AcipHex Sprinkle

Name: AcipHex Sprinkle

What is the most important information I should know about AcipHex Sprinkle (rabeprazole)?

Follow all directions on your medicine label and package. Tell each of your healthcare providers about all your medical conditions, allergies, and all medicines you use. Rabeprazole is not for immediate relief of heartburn symptoms.

What should I avoid while taking AcipHex Sprinkle (rabeprazole)?

This medicine can cause diarrhea, which may be a sign of a new infection. If you have diarrhea that is watery or bloody, call your doctor. Do not use anti-diarrhea medicine unless your doctor tells you to.

What other drugs will affect AcipHex Sprinkle (rabeprazole)?

Tell your doctor about all your current medicines and any you start or stop using, especially:

  • methotrexate (Otrexup, Rasuvo,Trexall); or

  • warfarin (Coumadin, Jantoven).

This list is not complete. Other drugs may interact with rabeprazole, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

Commonly used brand name(s)

In the U.S.

  • Aciphex
  • Aciphex Sprinkle

Available Dosage Forms:

  • Capsule, Delayed Release
  • Tablet, Enteric Coated

Therapeutic Class: Gastrointestinal Agent

Pharmacologic Class: Proton Pump Inhibitor

Contraindications

  • Aciphex Sprinkle 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 Sprinkle, are contraindicated with rilpivirine-containing products [see Drug Interactions (7)].

Use in specific populations

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 2-4% and of miscarriage is 15-20% 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. When maternal administration was confined to gestation only, there were no effects on bone physeal morphology in the offspring at any age [see Data].

Data

Animal Data

Embryo-fetal developmental studies have been performed in rats at intravenous doses of rabeprazole during organogenesis up to 50 mg/kg/day (plasma AUC of 11.8 µg•hr/mL, about 13 times the adult 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 adult human exposure at the recommended oral dose for GERD: 20 mg of rabeprazole delayed-release tablets per day) 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 adult 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 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 Sprinkle and any potential adverse effects on the breastfed infant from Aciphex Sprinkle or from the underlying maternal condition.

Pediatric Use

GERD in Pediatric Patients 1 to 11 Years of Age

The use of Aciphex Sprinkle for treatment of GERD in pediatric patients 1 to 11 years of age is supported by a randomized, multicenter, double-blind clinical trial which evaluated two dose levels of Aciphex Sprinkle in 127 pediatric patients with endoscopic and histologic evidence of GERD prior to study treatment. Dosing was determined by body weight: Patients weighing 6.0 to 14.9 kg received either 5 or 10 mg of Aciphex Sprinkle daily and those weighing 15.0 kg or more received 10 or 20 mg of Aciphex Sprinkle daily. After 12 weeks of rabeprazole treatment, 81% of patients demonstrated esophageal mucosal healing on endoscopic assessment. In patients who had esophageal mucosal healing at 12 weeks and elected to continue for 24 more weeks of rabeprazole, 90% retained esophageal mucosal healing at 36 weeks. No prespecified formal hypothesis testing for evaluation of efficacy was conducted. The absence of a placebo group does not allow assessment of sustained efficacy through 36 weeks. There were no adverse reactions reported in this study that were not previously observed in adolescents or adults.

Symptomatic GERD in Infants 1 to 11 Months of Age

The use of Aciphex Sprinkle is not recommended because studies conducted do not demonstrate efficacy for the treatment of GERD in pediatric patients younger than 1 year of age.

In a randomized, multicenter, placebo-controlled withdrawal trial, infants 1 to 11 months of age with a clinical diagnosis of symptomatic GERD, or suspected or endoscopically proven GERD, were treated up to 8 weeks in two treatment periods. In the first treatment period (open-label), 344 infants received 10 mg of Aciphex Sprinkle for up to 3 weeks. Infants with clinical response were then eligible to enter the second treatment period, which was double-blind and randomized. Two hundred sixty-eight infants were randomized to receive either placebo or 5 mg or 10 mg Aciphex Sprinkle.

This study did not demonstrate efficacy based on assessment of frequency of regurgitation and weight-for-age Z-score. Adverse reactions that occurred in ≥5% of patients in any treatment group and with a higher rate than placebo included pyrexia (7%) and increased serum gastrin levels (5%). There were no adverse reactions reported in this study that were not previously observed in adolescents and adults.

Neonates <1 Month and Preterm Infants <44 Weeks Corrected Gestational Age

The use of Aciphex Sprinkle is not recommended for the treatment of GERD, based on the risk of prolonged acid suppression and lack of demonstrated safety and effectiveness in neonates. Based on population pharmacokinetic analysis, the median (range) for the apparent clearance (CL/F) was 1.05 L/h (0.0543 to 3.44 L/h) in neonates and 4.46 L/h (0.822 to 12.4 L/h) in patients 1 to 11 months of age following once daily administration of oral Aciphex Sprinkle.

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.

Geriatric Use

No studies with Aciphex Sprinkle have been conducted in geriatric patients. Aciphex Sprinkle is not indicated for use in patients older than 11 years of age.

Hepatic Impairment

Administration of rabeprazole sodium delayed-release tablets to adult 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 of Aciphex Sprinkle 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 Sprinkle in patients with severe hepatic impairment; however, if treatment is necessary, monitor patients for adverse reactions [see Warnings and Precautions (5), Adverse Reactions (6)].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

In an 88/104-week carcinogenicity study in CD-1 mice, rabeprazole at oral doses up to 100 mg/kg/day did not produce any increased tumor occurrence. The highest tested dose produced a systemic exposure to rabeprazole (AUC) of 1.40 µg•hr/mL which is 1.6 times the adult human exposure (plasma AUC0-∞ = 0.88 µg•hr/mL) at the recommended dose for GERD (20 mg of rabeprazole sodium delayed-release tablets per day). In a 28-week carcinogenicity study in p53+/- transgenic mice, rabeprazole at oral doses of 20, 60, and 200 mg/kg/day did not cause an increase in the incidence rates of tumors but produced gastric mucosal hyperplasia at all doses. The systemic exposure to rabeprazole at 200 mg/kg/day is about 17 to 24 times the adult human exposure at the recommended dose for GERD (20 mg of rabeprazole sodium delayed-release tablets per day). In a 104-week carcinogenicity study in Sprague-Dawley rats, males were treated with oral doses of 5, 15, 30, and 60 mg/kg/day and females with 5, 15, 30, 60, and 120 mg/kg/day. Rabeprazole produced gastric enterochromaffin-like (ECL) cell hyperplasia in male and female rats and ECL cell carcinoid tumors in female rats at all doses including the lowest tested dose. The lowest dose (5 mg/kg/day) produced a systemic exposure to rabeprazole (AUC) of about 0.1 µg•hr/mL which is about 0.1 times the adult human exposure at the recommended dose for GERD (20 mg of rabeprazole sodium delayed-release tablets per day). In male rats, no treatment-related tumors were observed at doses up to 60 mg/kg/day producing a rabeprazole plasma exposure (AUC) of about 0.2 µg•hr/mL (0.2 times the adult human exposure at the recommended dose for GERD).

Rabeprazole was positive in the Ames test, the Chinese hamster ovary cell (CHO/HGPRT) forward gene mutation test, and the mouse lymphoma cell (L5178Y/TK+/–) forward gene mutation test. Its demethylated-metabolite was also positive in the Ames test. Rabeprazole was negative in the in vitro Chinese hamster lung cell chromosome aberration test, the in vivo mouse micronucleus test, and the in vivo and ex vivo rat hepatocyte unscheduled DNA synthesis (UDS) tests.

Rabeprazole at intravenous doses up to 30 mg/kg/day (plasma AUC of 8.8 µg•hr/mL, about 10 times the adult human exposure at the recommended dose for GERD) was found to have no effect on fertility and reproductive performance of male and female rats. The recommended dose for GERD in adults is 20 mg per day (rabeprazole sodium delayed-release tablets).

Side Effects of Aciphex Sprinkle

Serious side effects have been reported with Aciphex Sprinkle. See the “Drug Precautions” section.

Common side effects with Aciphex Sprinkle include the following

  • headache
  • pain
  • sore throat
  • gas
  • infection
  • constipation

People who are taking multiple daily doses of proton pump inhibitor medicines for a long period of time may have an increased risk of fractures of the hip, wrist, or spine.

This is not a comple list of Aciphex Sprinkle side effects. Ask your doctor or pharmacist for more information.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Aciphex Sprinkle and Lactation

Tell your doctor if you are breastfeeding or plan to breastfeed.

It is not known if Aciphex Sprinkle is excreted in human breast milk or if it can harm your nursing baby. Since many drugs can pass into breastmilk, and because of the possibility for serious reactions to infants from Aciphex Sprinkle, a decision should be made to stop nursing or the drug. The importance of the drug to the mother should be considered.

(web3)