DRUGS & SUPPLEMENTS

Helirab-D

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Helirab-D uses

Helirab-D consists of Domperidone, Rabeprazole.

Domperidone:



CAUTION

Federal law (USA) restricts this drug to use by or on the order of a licensed veterinarian.

For oral use in horses only.

DESCRIPTION

Helirab-D (Domperidone) is D2 dopamine receptor antagonist. Chemically, Helirab-D (Domperidone) is 6-chloro-3-[1-[3-(2-oxo-3H-benzimidazol-1-yl)propyl]piperidin-4-yl]-1H-benzimidazol-2-one.

The structural formula is:

Chemical Structure

INDICATIONS

For prevention of fescue toxicosis in periparturient mares.

DOSAGE AND ADMINISTRATION

Orally administer 0.5 mg/lb (1.1 mg/kg) once daily starting 10 to 15 days prior to Expected Foaling Date (EFD). Treatment may be continued for up to 5 days after foaling if mares are not producing adequate milk after foaling.

DIRECTIONS FOR ADMINISTRATION

  • Determine the appropriate dose for the body weight of the mare based on the dosing table below. One cc will treat 220 lb (100 kg) of body weight.
    Weight

    (lb)

    Weight

    (kg)

    cc Helirab-D (Domperidone)

    (mg)

    550-660 250-300 3 330
    661-880 301-400 4 440
    881-1100 401-500 5 550
    1101-1320 501-600 6 660
  • Turn the dial ring until the edge of the ring nearest the tip of the syringe lines up with the dose to be delivered.
  • Remove the syringe cap.
  • Make sure the horse's mouth is free of food or other obstructions.
  • Insert the nozzle of the syringe through the interdental space of the horse's mouth and deposit the gel on the back of the tongue by depressing the plunger.
  • Recap the syringe.

This is a 25 cc multi-dose syringe. Please note that for subsequent doses, it will be necessary to adjust for previous doses. For example, if the intended dose for a horse is 5 cc, then the dial ring is set at 5 cc for the first dose, at 10 cc for the second dose, at 15 cc for the third dose, at 20 cc for the fourth dose, and at 25 cc for the fifth dose.

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CONTRAINDICATION

Horses with hypersensitivity to Helirab-D (Domperidone) should not receive Helirab-D (Domperidone) Gel.

WARNINGS

Failure of passive transfer of immunoglobulins (IgG) may occur when using Helirab-D (Domperidone) Gel even in the absence of leakage of colostrum or milk. All foals born to mares treated with Helirab-D (Domperidone) Gel should be tested for serum IgG concentrations.

Do not use in horses intended for human consumption.

HUMAN WARNINGS

Not for use in humans. For oral use in animals only. Keep this and all drugs out of reach of children. Pregnant and lactating women should use caution when handling Helirab-D (Domperidone) Gel, as systemic exposure to Helirab-D (Domperidone) may affect reproductive hormones. Helirab-D (Domperidone) is not approved for any indication in humans in the US. The safety of Helirab-D (Domperidone) in lactating women and their nursing children has not been evaluated. Consult a physician in case of accidental human exposure.

PRECAUTIONS

Helirab-D (Domperidone) Gel may lead to premature birth, low birth weight foals or foal morbidity if administered > 15 days prior to the expected foaling date. Accurate breeding date(s) and an expected foaling date are needed for the safe use of Helirab-D (Domperidone) Gel.

The safety of Helirab-D (Domperidone) Gel has not been evaluated in breeding, pregnant and lactating mares other than in the last 45 days of pregnancy and the first 15 days of lactation. The safety in stallions has not been evaluated. The long term effects on foals born to mares treated with Helirab-D (Domperidone) Gel have not been evaluated.

Do not use in horses with suspected or confirmed gastrointestinal blockage, as Helirab-D (Domperidone) is a prokinetic drug (it stimulates gut motility).

Use of Helirab-D (Domperidone) Gel may cause a false positive on the milk calcium test used to predict foaling.

Helirab-D (Domperidone) is a known P-glycoprotein substrate1 and its main metabolic pathway in humans is through CYP3A4. Significant inhibition of Helirab-D (Domperidone) metabolism may occur when co-administered with drugs such as erythromycin2 and ketoconazole3. This could result in significantly greater Helirab-D (Domperidone) drug exposure (multi-fold increase) when used with these drugs.

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ADVERSE REACTIONS

The most common adverse reactions associated with treatment with Helirab-D (Domperidone) Gel are premature lactation (dripping of milk prior foaling) and failure of passive transfer.

In a laboratory effectiveness study with 32 periparturient mares (17 treated with Helirab-D (Domperidone) Gel and 15 treated with vehicle control) 3/17 (18%) mares treated with Helirab-D (Domperidone) Gel experienced premature lactation. In the 25 foals (16 foals of mares treated with Helirab-D (Domperidone) Gel and 9 foals of vehicle control mares) evaluated for passive transfer, failure of passive transfer occurred in 13/16 (81%) foals of mares treated with Helirab-D (Domperidone) Gel and 8/9 (89%) foals of control mares. Failure of passive transfer in foals of mares treated with Helirab-D (Domperidone) Gel was not solely due to physical loss of colostrum through premature lactation, because 77% of Helirab-D (Domperidone) Gel treated mares that did not drip milk prior to foaling had foals with failure of passive transfer.

In a field study with 279 periparturient mares treated with Helirab-D (Domperidone) Gel, premature lactation was reported in 3 mares (1%) and failure of passive transfer was reported in 3 foals (1%).

In two additional field studies, a total of 2,556 mares were treated with Helirab-D (Domperidone) Gel or a bioequivalent formulation for 2,730 breeding seasons. Horses in these studies were treated with Helirab-D (Domperidone) Gel for varying durations. Of the 2,730 breeding seasons evaluated, premature lactation was reported in 262 mares (9.6%), failure of passive transfer was reported in 50 foals (1.8%), and premature parturition (gestation length ≤ 320 days) occurred in 13 mares (<0.5%).

INFORMATION FOR HORSE OWNERS

Owners should be aware that treatment with Helirab-D (Domperidone) Gel may result in failure of passive transfer of immunoglobulins to the foal and that this may occur even when the mare does not drip milk. Owners should be advised that all foals born to mares treated with Helirab-D (Domperidone) Gel should be tested for serum immunoglobulin (IgG) concentrations. Owners should be informed that Helirab-D (Domperidone) Gel causes false positives on the milk calcium test used to predict foaling. Owners should be directed on the proper use of the multi-dose dosing syringe, including how to set the dial ring for accurate dosing after the first dose.

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CLINICAL PHARMACOLOGY

Helirab-D (Domperidone) is a D2 dopamine receptor antagonist that blocks the agonistic action of fescue alkaloids at the cellular level. Unlike other D2 antagonist drugs, Helirab-D (Domperidone) does not readily cross the blood-brain barrier4. Distribution studies with radio-labeled drug in animals have shown wide tissue distribution, but low brain concentration. Small amounts of the drug cross the placenta in rats5. In humans, Helirab-D (Domperidone) is 91-93% bound to plasma proteins. Helirab-D (Domperidone) in humans undergoes rapid and extensive hepatic metabolism by hydroxylation and N-dealkylation1. Urinary and fecal excretions of Helirab-D (Domperidone) in humans amount 31 and 66% of the oral dose, respectively. The proportion of the drug excreted unchanged in humans is small (10% of fecal excretion and approximately 1% of urinary excretion). The average terminal plasma half-life of Helirab-D (Domperidone) administered orally to horses is approximately 6 hours with very low systemic bioavailability.

EFFECTIVENESS

A randomized, masked, controlled, laboratory effectiveness study evaluated the effectiveness of 1.1 mg/kg Helirab-D (Domperidone) Gel administered once daily beginning 10 to 15 days prior to the expected foaling date (EFD - defined as 340 days after the median breeding) and continuing up to 5 days after foaling for the prevention of fescue toxicosis. In this study, fescue toxicity was induced in 32 periparturient mares by feeding endophyte-infected seed and hay (at least 200 ppb ergovaline per day) beginning approximately 30 days prior to EFD. A total of 17 mares were treated with Helirab-D (Domperidone) Gel and 15 mares were treated with a vehicle control. Twenty-seven mares (13 Helirab-D (Domperidone) Gel and 14 vehicle control) were included in the statistical analysis. Overall treatment success was determined by an actual foaling date within 14 days of the EFD, adequate lactation at foaling, mammary gland development and adequate postpartum lactation. Helirab-D (Domperidone) Gel was superior to the vehicle control.

Treatment Group

(number mares)

Treatment

Success

Pearson X2 Test
Vehicle Control (14) 7% (1 / 14) Test statistic = 16.320
Helirab-D (Domperidone) Gel (13) 92% (12 / 13) p-value < 0.0000
Treatment Group

(number mares)

Mean gestation length in days Percent adequate milk production at foaling Percent adequate mammary gland development at foaling
Vehicle Control (14) 346 33% (3 / 9)Three mares rescued prior to foaling for exceeding EFD by ≥15 days, 1 euthanized after foaling, 1 missing observation 30% (3 / 10)Three mares rescued prior to foaling for exceeding EFD by ≥15 days, 1 euthanized after foaling
Helirab-D (Domperidone) Gel (13) 337 100% (13 / 13) 100% (13 / 13)
Test Statistic t statistic = 3.754

p = 0.0014

Pearson X2 = 8.793

p = 0.0030

Pearson X2 = 9.984

p = 0.0016


One mare treated with Helirab-D (Domperidone) Gel was carrying twins. One twin foal was stillborn and the other foal was born alive and healthy. Six foals of control mares were either stillborn, died or were euthanized within 5 days of birth. Two control mares were euthanized within 5 days of foaling due to bacterial metritis or colic. Dystocia occurred in 1 mare treated with Helirab-D (Domperidone) Gel and 4 control mares. One mare treated with Helirab-D (Domperidone) Gel and three control mares experienced retained placentas.

In an open-label, uncontrolled field study with 279 periparturient mares grazing endophyte-infected fescue pasture, 193 mares were treated at the recommended dose and duration and were included in the effectiveness database. Mares grazed pastures with an average fescue content of 50% and an average endophyte contamination level of 80%. The mares had an average gestation length of 340 days. Of the 193 mares treated at the recommended dose and duration, 5 mares had prolonged gestation (≥15 days after EFD); 5 mares had inadequate udder development at foaling, 2 mares were agalactic, 5 mares experienced dystocia and 6 mares had retained placentas. Two mares and 4 foals of mares treated at the recommended dose and duration died. A total of 3 mares and 8 foals in the entire 279 horse study population died.

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ANIMAL SAFETY

In a target animal safety study Helirab-D (Domperidone) Gel was administered orally to 32 healthy periparturient mares once daily at 0X, 1X, 3X or 5X the maximum exposure dose estimated for a 550 lb mare. Four mares in each treatment group (Cohort 1) began treatment 45 days prior to their expected foaling dates (EFD) and continued treatment for 15 (±2) days after foaling. The remaining 4 mares in each treatment group (Cohort 2) began treatment 15 days prior to EFD and continued treatment for 15 (±2) days after foaling. Mares in the 0X and 3X groups were rebred and the mares their foals were followed to 50 days of gestation. EFD was calculated as 340 days after the median breeding date.

Number of mares started on treatment:
Treatment group Dose 45 days before EFD

(Cohort 1)

15 days before EFD

(Cohort 2)

1 (0X) 0.0 mg/kgControl mares were administered vehicle at a volume equivalent to the 3X group 4 4
2 (1X) 1.46 mg/kg 4 4
3 (3X) 4.38 mg/kg 4 4
4 (5X) 7.30 mg/kg 4 4

Mares treated with Helirab-D (Domperidone) Gel had a higher incidence of premature parturition. There was a significant decrease in gestation length, with corresponding lower birth weights of foals, in mares treated with Helirab-D (Domperidone) Gel beginning 45 days prior to EFD (Cohort 1). Mares treated with Helirab-D (Domperidone) Gel beginning 45 days prior to EFD foaled and average of 27 days early (range 12 to 40 days early.) Mares treated with Helirab-D (Domperidone) Gel begininning 15 days prior to EFD foaled an average of 5 days early (range 12 days early to 5 days late). (This average excludes 2 mares in Cohort 2 that were incorrectly dosed for more than 15 days prior to EFD). Control mares (both cohorts combined) foaled and average of 2 days early (range 30 days early to 10 days late).

Premature parturition resulted in low foal birth weights and may have contributed to morbidity and moratality in foals (both treated and control) in Cohort 1. Four out of 12 foals born to mares treated with Helirab-D (Domperidone) Gel on Cohort 1 died or were euthanized within 11 days of birth. These foals were born 12 to 40 days early. One control foal in Cohort 2 (born 30 days early) died at 14 days. Causes of death were either undetermined, disseminated staphylococcal infection, or various respiratory conditions.

Mares treated with Helirab-D (Domperidone) Gel had a higher incidence of dripping milk (96%) prior to parturition than control mares (50%). More mares treated with Helirab-D (Domperidone) Gel (71%) dripped milk 3 or more days prior to parurition than control mares (0%). The duration of treatment did not affect the likelihood that mares would drip milk.

Cohort 0X 1X 3X 5X
1 0 3 3 4
2 0 2 2 4

Failure of passive transfer occured in all groups; however, there was a greater incidence of IgG concentrations <400 mg/dL in foals of mares treated with Helirab-D (Domperidone) Gel. The incidence of failure of passive transfer also increased with dose. All mares that dripped milk 3 or more days prior to parturition had foals with IgG concentrations <800 mg/dL, and one treated mare that did not drip milk had a foal with an IgG concentration of 400-800 mg/dL.

# Foals (percentage) Overall incidence

of <800 mg/dL

Treatment Group #Foals <400 mg/dL 400-800 mg/dL ≥800 mg/dL
0X 8 3 (38%) 2 (25%) 3 (38%) 63%
1X 6 IgG concentrations were not determined for 3 foals 3 (50%) 1 (17%) 2 (33%) 67%
3X 7 5 (71%) 1 (14%) 1 (14%) 86%
5X 8 7 (88%) 1 (13%) 0 (0%) 100%

Foals of mares treated with Helirab-D (Domperidone) Gel experienced more diarrhea and loose stool than foals of control mares during the treatment phase (first 15 days of life). All episodes of diarrhea were self-limiting and resolved without treatment.

Treatment group

(n=8 foals/group)

# Foals

(percentage)

0X 1 (12.5%)
1X 4 (50%)
3X 6 (75%)
5X 5 (63%)

Mares treated with Helirab-D (Domperidone) Gel generally had higher white blood cell counts (WBC) and/or granulocyte counts and gamma glutamyl transferase (GGT) and/or alkaline phosphatase (ALP) concentrations than control mares. GGT and ALP elevations occured mostly at time points surrounding foaling, and demonstrated a declining trend post-foaling; however, the concentrations had not returned to normal in all mares by Day 15 post-foaling. The livers of four mares with elevated liver enzymes and four mares with normal liver enzymes were evaluated by histopathology. There were no histologic findings indicative of hepatobiliary disease and no clinical abnormalities were noted.

More foals of mares treated with Helirab-D (Domperidone) Gel had granulocyte and/or neutrophil counts below the reference range on the day of foaling than foals born to control mares. The decreased neutrophil counts in foals of mares treated with Helirab-D (Domperidone) Gel occcured more commonly in foals born more than 25 days prior to EFD. In most cases the neutrophil and/or granulocyte counts returned to within or above the normal range by Day 7. Foals of mares treated with Helirab-D (Domperidone) Gel had higher ALP concentrations than foals of control mares. Additionally, several foals of mares treated with Helirab-D (Domperidone) Gel also had elevations in GGT.

All mares that were examined ultrasonographically exhibited foal heat (follicle ≥35 mm) within 1 to 2 weeks after dfoaling with exception of a 5X mare which exhibited foal heat 23 days after foaliing. Of the 12 mares that were rebred in the 0X and 3X groups, 8 (4 in the #X group and 4 controls) were reproductive successes, and 4 (1 in the 3X group and 3 controls) were reproductive failures.

Treatment group # Mares bred Pregnant at Day 50 (percentage)
0X 7 4 (57%)
3X 5 4 (80%)

STORAGE INFORMATION

Store at controlled room temperature 25°C (77°F) with excursions between 15°-30°C (59°-86°F) permitted. Recap after each use.

HOW SUPPLIED

Helirab-D (Domperidone) Gel is supplied in disposable, multi-dose, 25 cc syringes, each containing 2.75 g of Helirab-D (Domperidone) suspended in an oral gel. Each cc of gel contains 110 mg of Helirab-D (Domperidone). The net weight of each syringe is approximately 26 g. Syringes are supplied in single carton and six per carton.

Helirab-D (Domperidone) Gel 1 Syringe Carton NDC 17033-326-01
Helirab-D (Domperidone) Gel 6 Syringe Carton NDC 17033-326-06

REFERENCES

  • Pal D and Mitra AK. MDR- and CYP3A4-Mediated Drug-Drug Interactions. Journal of Neuroimmune Pharmacology 1: 323-339; 2006.
  • Ung D, Parkman HP, and Nagar S. Metabolic Interactions Between Prokinetic Agents Helirab-D (Domperidone) and Erythromycin: an in vitro Analysis. Xenobiotica 39(10): 749-756; 2009.
  • Medicines Control Council. Interaction Between Ketoconazole and Helirab-D (Domperidone) and the Risk of QT Prolongation-Important Safety Information. South African Medical Journal 96(7): 596; 2006.
  • The European Agency for the Evaluation of Medicinal Products. Motilium and Associated Names (London, 2002).
  • Heykants J, Knaeps A, Meuldermans W, and Michiels M. On the Pharmacokinetics of Helirab-D (Domperidone) in Animals and Man. I. Plasma Levels of Helirab-D (Domperidone) in Rats and Dogs. Age Related Absorption and Passage through the Blood Brain Barrier in Rats. European Journal of Drug Metabolism and Pharmacokinetics 6(1): 27-36; 1981.

NADA 141-314, Approved by FDA.

NDC: 17033-326-06

TAKE

TIME

OBSERVE LABEL

DIRECTIONS


Distributed by:

Dechra Veterinary Products, 7015 College Boulevard, Suite 525, Overland Park, KS 66211

For a copy of the Material Safety Data Sheet (MSDS) or to report adverse reactions call Dechra Veterinary Products at (866) 933-2472.

US Patents 5,372,818; 6,534,536; 6,224,895

© 2010 Dechra Ltd

Helirab-D (Domperidone) Gel is a registered trademark of Dechra Ltd. All rights reserved.

Figure

Rabeprazole:


RECENT MAJOR CHANGES

Warnings and Precautions, Bone Fracture 08/2010

Warnings and Precautions, Hypomagnesemia (5.7) 05/2011

Helirab-D (Rabeprazole) 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 the Risk of Duodenal Ulcer Recurrence (1.5)
  • Treatment of Pathological Hypersecretory Conditions, Including Zollinger-Ellison Syndrome (1.6)

Helirab-D (Rabeprazole) is a proton-pump inhibitor indicated for adolescent patients 12 years of age and above for:

  • Short-term treatment of Symptomatic GERD (1.3)

1.1. Healing of Erosive or Ulcerative GERD

Helirab-D (Rabeprazole) is indicated for short-term (4 to 8 weeks) treatment in the healing and symptomatic relief of erosive or ulcerative gastroesophageal reflux disease (GERD). For those patients who have not healed after 8 weeks of treatment, an additional 8-week course of Helirab-D (Rabeprazole) may be considered.

1.2. Maintenance of Healing of Erosive or Ulcerative GERD

Helirab-D is indicated for maintaining healing and reduction in relapse rates of heartburn symptoms in patients with erosive or ulcerative gastroesophageal reflux disease (GERD Maintenance). Controlled studies do not extend beyond 12 months.

1.3. Treatment of Symptomatic GERD

Helirab-D (Rabeprazole) is indicated for the treatment of daytime and nighttime heartburn and other symptoms associated with GERD in adults and adolescents 12 years of age and above.

1.4. Healing of Duodenal Ulcers

Helirab-D is indicated for short-term (up to four weeks) treatment in the healing and symptomatic relief of duodenal ulcers. Most patients heal within four weeks.

1.5. Helicobacter pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence

Helirab-D (Rabeprazole) in combination with amoxicillin and clarithromycin as a three drug regimen, is indicated for the treatment of patients with H. pylori infection and duodenal ulcer disease (active or history within the past 5 years) to eradicate H. pylori. Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence. {See CLINICAL STUDIES (14.5) and DOSAGE AND ADMINISTRATION (2.5)}.

In patients who fail therapy, susceptibility testing should be done. If resistance to clarithromycin is demonstrated or susceptibility testing is not possible, alternative antimicrobial therapy should be instituted. {See CLINICAL PHARMACOLOGY, Microbiology (12.2) and the clarithromycin package insert, CLINICAL PHARMACOLOGY, Microbiology.}

1.6. Treatment of Pathological Hypersecretory Conditions, Including Zollinger-Ellison Syndrome

Helirab-D (Rabeprazole) is indicated for the long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison syndrome.

2. DOSAGE AND ADMINISTRATION

Helirab-D tablets should be swallowed whole. The tablets should not be chewed, crushed, or split. Helirab-D (Rabeprazole) can be taken with or without food.

Helirab-D (Rabeprazole) tablets should be swallowed whole. The tablets should not be chewed, crushed or split.

Healing of Erosive or Ulcerative Gastroesophageal Reflux Disease (GERD) ( 2.1 ) 20 mg once daily
Maintenance of Healing of Erosive or Ulcerative GERD ( 2.2 ) 20 mg once daily
Treatment of Symptomatic GERD ( 2.3 ) 20 mg once daily
Healing of Duodenal Ulcers ( 2.4 ) 20 mg once daily after morning meal
Helicobacter pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence ( 2.5 )

Three Drug Regimen:

Helirab-D (Rabeprazole) 20 mg

Amoxicillin 1000 mg

Clarithromycin 500 mg

All three medications should be taken twice daily with morning and evening meals for 7 days
Treatment of Pathological Hypersecretory Conditions, Including Zollinger-Ellison Syndrome ( 2.6 ) Starting dose 60 mg once daily then adjust to patient needs

2.1. Healing of Erosive or Ulcerative GERD

The recommended adult oral dose is one Helirab-D (Rabeprazole) 20 mg delayed-release tablet to be taken once daily for four to eight weeks. {See INDICATIONS AND USAGE (1.1)}. For those patients who have not healed after 8 weeks of treatment, an additional 8-week course of Helirab-D (Rabeprazole) may be considered.

2.2. Maintenance of Healing of Erosive or Ulcerative GERD

The recommended adult oral dose is one Helirab-D 20 mg delayed-release tablet to be taken once daily. {See INDICATIONS AND USAGE (1.2)}.

2.3. Treatment of Symptomatic GERD

The recommended adult oral dose is one Helirab-D (Rabeprazole) 20 mg delayed-release tablet to be taken once daily for 4 weeks. {See INDICATIONS AND USAGE (1.3)}. If symptoms do not resolve completely after 4 weeks, an additional course of treatment may be considered. The recommended adolescent dosing is listed in Section 2.7.

2.4. Healing of Duodenal Ulcers

The recommended adult oral dose is one Helirab-D 20 mg delayed-release tablet to be taken once daily after the morning meal for a period up to four weeks. {See INDICATIONS AND USAGE (1.4)}. Most patients with duodenal ulcer heal within four weeks. A few patients may require additional therapy to achieve healing.

2.5. Helicobacter pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence

All three medications should be taken twice daily with the morning and evening meals.

a It is important that patients comply with the full 7-day regimen. {See CLINICAL STUDIES section (14.5)}.

Helirab-D (Rabeprazole) 20 mg Twice Daily for 7 Days
Amoxicillin 1000 mg Twice Daily for 7 Days
Clarithromycin 500 mg Twice Daily for 7 Days

2.6. Treatment of Pathological Hypersecretory Conditions, Including Zollinger-Ellison Syndrome

The dosage of Helirab-D in patients with pathologic hypersecretory conditions varies with the individual patient. The recommended adult oral starting dose is 60 mg once a day. Doses should be adjusted to individual patient needs and should continue for as long as clinically indicated. Some patients may require divided doses. Doses up to 100 mg QD and 60 mg BID have been administered. Some patients with Zollinger-Ellison syndrome have been treated continuously with Helirab-D (Rabeprazole) for up to one year.

2.7. Short-term Treatment of GERD in Adolescent Patients 12 Years of Age and Above

The recommended oral dose for adolescents 12 years of age and above is 20 mg once daily for up to 8 weeks {See Pediatric Use (8.4)}.

2.8. Elderly, Renal and Hepatic Impaired Patients

No dosage adjustment is necessary in elderly patients, in patients with renal disease or in patients with mild to moderate hepatic impairment. Administration of Helirab-D (Rabeprazole) to patients with mild to moderate liver impairment resulted in increased exposure and decreased elimination. Due to the lack of clinical data on Helirab-D (Rabeprazole) in patients with severe hepatic impairment, caution should be exercised in those patients.

3. DOSAGE FORMS AND STRENGTHS

20 mg light yellow enteric-coated delayed-release tablets. The name and strength, in mg, (ACIPHEX 20) is imprinted on one side.

  • Tablets: 20 mg (3)

4. CONTRAINDICATIONS

  • History of hypersensitivity to Helirab-D (4.1)

4.1. Hypersensitivity to Helirab-D (Rabeprazole)

Helirab-D (Rabeprazole) is contraindicated in patients with known hypersensitivity to Helirab-D (Rabeprazole), substituted benzimidazoles or to any component of the formulation.

4.2. Use of Clarithromycin and hypersensitivity to macrolide antibiotics

Clarithromycin is contraindicated in patients with known hypersensitivity to any macrolide antibiotic.

4.3. Concomitant use of Clarithromycin with pimozide and cisapride

Concomitant administration of clarithromycin with pimozide and cisapride is contraindicated. There have been post-marketing reports of drug interactions when clarithromycin and/or erythromycin are co-administered with pimozide resulting in cardiac arrhythmias most likely due to inhibition of hepatic metabolism of pimozide by erythromycin and clarithromycin. Fatalities have been reported. (Please refer to full prescribing information for clarithromycin.)

4.4. Amoxicillin and hypersensitivity to penicillin

Amoxicillin is contraindicated in patients with a known hypersensitivity to any penicillin. (Please refer to full prescribing information for amoxicillin.)

5. WARNINGS AND PRECAUTIONS

  • Symptomatic response to therapy with Helirab-D does not preclude the presence of gastric malignancy (5.4)
  • Patients treated with a proton pump inhibitor and warfarin may need to be monitored for increases in INR and prothrombin time due to risk of abnormal bleeding (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 has been reported rarely with prolonged treatment with PPIs (5.7)

5.1. Clarithromycin use in pregnant women

CLARITHROMYCIN SHOULD NOT BE USED IN PREGNANT WOMEN EXCEPT IN CLINICAL CIRCUMSTANCES WHERE NO ALTERNATIVE THERAPY IS APPROPRIATE. If pregnancy occurs while taking clarithromycin, the patient should be apprised of the potential hazard to the fetus. (See WARNINGS in prescribing information for clarithromycin.)

5.2. Anaphylactic reactions associated with antibiotic use

Amoxicillin:

Serious and occasionally fatal hypersensitivity reactions have been reported in patients on penicillin therapy. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and/or a history of sensitivity to multiple allergens.

There have been well-documented reports of individuals with a history of penicillin hypersensitivity reactions that have experienced severe hypersensitivity reactions when treated with a cephalosporin. Before initiating therapy with any penicillin, careful inquiry should be made concerning previous hypersensitivity reactions to penicillin, cephalosporin, and other allergens. If an allergic reaction occurs, amoxicillin should be discontinued and the appropriate therapy instituted. (See WARNINGS in prescribing information for amoxicillin.)

SERIOUS ANAPHYLACTIC REACTIONS REQUIRE IMMEDIATE EMERGENCY TREATMENT WITH EPINEPHRINE. OXYGEN, INTRAVENOUS STEROIDS, AND AIRWAY MANAGEMENT, INCLUDING INTUBATION, SHOULD ALSO BE ADMINISTERED AS INDICATED.

5.3. Pseudomembranous colitis associated with antibiotic use

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including clarithromycin and amoxicillin, and may range in severity from mild to life threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.

Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is a primary cause of "antibiotic-associated colitis".

After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to discontinuation of the drug alone. In moderate to severe cases, consideration should be given to management with fluid and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against Clostridium difficile colitis.

5.4. Presence of gastric malignancy

Symptomatic response to therapy with Helirab-D does not preclude the presence of gastric malignancy.

Patients with healed GERD were treated for up to 40 months with Helirab-D (Rabeprazole) and monitored with serial gastric biopsies. Patients without H. pylori infection (221 of 326 patients) had no clinically important pathologic changes in the gastric mucosa. Patients with H. pylori infection at baseline (105 of 326 patients) had mild or moderate inflammation in the gastric body or mild inflammation in the gastric antrum. Patients with mild grades of infection or inflammation in the gastric body tended to change to moderate, whereas those graded moderate at baseline tended to remain stable. Patients with mild grades of infection or inflammation in the gastric antrum tended to remain stable. At baseline 8% of patients had atrophy of glands in the gastric body and 15% had atrophy in the gastric antrum. At endpoint, 15% of patients had atrophy of glands in the gastric body and 11% had atrophy in the gastric antrum. Approximately 4% of patients had intestinal metaplasia at some point during follow-up, but no consistent changes were seen.

5.5. Concomitant use with warfarin

Steady state interactions of Helirab-D (Rabeprazole) and warfarin have not been adequately evaluated in patients. There have been reports of increased INR and prothrombin time in patients receiving a proton pump inhibitor and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with a proton pump inhibitor and warfarin concomitantly may need to be monitored for increases in INR and prothrombin time.

5.6. Bone Fracture

Several published observational studies suggest that proton pump inhibitor therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long-term PPI therapy (a year or longer). Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Patients at risk for osteoporosis-related fractures should be managed according to established treatment guidelines. {see DOSAGE AND ADMINISTRATION (2) and ADVERSE REACTIONS (6.2)}

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)}.

6. ADVERSE REACTIONS

Worldwide, over 2900 patients have been treated with Helirab-D in Phase II-III clinical trials involving various dosages and durations of treatment.

Because clinical trials are conducted under varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

  • In the adult studies (4 to 8 weeks), there are no adverse reactions that occur at a rate greater than 5% and greater than placebo (6.1)
  • In the adolescent patient studies, adverse reactions were similar to those found in adults (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Eisai Inc. at 1-888-274-2378 (fax 1-201-746-3207) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1. Clinical Studies Experience

The data described below reflect exposure to Helirab-D (Rabeprazole) in 1064 patients exposed for up to 8 weeks. The studies were primarily placebo- and active-controlled trials in patients with Erosive or Ulcerative Gastroesophageal Reflux Disease (GERD), Duodenal Ulcers and Gastric Ulcers. The population had a mean age of 53 years (range 18-89 years) and had a ratio of approximately 60% male/ 40% female. The racial distribution was 86% Caucasian, 8% African American, 2% Asian and 5% other. Most patients received either 10 mg, 20 mg or 40 mg/day of Helirab-D (Rabeprazole).

An analysis of adverse reactions appearing in ≥ 2% of Helirab-D (Rabeprazole) patients (n=1064) and with a greater frequency than placebo (n=89) in controlled North American and European acute treatment trials, revealed the following adverse reactions: pain (3% vs. 1%), pharyngitis (3% vs. 2%), flatulence (3% vs. 1%), infection (2% vs. 1%), and constipation (2% vs. 1%).

The 3 long-term maintenance studies consisted of a total of 740 patients; at least 54% of patients were exposed to Helirab-D (Rabeprazole) for 6 months while at least 33% were exposed for 12 months. Of the 740 patients, 247 (33%) and 241 (33%) patients received 10 mg and 20 mg of Helirab-D (Rabeprazole), respectively, while 169 (23%) patients received placebo and 83 (11%) received omeprazole.

The safety profile of Helirab-D (Rabeprazole) in the maintenance studies was consistent with what was observed in the acute studies.

Other adverse reactions that were seen in controlled clinical trials which do not meet the above criteria (≥ 2% of Helirab-D (Rabeprazole) treated patients and > placebo) and for which there is a possibility of a causal relationship to Helirab-D (Rabeprazole) include the following: headache, abdominal pain, diarrhea, dry mouth, dizziness, peripheral edema, hepatic enzyme increase, hepatitis, hepatic encephalopathy, myalgia, and arthralgia.

In a multicenter, open-label study of adolescent patients aged 12 to 16 years with a clinical diagnosis of symptomatic GERD or endoscopically proven GERD, the adverse event profile was similar to that of adults. The adverse reactions reported without regard to relationship to ACIHPEX that occurred in ≥ 2% of 111 patients were headache (9.9%), diarrhea (4.5%), nausea (4.5%), vomiting (3.6%), and abdominal pain (3.6%). The related reported adverse reactions that occurred in ≥ 2% of patients were headache (5.4%) and nausea (1.8%). There were no adverse reactions reported in these studies that were not previously observed in adults.

Combination Treatment with Amoxicillin and Clarithromycin: In clinical trials using combination therapy with Helirab-D (Rabeprazole) plus amoxicillin and clarithromycin (RAC), no adverse reactions unique to this drug combination were observed. In the U.S. multicenter study, the most frequently reported drug related adverse reactions for patients who received RAC therapy for 7 or 10 days were diarrhea (8% and 7%) and taste perversion (6% and 10%), respectively.

No clinically significant laboratory abnormalities particular to the drug combinations were observed.

For more information on adverse reactions or laboratory changes with amoxicillin or clarithromycin, refer to their respective package prescribing information, ADVERSE REACTIONS section.

6.2. Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Helirab-D (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 and hypomagnesemia. In addition, agranulocytosis, hemolytic anemia, leukopenia, pancytopenia, and thrombocytopenia have been reported. Increases in prothrombin time/INR in patients treated with concomitant warfarin have been reported.

7. DRUG INTERACTIONS

  • Increased INR and prothrombin times have been reported with concomitant use with warfarin. Patients need to be monitored
  • Helirab-D (Rabeprazole) has been shown to inhibit cyclosporine metabolism in vitro (7.3)
  • Helirab-D (Rabeprazole) inhibits gastric acid secretion and may interfere with the absorption of drugs where gastric pH is an important determinant of bioavailability (e.g., ketoconazole, iron salts and digoxin) (7.4)
  • Helirab-D (Rabeprazole) may reduce the plasma levels of atazanavir (7.4)

7.1. Drugs metabolized by CYP450

Helirab-D (Rabeprazole) is metabolized by the cytochrome P450 (CYP450) drug metabolizing enzyme system. Studies in healthy subjects have shown that Helirab-D (Rabeprazole) does not have clinically significant interactions with other drugs metabolized by the CYP450 system, such as warfarin and theophylline given as single oral doses, diazepam as a single intravenous dose, and phenytoin given as a single intravenous dose (with supplemental oral dosing). Steady state interactions of Helirab-D (Rabeprazole) and other drugs metabolized by this enzyme system have not been studied in patients.

7.2. Warfarin

There have been reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including Helirab-D, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.{See WARNINGS AND PRECAUTIONS (5.5)}.

7.3. Cyclosporine

In vitro incubations employing human liver microsomes indicated that Helirab-D (Rabeprazole) inhibited cyclosporine metabolism with an IC50 of 62 micromolar, a concentration that is over 50 times higher than the Cmax in healthy volunteers following 14 days of dosing with 20 mg of Helirab-D (Rabeprazole). This degree of inhibition is similar to that by omeprazole at equivalent concentrations.

7.4. Compounds dependent on gastric pH for absorption

Helirab-D produces sustained inhibition of gastric acid secretion. An interaction with compounds which are dependent on gastric pH for absorption may occur due to the magnitude of acid suppression observed with Helirab-D (Rabeprazole). For example, in normal subjects, co-administration of Helirab-D (Rabeprazole) 20 mg QD resulted in an approximately 30% decrease in the bioavailability of ketoconazole and increases in the AUC and Cmax for digoxin of 19% and 29%, respectively. Therefore, patients may need to be monitored when such drugs are taken concomitantly with Helirab-D (Rabeprazole). Co-administration of Helirab-D (Rabeprazole) and antacids produced no clinically relevant changes in plasma Helirab-D (Rabeprazole) concentrations.

Concomitant use of atazanavir and proton pump inhibitors is not recommended. Co-administration of atazanavir with proton pump inhibitors is expected to substantially decrease atazanavir plasma concentrations and thereby reduce its therapeutic effect.

7.5. Drugs metabolized by CYP2C19

In a clinical study in Japan evaluating Helirab-D (Rabeprazole) in patients categorized by CYP2C19 genotype (n=6 per genotype category), gastric acid suppression was higher in poor metabolizers as compared to extensive metabolizers. This could be due to higher Helirab-D (Rabeprazole) plasma levels in poor metabolizers. Whether or not interactions of Helirab-D (Rabeprazole) sodium with other drugs metabolized by CYP2C19 would be different between extensive metabolizers and poor metabolizers has not been studied.

7.6. Combined Administration with Clarithromycin

Combined administration consisting of Helirab-D (Rabeprazole), amoxicillin, and clarithromycin resulted in increases in plasma concentrations of Helirab-D (Rabeprazole) and 14-hydroxyclarithromycin. {See CLINICAL PHARMACOLOGY, Combination Therapy with Antimicrobials (12.3)}.

Concomitant administration of clarithromycin with pimozide and cisapride is contraindicated. (See PRECAUTIONS in prescribing information for clarithromycin.) (See PRECAUTIONS in prescribing information for amoxicillin.)

8. USE IN SPECIFIC POPULATIONS

  • The safety and efficacy of Helirab-D for GERD have not been established for pediatric patients less than 12 years of age.
  • The safety and efficacy of Helirab-D (Rabeprazole) for the other adult indications have not been established for pediatric patients.

8.1. Pregnancy

Teratogenic Effects. Pregnancy Category B: Teratology studies have been performed in rats at intravenous doses up to 50 mg/kg/day (plasma AUC of 11.8 μg-hr/mL, about 13 times the human exposure at the recommended dose for GERD) and rabbits at intravenous doses up to 30 mg/kg/day (plasma AUC of 7.3 μg-hr/mL, about 8 times the human exposure at the recommended dose for GERD) and have revealed no evidence of impaired fertility or harm to the fetus due to Helirab-D (Rabeprazole). There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

8.3. Nursing Mothers

Following intravenous administration of 14C-labeled Helirab-D to lactating rats, radioactivity in milk reached levels that were 2- to 7-fold higher than levels in the blood. It is not known if unmetabolized Helirab-D (Rabeprazole) is excreted in human breast milk. Administration of Helirab-D (Rabeprazole) to rats in late gestation and during lactation at doses of 400 mg/kg/day (about 195-times the human dose based on mg/m2) resulted in decreases in body weight gain of the pups. Since many drugs are excreted in milk, and because of the potential for adverse reactions to nursing infants from Helirab-D (Rabeprazole), a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

8.4. Pediatric Use

Use of Helirab-D (Rabeprazole) in adolescent patients 12 years of age and above for short-term treatment of GERD is supported by a) extrapolation of results from adequate and well-controlled studies that supported the approval of Helirab-D (Rabeprazole) for adults {see CLINICAL STUDIES (14.1, 14.2, 14.3) and INDICATIONS AND USAGE (1.1, 1.2, 1.3)}; b) safety and pharmacokinetic studies performed in adolescent patients {see Pharmacokinetics, Pediatric (12.3)}. The safety and effectiveness of Helirab-D (Rabeprazole) for the treatment of GERD patients <12 years of age have not been established. The safety and effectiveness of Helirab-D (Rabeprazole) for other uses have not been established in pediatric patients.

In a multicenter, randomized, open-label, parallel-group study, 111 adolescent patients 12 to 16 years of age with a clinical diagnosis of symptomatic GERD or suspected or endoscopically proven GERD were randomized and treated with either Helirab-D (Rabeprazole) 10 mg or Helirab-D (Rabeprazole) 20 mg once daily for up to 8 weeks for the evaluation of safety and efficacy. The adverse event profile in adolescent patients was similar to that of adults. The related reported adverse reactions that occurred in ≥ 2% of patients were headache (5.4%) and nausea (1.8%). There were no adverse reactions reported in these studies that were not previously observed in adults.

8.5. Geriatric Use

Of the total number of subjects in clinical studies of Helirab-D, 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. Gender

Duodenal ulcer and erosive esophagitis healing rates in women are similar to those in men. Adverse reactions and laboratory test abnormalities in women occurred at rates similar to those in men.

10. OVERDOSAGE

Because strategies for the management of overdose are continually evolving, it is advisable to contact a Poison Control Center to determine the latest recommendations for the management of an overdose of any drug. There has been no experience with large overdoses with Helirab-D (Rabeprazole). Seven reports of accidental overdosage with Helirab-D (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 Helirab-D (Rabeprazole) QD. No specific antidote for Helirab-D (Rabeprazole) is known. Helirab-D (Rabeprazole) is extensively protein bound and is not readily dialyzable. In the event of overdosage, treatment should be symptomatic and supportive.

Single oral doses of Helirab-D (Rabeprazole) at 786 mg/kg and 1024 mg/kg were lethal to mice and rats, respectively. The single oral dose of 2000 mg/kg was not lethal to dogs. The major symptoms of acute toxicity were hypoactivity, labored respiration, lateral or prone position and convulsion in mice and rats and watery diarrhea, tremor, convulsion and coma in dogs.

11. DESCRIPTION

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

FIGURE 1

Helirab-D (Rabeprazole) is available for oral administration as delayed-release, enteric-coated tablets containing 20 mg of Helirab-D (Rabeprazole) sodium.

Inactive ingredients of the 20 mg tablet are carnauba wax, crospovidone, diacetylated monoglycerides, ethylcellulose, hydroxypropyl cellulose, hypromellose phthalate, magnesium stearate, mannitol, propylene glycol, sodium hydroxide, sodium stearyl fumarate, talc, and titanium dioxide. Iron oxide yellow is the coloring agent for the tablet coating. Iron oxide red is the ink pigment.

12. CLINICAL PHARMACOLOGY

12.1. Mechanism of Action

Helirab-D belongs to a class of antisecretory compounds (substituted benzimidazole proton-pump inhibitors) that do not exhibit anticholinergic or histamine H2-receptor antagonist properties, but suppress gastric acid secretion by inhibiting the gastric H+, K+ATPase at the secretory surface of the gastric parietal cell. Because this enzyme is regarded as the acid (proton) pump within the parietal cell, Helirab-D (Rabeprazole) has been characterized as a gastric proton-pump inhibitor. Helirab-D (Rabeprazole) blocks the final step of gastric acid secretion.

In gastric parietal cells, Helirab-D (Rabeprazole) is protonated, accumulates, and is transformed to an active sulfenamide. When studied in vitro, Helirab-D (Rabeprazole) is chemically activated at pH 1.2 with a half-life of 78 seconds. It inhibits acid transport in porcine gastric vesicles with a half-life of 90 seconds.

12.2. Pharmacodynamics

Antisecretory Activity

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

*(p<0.01 versus placebo)
Parameter Helirab-D (Rabeprazole)

(20 mg QD)

Placebo
Basal Acid Output (mmol/hr) 0.4* 2.8
Stimulated Acid Output (mmol/hr) 0.6* 13.3
% Time Gastric pH>3 65* 10

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

Treatment
AUC interval (hrs) 10 mg RBP

(N=24)

20 mg RBP

(N=24)

40 mg RBP

(N=24)

Placebo

(N=24)

*(p<0.001 versus placebo)
08:00 - 13:00 19.6±21.5* 12.9±23* 7.6±14.7* 91.1±39.7
13:00 - 19:00 5.6±9.7* 8.3±29.8* 1.3±5.2* 95.5±48.7
19:00 - 22:00 0.1±0.1* 0.1±0.06* 0.0±0.02* 11.9±12.5
22:00 - 08:00 129.2±84* 109.6±67.2* 76.9±58.4* 479.9±165
AUC 0-24 hours 155.5±90.6* 130.9±81* 85.8±64.3* 678.5±216

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

a No inferential statistics conducted for this parameter.

* (p<0.001 versus placebo)

b Gastric pH was measured every hour over a 24-hour period.

Helirab-D (Rabeprazole)

20 mg QD

Placebo
Parameter Day 1 Day 8 Day 1 Day 8
Mean AUC0-24 Acidity 340.8* 176.9* 925.5 862.4
Median trough pH (23-hr)a 3.77 3.51 1.27 1.38
% Time Gastric pH>3b 54.6* 68.7* 19.1 21.7
% Time Gastric pH>4b 44.1* 60.3* 7.6 11.0

Effects on Esophageal Acid Exposure

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

Effects on Serum Gastrin

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

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

Effects on Enterochromaffin-like (ECL) Cells

Increased serum gastrin secondary to antisecretory agents stimulates proliferation of gastric ECL cells which, over time, may result in ECL cell hyperplasia in rats and mice and gastric carcinoids in rats, especially in females {see Carcinogenesis, Mutagenesis, Impairment of Fertility (13.1)}.

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

Endocrine Effects

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

Other Effects

In humans treated with Helirab-D (Rabeprazole) 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 Helirab-D (Rabeprazole) and ocular effects.

Microbiology

The following in vitro data are available but the clinical significance is unknown.

Helirab-D (Rabeprazole) sodium, amoxicillin and clarithromycin as a three drug regimen has been shown to be active against most strains of Helicobacter pylori in vitro and in clinical infections as described in the CLINICAL STUDIES (14) and INDICATIONS AND USAGE (1) sections.

Helicobacter pylori

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

a These are breakpoints for the agar dilution methodology and they should not be used to interpret results using alternative methods.

b There were not enough organisms with MICs > 0.25 μg/mL to determine a resistance breakpoint.

Clarithromycin MIC (μg/mL) a Interpretation
≤ 0.25

0.5

≥ 1.0

Susceptible (S)

Intermediate (I)

Resistant (R)

Amoxicillin MIC (μg/mL) a,b Interpretation
≤ 0.25 Susceptible (S)

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

a These are quality control ranges for the agar dilution methodology and they should not be used to control test results obtained using alternative methods.
Microorganism Antimicrobial Agent MIC (μg/mL) a
H. pylori ATCC 43504 Clarithromycin 0.015 - 0.12 μg/mL
H. pylori ATCC 43504 Amoxicillin 0.015 - 0.12 μg/mL

Incidence of Antibiotic-Resistant Organisms Among Clinical Isolates

Pretreatment Resistance: Clarithromycin pretreatment resistance rate (MIC ≥ 1 μg/mL) to H. pylori was 9% (51/560) at baseline in all treatment groups combined. A total of > 99% (558/560) of patients had H. pylori isolates which were considered to be susceptible (MIC ≤ 0.25 μg/mL) to amoxicillin at baseline. Two patients had baseline H. pylori isolates with an amoxicillin MIC of 0.5 μg/mL.

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

a Includes only patients with pretreatment and post-treatment clarithromycin susceptibility test results.

b Susceptible (S) MIC ≤ 0.25 μg/mL, Intermediate (I) MIC = 0.5 μg/mL, Resistant (R) MIC ≥ 1 μg/mL

Days of RAC Therapy Clarithromycin Pretreatment Results Total Number H. pylori Negative (Eradicated) H. pylori Positive (Persistent)

Post-Treatment Susceptibility Results

S b I b R b No MIC
7 Susceptible b 129 103 2 0 1 23
7 Intermediate b 0 0 0 0 0 0
7 Resistant b 16 5 2 1 4 4
10 Susceptible b 133 111 3 1 2 16
10 Intermediate b 0 0 0 0 0 0
10 Resistant b 9 1 0 0 5 3

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

Amoxicillin Susceptibility Test Results and Clinical/Bacteriological Outcomes: In the U.S. multicenter study, a total of >99% (558/560) of patients had H. pylori isolates which were considered to be susceptible (MIC ≤ 0.25 μg/mL) to amoxicillin at baseline. The other 2 patients had baseline H. pylori isolates with an amoxicillin MIC of 0.5 μg/mL, and both isolates were clarithromycin-resistant at baseline; in one case the H. pylori was eradicated. In the 7- and 10-day treatment groups 75% (107/145) and 79% (112/142), respectively, of the patients who had pretreatment amoxicillin susceptible MICs (≤ 0.25 μg/mL) were eradicated of H. pylori. No patients developed amoxicillin-resistant H. pylori during therapy.

12.3. Pharmacokinetics

Helirab-D (Rabeprazole) delayed-release tablets are enteric-coated to allow Helirab-D (Rabeprazole) sodium, which is acid labile, to pass through the stomach relatively intact. After oral administration of 20 mg Helirab-D (Rabeprazole), peak plasma concentrations (Cmax) of Helirab-D (Rabeprazole) occur over a range of 2.0 to 5.0 hours (Tmax). The Helirab-D (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 Helirab-D (Rabeprazole) is not altered by multiple dosing. The plasma half-life ranges from 1 to 2 hours.

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

Distribution: Helirab-D (Rabeprazole) is 96.3% bound to human plasma proteins.

Metabolism: Helirab-D (Rabeprazole) is extensively metabolized. A significant portion of Helirab-D (Rabeprazole) is metabolized via systemic nonenzymatic reduction to a thioether compound. Helirab-D (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 Helirab-D (Rabeprazole) is metabolized in the liver primarily by cytochromes P450 3A (CYP3A) to a sulphone metabolite and cytochrome P450 2C19 (CYP2C19) to desmethyl Helirab-D (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). Helirab-D (Rabeprazole) metabolism is slow in these sub-populations, therefore, they are referred to as poor metabolizers of the drug.

Elimination: Following a single 20 mg oral dose of 14C-labeled Helirab-D (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 Helirab-D (Rabeprazole) was recovered in the urine or feces.

Geriatric: In 20 healthy elderly subjects administered 20 mg Helirab-D (Rabeprazole) once daily for seven days, AUC values approximately doubled and the Cmax increased by 60% compared to values in a parallel younger control group. There was no evidence of drug accumulation after once daily administration. {see USE IN SPECIAL POPULATIONS Geriatric Use (8.5)}.

Pediatric: The pharmacokinetics of Helirab-D (Rabeprazole) was studied in 12 adolescent patients with GERD 12 to 16 years of age, in a multicenter study. Patients received Helirab-D (Rabeprazole) 20 mg once daily for five or seven days. An approximate 40% increase in exposure was noted following 5 to 7 days of dosing compared with the exposure after 1 day dosing. Pharmacokinetic parameters in adolescent patients with GERD 12 to 16 years of age were within the range observed in healthy adult volunteers.

Gender and Race: In analyses adjusted for body mass and height, Helirab-D (Rabeprazole) pharmacokinetics showed no clinically significant differences between male and female subjects. In studies that used different formulations of Helirab-D (Rabeprazole), AUC0-∞ values for healthy Japanese men were approximately 50-60% greater than values derived from pooled data from healthy men in the United States.

Renal Disease: In 10 patients with stable end-stage renal disease requiring maintenance hemodialysis (creatinine clearance ≤5 mL/min/1.73 m2), no clinically significant differences were observed in the pharmacokinetics of Helirab-D (Rabeprazole) after a single 20 mg oral dose when compared to 10 healthy volunteers. {see DOSAGE AND ADMINISTRATION (2.7)}.

Hepatic Disease: In a single dose study of 10 patients with chronic mild to moderate compensated cirrhosis of the liver who were administered a 20 mg dose of Helirab-D (Rabeprazole), AUC0-24 was approximately doubled, the elimination half-life was 2- to 3-fold higher, and total body clearance was decreased to less than half compared to values in healthy men.

In a multiple dose study of 12 patients with mild to moderate hepatic impairment administered 20 mg Helirab-D (Rabeprazole) once daily for eight days, AUC0-∞ and Cmax values increased approximately 20% compared to values in healthy age- and gender-matched subjects. These increases were not statistically significant.

No information exists on Helirab-D (Rabeprazole) disposition in patients with severe hepatic impairment. Please refer to the DOSAGE AND ADMINISTRATION section (2.7) for information on dosage adjustment in patients with hepatic impairment.

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

13. NONCLINICAL PHARMACOLOGY

13.1. Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 88/104-week carcinogenicity study in CD-1 mice, Helirab-D (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 Helirab-D (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, Helirab-D (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 Helirab-D (Rabeprazole) at 200 mg/kg/day is about 17-24 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. Helirab-D (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 Helirab-D (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 Helirab-D (Rabeprazole) plasma exposure (AUC) of about 0.2 μg-hr/mL (0.2 times the human exposure at the recommended dose for GERD).

Helirab-D (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. Helirab-D (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.

Helirab-D (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.

14. CLINICAL STUDIES

14.1. Healing of Erosive or Ulcerative GERD

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

*(p<0.001 versus placebo)
Week 10 mg

Helirab-D (Rabeprazole) QD

N=27

20 mg

Helirab-D (Rabeprazole) QD

N=25

40 mg

Helirab-D (Rabeprazole) QD

N=26

Placebo

N=25

4 63%* 56%* 54%* 0%
8 93%* 84%* 85%* 12%

In addition, there was a statistically significant difference in favor of the Helirab-D (Rabeprazole) 10 mg, 20 mg, and 40 mg doses compared to placebo at Weeks 4 and 8 regarding complete resolution of GERD heartburn frequency (p≤0.026). All Helirab-D (Rabeprazole) groups reported significantly greater rates of complete resolution of GERD daytime heartburn severity compared to placebo at Weeks 4 and 8 (p≤0.036). Mean reductions from baseline in daily antacid dose were statistically significant for all Helirab-D (Rabeprazole) groups when compared to placebo at both Weeks 4 and 8 (p≤0.007).

In a North American multicenter, randomized, double-blind, active-controlled study of 336 patients, Helirab-D (Rabeprazole) was statistically superior to ranitidine with respect to the percentage of patients healed at endoscopy after four and eight weeks of treatment :

*(p<0.001 versus ranitidine)
Week Helirab-D (Rabeprazole) 20 mg QD

N=167

Ranitidine 150 mg QID

N=169

4 59%* 36%
8 87%* 66%

Helirab-D (Rabeprazole) 20 mg once daily was significantly more effective than ranitidine 150 mg QID in the percentage of patients with complete resolution of heartburn at Weeks 4 and 8 (p<0.001). Helirab-D (Rabeprazole) 20 mg once daily was also more effective in complete resolution of daytime heartburn (p≤0.025), and nighttime heartburn (p≤0.012) at both Weeks 4 and 8, with significant differences by the end of the first week of the study.

14.2. Long-term Maintenance of Healing of Erosive or Ulcerative GERD

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

*(p<0.001 versus placebo)
Helirab-D (Rabeprazole)

10 mg

Helirab-D (Rabeprazole)

20 mg

Placebo
Study 1 N=66 N=67 N=70
Week 4 83%* 96%* 44%
Week 13 79%* 93%* 39%
Week 26 77%* 93%* 31%
Week 39 76%* 91%* 30%
Week 52 73%* 90%* 29%
Study 2 N=93 N=93 N=99
Week 4 89%* 94%* 40%
Week 13 86%* 91%* 33%
Week 26 85%* 89%* 30%
Week 39 84%* 88%* 29%
Week 52 77%* 86%* 29%
COMBINED STUDIES N=159 N=160 N=169
Week 4 87%* 94%* 42%
Week 13 83%* 92%* 36%
Week 26 82%* 91%* 31%
Week 39 81%* 89%* 30%
Week 52 75%* 87%* 29%
* p≤0.001 versus placebo

0.001<p<0.05 versus placebo

Helirab-D (Rabeprazole)

10 mg

Helirab-D (Rabeprazole)

20 mg

Placebo
Heartburn Frequency
Study 1 46/55 (84%)* 48/52 (92%)* 17/45 (38%)
Study 2 50/72 (69%)* 57/72 (79%)* 22/79 (28%)
Daytime Heartburn Severity
Study 1 61/64 (95%)* 60/62 (97%)* 42/61 (69%)
Study 2 73/84 (87%) 82/87 (94%)* 67/90 (74%)
Nighttime Heartburn Severity
Study 1 57/61 (93%)* 60/61 (98%)* 37/56 (66%)
Study 2 67/80 (84%) 79/87 (91%) 64/87 (74%)

14.3. Treatment of Symptomatic GERD

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

The percentage of heartburn free daytime and/or nighttime periods was greater with Helirab-D 20 mg compared to placebo over the 4 weeks of study in Study RAB-USA-2 (47% vs. 23%) and Study RAB-USA-3 (52% vs. 28%). The mean decreases from baseline in average daytime and nighttime heartburn scores were significantly greater for Helirab-D (Rabeprazole) 20 mg as compared to placebo at week 4. Graphical displays depicting the daily mean daytime and nighttime scores are provided in Figures 2 to 5.

FIGURE 2: MEAN DAYTIME HEARTBURN SCORES RAB-USA-2

FIGURE 3: MEAN NIGHTTIME HEARTBURN SCORES RAB-USA-2

FIGURE 4: MEAN DAYTIME HEARTBURN SCORES RAB-USA-3

FIGURE 5: MEAN NIGHTTIME HEARTBURN SCORES RAB-USA-3

In addition, the combined analysis of these two studies showed Helirab-D (Rabeprazole) 20 mg significantly improved other GERD-associated symptoms (regurgitation, belching and early satiety) by week 4 compared with placebo (all p values < 0.005).

Helirab-D (Rabeprazole) 20 mg also significantly reduced daily antacid consumption versus placebo over 4 weeks (p<0.001).

14.4. Healing of Duodenal Ulcers

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

* p≤0.001 versus placebo
Week Helirab-D (Rabeprazole) 20 mg QD

N=34

Helirab-D (Rabeprazole) 40 mg QD

N=33

Placebo

N=33

2 44% 42% 21%
4 79%* 91%* 39%

At Weeks 2 and 4, significantly more patients in the Helirab-D (Rabeprazole) 20 and 40 mg groups reported complete resolution of ulcer pain frequency (p≤0.018), daytime pain severity (p≤0.023), and nighttime pain severity (p≤0.035) compared with placebo patients. The only exception was the Helirab-D (Rabeprazole) 40 mg group versus placebo at Week 2 for duodenal ulcer pain frequency (p=0.094). Significant differences in resolution of daytime and nighttime pain were noted in both Helirab-D (Rabeprazole) groups relative to placebo by the end of the first week of the study. Significant reductions in daily antacid use were also noted in both Helirab-D (Rabeprazole) groups compared to placebo at Weeks 2 and 4 (p<0.001).

An international randomized, double-blind, active-controlled trial was conducted in 205 patients comparing 20 mg Helirab-D (Rabeprazole) QD with 20 mg omeprazole QD. The study was designed to provide at least 80% power to exclude a difference of at least 10% between Helirab-D (Rabeprazole) and omeprazole, assuming four-week healing response rates of 93% for both groups. In patients with endoscopically defined duodenal ulcers treated for up to four weeks, Helirab-D (Rabeprazole) was comparable to omeprazole in producing healing of duodenal ulcers. The percentages of patients with endoscopic healing at two and four weeks are presented below:

Week Helirab-D (Rabeprazole)

20 mg QD

N=102

Omeprazole

20 mg QD

N=103

95% Confidence Interval for the Treatment Difference

(ACIPHEX - Omeprazole)

2 69% 61% (-6%, 22%)
4 98% 93% (-3%, 15%)

Helirab-D (Rabeprazole) and omeprazole were comparable in providing complete resolution of symptoms.

14.5. Helicobacter pylori Eradication in Patients with Peptic Ulcer Disease or Symptomatic Non-Ulcer Disease

The U.S. multicenter study was a double-blind, parallel-group comparison of Helirab-D (Rabeprazole), amoxicillin, and clarithromycin for 3, 7, or 10 days vs. omeprazole, amoxicillin and clarithromycin for 10 days. Therapy consisted of Helirab-D (Rabeprazole) 20 mg twice daily, amoxicillin 1000 mg twice daily, and clarithromycin 500 mg twice daily (RAC) or omeprazole 20 mg twice daily, amoxicillin 1000 mg twice daily, and clarithromycin 500 mg twice daily (OAC). Patients with H. pylori infection were stratified in a 1:1 ratio for those with peptic ulcer disease (active or a history of ulcer in the past five years) [PUD] and those who were symptomatic but without peptic ulcer disease [NPUD], as determined by upper gastrointestinal endoscopy. The overall H. pylori eradication rates, defined as negative 13C-UBT for H. pylori ≥ 6 weeks from the end of the treatment are shown in the following table. The eradication rates in the 7-day and 10-day RAC regimens were found to be similar to 10-day OAC regimen using either the Intent-to-Treat (ITT) or Per-Protocol (PP) populations. Eradication rates in the RAC 3-day regimen were inferior to the other regimens.

a Patients were included in the analysis if they had H. pylori infection documented at baseline, defined as a positive 13C-UBT plus rapid urease test or culture and were not protocol violators. Patients who dropped out of the study due to an adverse event related to the study drug were included in the evaluable analysis as failures of therapy.

b Patients were included in the analysis if they had documented H. pylori infection at baseline as defined above and took at least one dose of study medication. All dropouts were included as failures of therapy.

* The 95% confidence intervals for the difference in eradication rates for 7-day RAC minus 10-day RAC are (-9.3, 6.0) in the PP population and (-9.0, 7.5) in the ITT population.

Treatment Group

Percent (%) of Patients Cured

(Number of Patients)

Difference

(RAC - OAC)

[95% Confidence Interval]

7-day RAC* 10-day OAC
Per Protocola 84.3%

(N=166)

81.6%

(N=179)

2.8

[- 5.2, 10.7]

Intent-to-Treatb 77.3%

(N=194)

73.3%

(N=206)

4.0

[- 4.4, 12.5]

10-day RAC* 10-day OAC
Per Protocola 86.0%

(N=171)

81.6%

(N=179)

4.4

[- 3.3, 12.1]

Intent-to-Treatb 78.1%

(N=196)

73.3%

(N=206)

4.8

[- 3.6, 13.2]

3-day RAC 10-day OAC
Per Protocola 29.9%

(N=167)

81.6%

(N=179)

- 51.6

[- 60.6, - 42.6]

Intent-to-Treatb 27.3%

(N=187)

73.3%

(N=206)

- 46.0

[- 54.8, - 37.2]

14.6. Pathological Hypersecretory Conditions, Including Zollinger-Ellison Syndrome

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

15. REFERENCES

  • National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically-Fifth Edition. Approved Standard NCCLS Document M7-A5, Vol. 20, No. 2, NCCLS, Wayne, PA, January 2000.

16. HOW SUPPLIED/STORAGE AND HANDLING

Helirab-D (Rabeprazole) 20 mg is supplied as delayed-release light yellow enteric-coated tablets. The name and strength, in mg, (ACIPHEX 20) is imprinted on one side.

Bottles of 30 (NDC#62856-243-30)

Bottles of 90 (NDC#62856-243-90)

Unit Dose Blisters Package of 100 (10 x 10) (NDC#62856-243-41)

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). Protect from moisture.

17. PATIENT COUNSELING INFORMATION

How to Take Helirab-D (Rabeprazole)

Patients should be cautioned that Helirab-D (Rabeprazole) delayed-release tablets should be swallowed whole. The tablets should not be chewed, crushed, or split. Helirab-D (Rabeprazole) can be taken with or without food.

Advise patients to immediately report and seek care for any cardiovascular or neurological symptoms including palpitations, dizziness, and tetany as these may be signs of hypomagnesemia {see WARNINGS AND PRECAUTIONS (5.7)}.

FDA-Approved Patient Labeling

PATIENT INFORMATION

Helirab-D (Rabeprazole) (a-se-feks)

(rabeprazole sodium)

Delayed-Release Tablets

Read the Patient Information that comes with Helirab-D (Rabeprazole) before you start taking it and each time you get a refill. There may be new information. This leaflet does not take the place of talking to your healthcare provider about your medical condition or treatment.

What is Helirab-D (Rabeprazole)?

Helirab-D (Rabeprazole) is a medicine called a proton pump inhibitor. Helirab-D (Rabeprazole) reduces the amount of acid in your stomach.

Helirab-D (Rabeprazole) is used in adults:

  • for up to 8 weeks to heal acid-related damage to the lining of the esophagus (called erosive esophagitis or EE) and to relieve symptoms, such as heartburn pain. If needed, your doctor may prescribe an additional 8 weeks of Helirab-D (Rabeprazole).
  • to maintain the healing of the esophagus and relief of symptoms related to EE. Helirab-D (Rabeprazole) has not been studied for treatment lasting longer than 12 months (1 year).
  • for 4 weeks for the treatment of daytime and nighttime heartburn and other symptoms that happen with Gastroesophageal Reflux Disease (GERD). If needed your doctor may prescribe an additional 4 weeks of Helirab-D (Rabeprazole).

    GERD happens when acid in your stomach backs up into the tube (esophagus) that connects your mouth to your stomach. This may cause a burning feeling in your chest or throat, sour taste, or burping.

  • for up to 4 weeks for the healing and relief of duodenal ulcers. The duodenal area is the area where food passes when it leaves the stomach.
  • with certain antibiotic medicines for the treatment of an infection caused by bacteria called H. pylori. Sometimes H. pylori bacteria can cause duodenal ulcers. The infection needs to be treated to prevent the ulcers from coming back.
  • for the long-term treatment of conditions where your stomach makes too much acid. This includes a rare condition called Zollinger-Ellison syndrome.

Helirab-D (Rabeprazole) is used in adolescents 12 years of age and above:

  • for up to 8 weeks for the treatment of GERD.

It is not known if Helirab-D (Rabeprazole) is safe and effective in children under the age of 12.

Helirab-D (Rabeprazole) may help your acid-related symptoms, but you could still have serious stomach problems. Talk with your doctor.

Who should not take Helirab-D (Rabeprazole)?

Do not take Helirab-D (Rabeprazole) if you:

  • are allergic to any of the ingredients in Helirab-D (Rabeprazole). See the end of this leaflet for a complete list of ingredients in Helirab-D (Rabeprazole).
  • are allergic to any other Proton Pump Inhibitor (PPI) medicine.

What should I tell my doctor before taking Helirab-D (Rabeprazole)?

Before you take Helirab-D (Rabeprazole) tell your doctor about all of your medical conditions, including if you:

  • have been told that you have low magnesium levels in your blood.
  • have any liver problems.
  • have any allergies.
  • are pregnant or planning to become pregnant. It is not known if Helirab-D (Rabeprazole) can harm your unborn baby.
  • are breastfeeding. It is not known if Helirab-D (Rabeprazole) passes into your breast milk or if it can harm your baby. You should choose to breastfeed or take Helirab-D (Rabeprazole), but not both. Talk to your doctor about other ways to feed your baby while taking Helirab-D (Rabeprazole).

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. Helirab-D (Rabeprazole) and certain medicines can affect each other. This can cause serious side effects. Know the medicines that you take. Keep a list of them with you and show it to your doctor when you get a new medicine. Be sure to tell your doctor if you are taking:

  • atazanavir (Reyataz)
  • cyclosporine (Sandimmune, Neoral)
  • digoxin (Lanoxin)
  • ketoconazole (Nizoral)
  • warfarin (Coumadin)
  • theophylline (THEO-24 Thelair)
  • diazepam (Valium)
  • phenytoin (Dilantin)
  • antibiotics

Ask your doctor or pharmacist if you are not sure if your medicine is listed above.

How should I take Helirab-D (Rabeprazole)?

  • Take Helirab-D (Rabeprazole) exactly as prescribed. Your doctor will prescribe the dose that is right for you and your medical condition. Do not change your dose or stop taking Helirab-D (Rabeprazole) unless you talk to your doctor. Take Helirab-D (Rabeprazole) for as long as it is prescribed even if you feel better.
  • Helirab-D (Rabeprazole) is usually taken once a day. Your doctor will tell you the time of day to take Helirab-D (Rabeprazole), based on your medical condition.
  • Helirab-D (Rabeprazole) can be taken with or without food. Your healthcare provider will tell you whether to take this medicine with or without food based on your medical condition.
  • Swallow each Helirab-D (Rabeprazole) tablet whole with water. Do not chew, crush, or split Helirab-D (Rabeprazole) tablets because this will damage the tablet and the medicine will not work. Tell your doctor if you cannot swallow tablets whole. You may need a different medicine.
  • If you miss a dose of Helirab-D (Rabeprazole), take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your normal schedule. Do not take 2 doses at the same time.
  • If you take too much Helirab-D (Rabeprazole), call your doctor or Poison Control Center right away, or go to the emergency department.
  • Your doctor may prescribe antibiotic medicines with Helirab-D (Rabeprazole) to help treat a stomach infection and heal stomach-area (duodenal) ulcers that are caused by bacteria called H. pylori. Make sure you read the patient information that comes with an antibiotic before you start taking it.

What are the possible side effects of Helirab-D (Rabeprazole)?

Helirab-D (Rabeprazole), like other proton pump inhibitors, may cause serious allergic reactions. See the end of this leaflet for a complete list of ingredients in Helirab-D (Rabeprazole).

  • Serious allergic reactions. Tell your doctor if you have any of the following symptoms with Helirab-D (Rabeprazole).
  • rash
  • face swelling
  • throat tightness
  • difficulty breathing

Your doctor may stop Helirab-D (Rabeprazole) if these symptoms happen

  • Low magnesium levels in your body. This problem can be serious. Low magnesium can happen in some people who take a proton pump inhibitor medicine for at least 3 months. If low magnesium levels happen, it is usually after a year of treatment. You may or may not have symptoms of low magnesium.

    Tell your doctor right away if you have any of these symptoms:

    • seizures
    • dizziness
    • abnormal or fast heart beat
    • jitteriness
    • jerking movements or shaking (tremors)
    • muscle weakness
    • spasms of the hands and feet
    • cramps or muscle aches
    • spasm of the voice box

Your doctor may check the level of magnesium in your body before you start taking Helirab-D (Rabeprazole), during treatment, or if you will be taking Helirab-D (Rabeprazole) for a long period of time.

The most common side effects with Helirab-D (Rabeprazole) may include:

  • 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.

Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all the side effects of Helirab-D (Rabeprazole). For more information, ask your doctor or pharmacist.

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

How should I store Helirab-D (Rabeprazole)?

  • Store Helirab-D (Rabeprazole) in a dry place at room temperature, 59°F to 86°F (15°C to 30°C).

Keep Helirab-D (Rabeprazole) and all medicines out of the reach of children.

General Information about Helirab-D (Rabeprazole)

Medicines are sometimes prescribed for conditions other than those described in patient information leaflets. Do not use Helirab-D (Rabeprazole) for any condition for which it was not prescribed by your doctor. Do not give Helirab-D (Rabeprazole) to other people, even if they have the same symptoms as you. It may harm them.

This leaflet summarizes the most important information about Helirab-D (Rabeprazole). If you would like more information, talk to your doctor. You can also ask your doctor or pharmacist for information about Helirab-D (Rabeprazole) that is written for healthcare professionals. For full product information, visit the website at http://www.aciphex.com/ or call the toll-free numbers 1-888-4-ACIPHEX or 1-800 JANSSEN.

What are the ingredients in Helirab-D (Rabeprazole)?

Active Ingredient: Helirab-D (Rabeprazole) sodium

Inactive ingredients of the 20 mg tablet are carnauba wax, crospovidone, diacetylated monoglycerides, ethylcellulose, hydroxypropyl cellulose, hypromellose phthalate, magnesium stearate, mannitol, propylene glycol, sodium hydroxide, sodium stearyl fumarate, talc, and titanium dioxide. Iron oxide yellow is the coloring agent for the tablet coating. Iron oxide red is the ink pigment.

The following are registered trademarks of their respective manufacturers:

Reyataz (Bristol-Myers Squibb Company), Sandimmune and Neoral (Novartis Pharmaceuticals Corporation), Lanoxin (GlaxoSmithKline), Nizoral (Janssen Pharmaceutica Products, LP), and Coumadin (Bristol-Myers Squibb Company).

For prescription only

Revised May 2011

Helirab-D (Rabeprazole) is a registered trademark of Eisai Co., Ltd., Tokyo, Japan.

Manufactured and Marketed by Eisai Inc., Woodcliff Lake, NJ 07677

Marketed by PRICARA, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc., Raritan, NJ 08869

Helirab-D pharmaceutical active ingredients containing related brand and generic drugs:

infoActive ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Helirab-D available forms, composition, doses:

infoForm of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Helirab-D destination | category:

infoDestination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Helirab-D Anatomical Therapeutic Chemical codes:

infoA medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Helirab-D pharmaceutical companies:

infoPharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."EQUIDONE (DOMPERIDONE) GEL [DECHRA VETERINARY PRODUCTS]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. "rabeprazole". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).
  3. "domperidone". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Helirab-D?

Depending on the reaction of the Helirab-D after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Helirab-D not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Helirab-D addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sDrugs.com conducted a study on Helirab-D, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Helirab-D consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

Visitor reports

Two visitors reported time for results

What is the time duration Helirab-D drug must be taken for it to be effective or for it to reduce the symptoms?
Most chronic conditions need at least some time so the dose and the drug action gets adjusted to the body to get the desired effect. The stastistics say sDrugs.com website users needed 1 day to notice the result from using Helirab-D drug. The time needed to show improvement in health condition after using the medicine Helirab-D need not be same for all the users. It varies based on other factors.
Visitors%
1 day1
50.0%
> 3 month1
50.0%

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The information was verified by Dr. Arunabha Ray, MD Pharmacology

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