic response to therapy with ACIPHEX does not preclude the presence of gastric malignancy. Patients with healed GERD were treated for up to 40 months with ACIPHEX delayed-release tablets 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. 5.2 Interaction with W arfarin 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 ACIPHEX delayed-release tablets and warfarin concomitantly may need to be monitored for increases in INR and prothrombin time [see Drug Interactions (7) ]. 5.3 Acute Interstitial Nephritis Acute interstitial nephritis has been observed in patients taking PPIs including ACIPHEX. Acute interstitial nephritis may occur at any point during PPI therapy and is generally attributed to an idiopathic hypersensitivity reaction. Discontinue ACIPHEX if acute interstitial nephritis develops [ see Contraindications (4) ] . 5.4 Cyanocobalamin (vitamin B-12) Deficiency Daily 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 ACIPHEX. 5. 5 Clostridium difficile A ssociated D iarrhea Published observational studies suggest that PPI therapy like ACIPHEX 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 [ see Adverse Reactions (6.2) ]. 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 ACIPHEX, refer to Warnings and Precautions sections of the corresponding prescribing information. 5. 6 Bone Fracture Several 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 [ see Dosage and Administration (2) , Adverse Reactions (6.2) ]. 5. 7 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) ]. 5. 8 Interaction with Methotrexate Literature 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 [ see Drug Interactions (7) ].
6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in labeling: Acute Interstitial Nephritis [see Warnings and Precautions (5.3) ] Cyanocobalamin (vitamin B-12) Deficiency [see Warnings and Precautions (5.4) ] Clostridium difficile Associated Diarrhea [see Warnings and Precautions (5.5) ] Bone Fracture [see Warnings and Precautions (5.6) ] Hypomagnesemia [see Warnings and Precautions (5.7) ] Most common adverse reactions in adults (>2%) are pain, pharyngitis, flatulence, infection, and constipation (6.1). Most common adverse reactions in adolescents (≥2%) are headache, diarrhea, nausea, vomiting, and abdominal pain (6.1). To report SUSPECTED ADVERSE REACTIONS, contact Eisai Inc. at 1-888-274-2378 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Studies Experience 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. Adults The data described below reflect exposure to ACIPHEX 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 ACIPHEX delayed-release tablets. An analysis of adverse reactions appearing in ≥2% of patients treated with ACIPHEX 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 ACIPHEX 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 ACIPHEX 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 ACIPHEX 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 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 prescribing information, Adverse Reactions section. Pediatric s In 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 ACIPHEX 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. 6.2 Postmarketing Experience The 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: 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; hypomagnesemia and Clostridium diffic i le -associated diarrhea. 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 Table 2 includes drugs with clinically important drug interactions when administered concomitantly with ACIPHEX 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 ACIPHEX Delayed-Release Tablets 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. Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir, and nelfinavir) when used concomitantly with rabeprazole may reduce antiviral effect and promote the development of drug resistance. Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with rabeprazole may increase toxicity. There are other antiretroviral drugs which do not result in clinically relevant interactions with rabeprazole. Intervention: Rilpivirine -containing products: Concomitant use with ACIPHEX delayed-release tablets is contraindicated [see Contraindications (4) ]. See prescribing information. Atazanavir: See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with ACIPHEX 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 [see Warnings and Precautions (5.2) ]. 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 [see Warnings and Precautions (5.8) ]. Intervention: A temporary withdrawal of ACIPHEX delayed-release tablets may be considered in some patients receiving high dose methotrexate administration. Digoxin Clinical Impact: Potential for increased exposure of digoxin [ see Clinical Pharmacology (12.3) ] . 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., ir on salts, erlotinib, dasatinib, nilotinib, mycophenol ate mofetil, ketoconazole , itraconazole ) Clinical Impact: Rabeprazole can reduce the absorption of 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 PPIs and MMF. Use ACIPHEX 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. See full prescribing information for a list of clinically important drug interactions (7).
8 USE IN SPECIFIC POPULATIONS Pediatric Use: Dosage strength not appropriate for patients less than 12 years (2, 8.4). 8.1 Pregnancy Risk Summary There are no available human data on ACIPHEX 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 [ see Data ]. Changes in bone morphology were observed in offspring of rats treated with oral doses of a different PPI through most of pregnancy and lactation [see Data ]. Advise pregnant women of the potential risk to a fetus. Data Animal 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. 8.2 Lactation Risk Summary Lactation 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 ACIPHEX and any potential adverse effects on the breastfed infant from ACIPHEX or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of ACIPHEX 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 ACIPEX 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 ACIPHEX delayed-release tablets have not been established in pediatric patients for: Healing of Erosive or Ulcerative GERD Maintenance of Healing of Erosive or Ulcerative GERD Treatment of Symptomatic GERD Healing of Duodenal Ulcers Helicobacter pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence Treatment of Pathological Hypersecretory Conditions, Including Zollinger-Ellison Syndrome ACIPHEX 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 [see Dosage and Administration (2) ]. 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 Data Studies 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. 8.5 Geriatric Use Of the total number of subjects (n=2009) in clinical studies of ACIPHEX 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. 8 . 6 Hepatic Impairment Administration of ACIPHEX 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 [see Clinical Pharmacology (12.3) ]. 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 ACIPHEX delayed-release tablets in patients with severe hepatic impairment; however, if treatment is necessary, monitor patients for adverse reactions [see Warnings and Precautions (5) , Adverse Reactions (6) ].