Product Monograph

PRODUCT MONOGRAPHPARIT – D

(RABEPRAZOLE + DOMPERIDONE)

PREAMBLEGastroesophageal reflux disease (GERD) is a common chronic, relapsing condition caused by the com-bination of excess reflux of gastric juice and impaired clearance of this refluxate from the esophagus. It is one of the most prevalent gastrointestinal disorders affecting all age groups and carries a risk of significant morbidity and possible mortality from resultant complications thus affecting the quality of life of the patient.1,2 It is estimated that 5 - 7% of the global population, suffer from GERD.3 Population-based studies show that up to 15% of individuals have heartburn and/or regurgitation at least once a week and 7% have symptoms daily.4

GERD is commonly due to transient or permanent changes in the barrier between the esophagus and the stomach, which can be due to incompetence of the lower esophageal sphincter (LES), transient LES relaxation, impaired expulsion of gastric refluxate from the esophagus, or association with a hiatal her-nia.5 Reflux of gastric contents can cause esophageal mucosal abnormalities, such as ulcers and peptic strictures, as well as reflux-nduced asthma and acid laryngitis.6 Left untreated esophageal adenocarci-noma can develop in approximately 0.2 - 2.0% of patients with Barrett’s esophagus, a complication of GERD.7

Goals of GERD management include symptom control, promoting mucosal healing, preventing com-plications and symptom relapse, and improving health-related quality of life.8 For decades, histamine-2 receptor antagonist (H2RA) represented an important advance in the management of patients with acid-related disorders, achieving the reduction of gastric acid secretion while avoiding the inconvenience of large, multiple daily doses of antacids. Today, proton pump inhibitors (PPIs) have largely supplanted the H2RAs with superior efficacy in suppression of gastric acid secretion.9 A significant percentage of patients with GERD also have delayed gastric emptying. 10

Prokinetic drugs correct this defect without altering gastric acidity. These agents improve lower esopha-geal sphincter competence, esophageal clearance and gastric emptying.10 Therefore in GERD patients failing to Rabeprazole alone, combination of Rabeprazole and prokinetic agent may be more useful.

Sr. No. Topic Pg. No.

1. Introduction to GERD 7

2. Parit-D (Rabeprazole + Domperidone) 9

2.1 Chemical structure 10

2.2 Mechanism of action 11

2.3 Pharmacokinetics 12

2.4 Therapeutic indications 13

2.5 Posology and method of administration 13

2.6 Contraindications 13

2.7 Safety profile 13

2.8 Clinical studies 15

2.8.1 Rabeprazole in GERD 15

2.8.2 Domperidone in GERD 16

2.8.3 Recommended strategy for management of GERD 16

2.8.4 Rationale for combination 16

2.8.5 Rabeprazole + Domperidone in GERD 16

3. Prescribing information of Parit-D 19

4. References 29

CONTENTS

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1. INTRODUCTION TO GERD

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1. INTRODUCTION TO GERD

Acid peptic disorders comprise of a broad spectrum of clinical variants namely gastroesophageal reflux disease (GERD), peptic ulcer disease (PUD), gastritis and others. With an estimated prevalence of 25 - 35% in the general population, these disorders influence the quality of life and productivity of afflicted patients.9 GERD is defined as a condition which develops when the reflux of stomach contents causes troublesome symptoms and/or complications.11

Global Scenario

It is a common disease in the West, which now appears to be also increasing in prevalence in the Asian Pacific region.12 The prevalence in the Western world generally ranges between 15 - 25%, whereas in Asia the prevalence is reported to be <5%.13

Indian Scenario

The reasons for this changing epidemiology are two-fold: an increased awareness among doctors and patients, and/or a true increase in the prevalence of the disease. Prevalence rates of reflux esophagitis (RE) of up to 16% and prevalence of GERD symptoms of up to 9% have been reported in the Asian population. However, the frequency of strictures and Barrett’s esophagus remain very low.12 There are few studies with prevalence figures of GER (Gastro Esophageal Reflux) from the Indian subcontinent. Studies from Jaipur report a prevalence of 22%, with urban prevalence of 26% vs. 18% in the rural population.14

A study from Delhi reports a prevalence figure of 162/1000 amongst hospital employees.15,16 The prevalence of GER (Gastro Esophageal Reflux) amongst medical students was 10.3% in one report from Chennai.16

Clinical problem

Gastric acid is pivotal in the pathogenesis of reflux symptoms with (erosive esophagitis) or without (nonerosive reflux disease) esophageal mucosal injury. Several randomized controlled trials have reported that healing of esophagitis and resolution of symptoms are strongly correlated with percent time the intragastric and intraesophageal pH is kept above 4, over a 24-hour period. Defects in esophagogastric motility including transient lower esophageal sphincter relaxations (TLESr), LES incompetence, poor esophageal clearance, and delayed gastric emptying are central to the pathogenesis of GERD. Among them, the most important factor is inappropriate TLESr. Heartburn and acid regurgitation are the classic symptoms of GERD.17 If left untreated, chronic GERD could lead to bleeding from esophageal erosions or ulceration, stricture formation, and Barrett’s esophagus. Severe GERD is a major risk factor for esophageal adenocarcinoma.6

Pharmacological therapy is centered on correcting the acid peptic imbalance with the primary aim to neutralize or inhibit secretion of gastric acid. With the suppression of intragastric acidity, despite the continued reflux of gastric contents into the esophagus, the refluxate is rendered nonirritating to the esophageal mucosa.17 Management of GERD was a dilemma till the introduction of proton pump inhibitors (PPIs) which have not only emerged as the drugs of choice in the management but have also been found to be more effective than H2 receptor blockers (H2RA).18

A significant percentage of patients with GERD also have delayed gastric emptying.10 Though PPIs are known to decrease acid secretion, they do not have any effect on the lower esophageal sphincter tone or gut motility. Hence, in patients not responding to PPI alone addition of a prokinetic agent such as domperidone increases LES tone and esophageal clearance. Thus, Parit - D, the combination of rabeprazole and domperidone provides an additive effect in these patients of GERD.19

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[RABEPRAZOLE AND DOMPERIDONE]2.

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2.1. Chemical properties

• Rabeprazole

Rabeprazole sodium (Fig. 1) is a substituted benzimidazole that inhibits gastric acid secretion. Chemically it is known 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 381.43.20

It is available as rabeprazole sodium - a white to yellowish-white solid. It is highly soluble in water. The stability of rabeprazole sodium is a function of pH; it is rapidly degraded in acid media, and is more stable under alkaline conditions.20

[RABEPRAZOLE AND DOMPERIDONE]2.

Fig 2: Structure of Domperidone

N

N

NHCIO

O

N NH

HH

HH H

H HH

HH

H

H

HH

HH

H HH

HH

O

O

NO

SN

N

Fig 1 : Structure of Rabeprazole

• Domperidone

Domperidone (Fig. 2) is a peripheral dopamine antagonist that does not readily enter the central nervous system.21 It is structurally related to the butyrophenones with antiemetic and gastroprokinetic properties.22

Chemically it is known as 5-chloro-1-(1-[3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl]piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one. It has an empirical formula of C22H24ClN5O2 and molecular weight of 425.92.

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2.2 Mechanism of action

• Rabeprazole

Rabeprazole is a partially reversible inhibitor of H+K+ ATPase which is activated in the acidic lumen of the gastric parietal cells.17 The canalicular membrane of the gastric parietal cells contains the proton pump - H+K+ ATPase enzyme (Fig. 3). It exchanges H+ ions for K+ ions using energy generated by the breakdown of ATP to ADP. This enzyme represents the final step for acid production in the stomach. It dissociates more quickly and completely from H+/K+ ATPase than omeprazole.23

Magnified view

Parietal CellProton Pump

• Domperidone

Domperidone, a prokinetic agent, acts on the gastrointestinal activity by acting as a competitive antagonist at dopamine D2 receptors. Dopamine inhibits gastrointestinal motility, reduces gastric and esophageal sphincter tone and inhibits gastroduodenal coordination.24 This effect of dopamine is inhibited by domperidone effectively as it increases esophageal peristalsis and lower esophageal sphincter pressure (LESP), increases gastric motility and peristalsis, enhances gastroduodenal co-ordination and consequently facilitates gastric emptying and decreases small bowel transit time.22 It is also known to act on the chemoreceptor trigger zone, producing an antiemetic activity.24

Domperidone increases lower esophageal sphincter tone and enhances upper GI motility, thereby preventing reflux of gastric contents into esophagus.

Rabeprazole inhibits the H+-K+-ATPase enzyme and thereby decreases gastric acid secretion.

Fig. 4: Mechanism of action of Parit - D

Fig. 3: Proton pump on gastric cell

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2.3 Pharmacokinetics

• Rabeprazole

Absorption - Rabeprazole sodium is acid labile and formulated as an enteric coated tablet. It is rapidly, dose dependently absorbed after oral administration. Food does not affect the absorption or the peak plasma concentration but delays the time to peak plasma concentration (tmax) by about 1.5 hours. Bioavailability is not influenced by the co-ingestion of either food or antacids.23

Distribution – Rabeprazole is 97% bound to human plasma proteins.25

Metabolism - It undergoes extensive metabolism via nonenzyme metabolism to form major inactive metabolites (a thioether carboxylic acid metabolite and its glucuronide) and also minor metabolism by CYP2C19 and CYP 3 A4 to desmethyl and sulfone metabolites. Rabeprazole does not accumulate significantly during repeated administration.17

Excretion – Approximately 90% of the drug was eliminated in urine, primarily as thioether carboxylic acid; its glucoronise and mercapturic acid metabolites. The remainder of the dose is recovered in the faeces.20 (Table 1)

• Domperidone

Absorption - Domperidone available in PARIT-D capsules is in the form of controlled-release pellets, facilitating the use of PARIT-D as once daily dosage. In vitro dissolution test using 0.1 N HCl at 37 ± 5˚C demonstrated a release of 15 - 40%, 30 - 60% and 55 - 85% of domperidone from PARIT-D at 1, 4 and 8 hours respectively. The released domperidone is rapidly absorbed following oral administration.26 Systemic bioavailability of oral domperidone is 13 - 17%, probably the result of hepatic first-pass and gut wall metabolism. The half-life is approximately 7.0 hours. Oral bioavailability is decreased by prior administration of cimetidine or sodium bicarbonate.27

Distribution - Oral domperidone does not appear to accumulate or to induce its own metabolism; a peak plasma level after 90 minutes of 21 ng/mL after two weeks oral administration of 30 mg per day was almost the same as that of 18 ng/mL after the first dose. Domperidone is 91 - 93% bound to plasma proteins.26 It does not readily cross the blood brain barrier and therefore is not expected to have central effects.22 However, according to animal studies, very low amounts cross the placental barrier and it is excreted in the breast milk.27 Metabolism - Oral domperidone does not appear to accumulate or induce its own metabolism. It undergoes rapid and extensive hepatic metabolism by hydroxylation and N-dealkylation. In vitro metabolism experiments with diagnostic inhibitors revealed that CYP3A4 is a major form of cytochrome P-450 involved in the N-dealkylation of domperidone, whereas CYP3A4, CYP1A2 and CYP2E1 are involved in domperidone aromatic hydroxylation.27 Elimination - Urinary and faecal excretion amounts to 31 and 66%, respectively, of the oral dose. The proportion of the medicine excreted unchanged is small (10% of faecal excretion and approximately 1%

Moderate persistent• Table 1: Pharmacokinetic properties of Rabeprazole23

tmax 3.5 hours

t1/2 (half life) 0.7 - 1.5 hours

Plasma protein binding 97%

Oral bioavailability ~52%

Excretion ~90% in urine (metabolites)

~10% in faeces (unchanged)

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of urinary excretion). The plasma half-life after a single oral dose is 7-9 hours in healthy subjects but is prolonged in patients with severe renal insufficiency.27

2.4 Therapeutic Indications:

Treatment of gastroesophageal reflux disease (GERD) not responding to rabeprazole alone.

2.5 Posology and Method of Administration:

For Adults and Children over 16 years of age:

• One PARIT-D Capsule is to be taken once daily for 4 to 8 weeks.

• PARIT-D Capsule should be swallowed whole, before breakfast in the morning.

2.6 Contraindications

PARIT-D is contraindicated in patients with known hypersensitivity to rabeprazole, domperidone, or substituted benzimidazoles or to any excipient used in the formulation.

PARIT-D is contraindicated in patients with hepatic and/or renal impairment, prolactin-releasing pituitary tumour (prolactinoma).

PARIT-D should not be used when stimulation of the gastric motility could be harmful, like gastro-intestinal hemorrhage, mechanical obstruction or perforation.

PARIT-D is contraindicated in pregnancy and during breast feeding.

2.7 Safety profile

• Rabeprazole

Rabeprazole sodium tablets were generally well tolerated during clinical trials. The observed adverse events have generally been mild/moderate and transient in nature.

The adverse events reported in clinical studies were headache, abdominal pain, diarrhea, flatulence, constipation, dry mouth, dizziness, rash, peripheral edema.

There have been reports of hepatic enzyme increase, and rarely reports of hepatitis and jaundice. Rare reports of hepatic encephalopathy have been received in patients with underlying cirrhosis. There have also been rare reports of thrombocytopenia, neutropenia, leukopenia, bullous or urticarial skin eruptions, and acute systemic allergic reactions, myalgia and arthralgia. There have been very rare reports of interstitial nephritis, gynaecomastia, erythema multiforme, toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome.

There has been no other notable abnormality in laboratory values attributable to treatment with rabeprazole sodium.

• Domperidone

Domperidone is generally very well tolerated with few undesirable effects when used within recommended dosages and duration.

Immune system disorder: Very rare; allergic reactions including anaphylaxis, anaphylactic shock, anaphylactic reaction, urticaria and angioedema.

Endocrine disorder: Rare; increased prolactin levels.

Nervous system disorders: Very rare; extrapyramidal side effects.

Cardiac disorders: QTc prolongation (frequency not known). Very rare; ventricular arrhythmias.

Gastrointestinal disorders: Rare; gastrointestinal disorders, including very rare transient intestinal cramps. Very rare: diarrhea.

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Skin and subcutaneous tissue disorders: Very rare; pruritus, rash.

Reproductive system and breast disorders: Rare; galactorrhea, gynaecomastia, amenorrhea.

As the hypophysis is outside the blood brain barrier, domperidone may cause an increase in prolactin levels. In rare cases, this hyperprolactinemia may lead to neuro endocrinological side effects such as galactorrhea, gynecomastia and amenorrhea.

Extrapyramidal side effects are exceptional in adults. These side effects reverse spontaneously and completely as soon as treatment is stopped.

Usage in Special Population

In patients with hepatic renal dysfunction:

Both Rabeprazole and Domperidone are metabolized in liver and excreted in kidney. Therefore, Parit-D is contraindicated in patients with hepatic or renal dysfunction.

In pediatrics patients:

PARIT-D is not recommended for use in children under 16 years of age, as there is no experience of its use in this group.

In geriatric patients:

No overall differences in safety or effectiveness were observed between elderly subjects and younger subjects in the clinical studies with rabeprazole. 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.

In pregnancy and lactation:

PARIT-D is contraindicated during pregnancy and should not be used during breast feeding.

As monotherapy, rabeprazole is administered as 20 mg/day, while domperidone is administered as 10 mg thrice daily; however, considering the large number of pills of domeridone that must be taken in such a therapy, the compliance to such a treatment maybe a problem. Domperidone is available as sustained release pellets with rabeprazole in Parit-D, which overcomes the need for frequent dosing of domperidone and conveniently fills this gap due to its single dose once a day regime.28

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2.8 Clinical studies

2.8.1 ClinicalefficacyofRabeprazoleinGERD

A. Symptom Relief

Cutler et al evaluated the efficacy of rabeprazole in patients with gastroesophageal reflux disease through 4 weeks to 8 weeks. A large cohort of 2,449 was administered 20 mg of rabeprazole once daily. Participants exhibited a significant overall improvement in symptoms compared to baseline (P < 0.001). There was sustained relief of symptoms over a period of 8 weeks. By week 4, a significant number of patients experienced complete relief from symptoms (Fig. 5)29.

75.177.6

50.7

90.787.5

100

80

60

40

20

0Completerelief ofdaytimeheartburn

Nighttimeheartburn

Belching Regurgitation Dysphagia%of

patie

ntswith

comp

lete r

elief.

Fig. 5: Efficacy of Rabeprazole on various symptoms of GERD by 4th week

In elderly participants (<65 or ≥65 years) there were improvements in symptoms in rabeprazole treated cases. The drug was well tolerated. In patients with endoscopy-confirmed erosive esophagitispatientstreatedwithonce-dailyrabeprazole20mg,promptandcontinuingimprovementswereseeninday-timeandnight-timeheartburn,belching,regurgitationanddysphagia.29

B. Early heartburn relief

Pace et al compared the efficacy of rabeprazole and omeprazole in inducing complete endoscopic healing and symptom relief in patients with reflux esophagitis (n = 560). The results are shown the table 2.30

Moderate persistent• Table 2: Efficacy of rabeprazole and omeprazole in reflux esophagitis

Drug Time for Symptomatic relief Endoscopic healing rate

Rabeprazole 2.8+/-0.2 days 97.9%

Omeprazole 4.7+/-0.5 days 97.5%

Rabeprazolewasfoundtobeequivalenttoomeprazoleinhealingrefluxesophagitis,butshowsafasteractivityonrefluxsymptomsintheearlytreatmentphase.30

C. Maintenance of pH >4 for long time

Since rabeprazole has a higher pKa value it has major antisecretory effect during the first 24 hours post-dose compared with the other PPIs. A comparative trial in 18 H. pylori negative adults effectively evaluated that rabeprazole 20 mg could maintain a median 24-hour gastric pH of 3.4, compared with 2.9 for lansoprazole 30 mg, 2.2 for pantoprazole 40 mg, 1.9 for omeprazole 20 mg, 1.8 for omeprazole 20 mg MUPS (multiple unit pellet system), and 1.3 for placebo (p < 0.05 vs. all other PPIs and placebo). The former also maintained pH >4 for nearly 8 hours during the 24 h post dose period which was significantly greater than other agents.31

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Additionally rabeprazole is known to be significantly superior to placebo in preventing relapse of heartburn frequency and improving patient quality of life.32

Management of GERD with rabeprazole was more effective and may be more cost effective, than with ranitidine.33

2.8.2 ClinicalefficacyofDomperidoneinGERD

A study involving of 44 patients who received 10 mg domperidone, three times daily, or placebo, the domperidone group exhibited a significant reduction of symptoms of belching, fullness, abdominal distension after meals, and heartburn compared with placebo group.24

Another study involving 23 patients having complaints of gastrointestinal distress, received 10 mg domperidone, three times daily, and 18 patients received placebo. A significantly higher proportion of patients taking domperidone showed symptom relief as compared to placebo.24

Another parallel group study with 20 patients suffering from dyspepsia, receiving domperidone 10 mg, three times daily, and 20 similar patients receiving placebo showed improvements in symptom scores more with domperidone than with placebo.24

2.8.3RecommendedStrategyforManagementofGERD

The goals of GERD treatment are to relieve symptoms and improve health related quality of life, heal erosive esophagitis, if present, manage and prevent complications, and avoid recurrence and progression of disease using medications such as antacids, H2RAs, PPIs and prokinetics.34

Initial empirical pharmacotherapy should consist of an H2RA or PPI and is reasonable without the need for immediate diagnostic testing in most cases. Expert opinion supports step-up or step-down therapy for the initial treatment of patients with GERD. In patients who incompletely respond to a trial of OTC or prescription H2RAs, PPIs taken once daily 15 to 30 minutes before the first meal of the day are preferred over continuing H2RA therapy because of their greater efficacy and faster symptom control, as well as the limited additional benefit gained from extending therapy with the same or higher dose of H2RA. An inadequate response to a 4 or 8 week trial of standard-dose PPI may indicate that longer treatment is needed, more severe disease, or an incorrect diagnosis.

Pharmacologic options for maintenance therapy of GERD include step-down management with attempted discontinuation of therapy, or continuation of the current medication regimen. This decision should be individualized, considering the patient’s clinical status, presence or likelihood of complications, patient’s previous response to treatment, likelihood of patient follow-up, and overall cost.34

2.8.4 Rationaleforcombination

Rabeprazole being the fastest acting PPI gives a quick relief from the hyper acid secretory conditions. A significant percentage of GERD patients have delayed gastric emptying10 and hypotensive esophageal sphincter.35

Domperidone, a prokinetic and anti-emetic improves the LES tone, increases the gastric motility and thus helps in gastric emptying. In GERD patients not responding to Rabeprazole alone, combination of Rabeprazole and Domperidone may be effective.36

2.8.5Rabeprazole+DomperidoneinGERD37

An Indian open, prospective, non-comparative study was conducted to evaluate the efficacy and tolerability of rabeprazole and domperidone in the treatment of patients suffering from GERD. Fifty adult patients with the clinical diagnosis of GERD were selected. A combination of single pill consisting of rabeprazole and domperidone was swallowed on empty stomach each day for 4 weeks by the patients.

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At the end of 2 weeks rabeprazole and domperidone provided significant and remarkable improvement in symptoms of GERD. These benefits provided additional benefits at the end of 4 weeks (Table 3, Fig. 6). Most patients (94%) had excellent or good relief as assessed by their physician whilst 86% of patients rated treatment with rabeprazole and domperidone as good or excellent. Thus, Rabeprazole and Domperidone were found to be effective and well tolerated.37

Moderate persistent• Table 3: Showing mean symptom scores from baseline to end of study

Symptom Baseline Visit 1 (2-week) Visit 2 (4-week) P-value

Heartburn 2.22 1.32 0.72 < 0.001

Nausea 1.26 0.66 0.14 < 0.001

Vomiting 0.74 0.28 0.08 < 0.001

Waterbrash 0.74 0.54 0.18 < 0.001

Fullness 1.9 1.04 0.28 < 0.001

Total symptom score 6.86 3.84 1.4 < 0.001

8

7

6

5

4

3

2

1

0Baseline scores Visit 1 scores (2-week) Visit 2 scores (4-week)HeartburnWaterbrash

NauseaFullness

VomitingTotal symptom score

Meansymptomscore

Fig. 6: Improvement of GERD symptoms with Rabeprazole and Domperidone combination

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DISCUSSION

Globally, the gold standard for treating GERD is proton pump inhibitor therapy. Antisecretory agents cause decrease in acid production and show a high healing rates and rates of resolution of reflux symptoms, but they do improve underlying disturbance in gut motility or improve tone of lower esophageal sphincter. So in cases where Rabeprazole alone is not sufficient, use of a prokinetic may further enhance the healing rates in GERD. Domperidone acts by increasing LES tone and by enhancing upper GIT motility and thus acting on one of the pathophysiological mechanisms of GERD. Clinical study done in Indian patients has also demonstrated that by altering the pathophysiology of GERD, rabeprazole and domperidone combination can be used effectively. Hence, in the management of GERD beyond rabeprazole alone, Parit-D can be an effective option.

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3. Prescribing information of

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QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains:

Rabeprazole sodium lP 20 mg

(as enteric coated pellets)

Domperidone BP 30 mg

(as sustained release pellets)

Colours: Ferric Oxide USP-NF (Red and Yellow), Black Oxide of Iron, Titanium Dioxide IP

Colours in capsule shells: Brilliant Blue FCF, Carmoisine, Lake of Tartrazine

PHARMACEUTICAL FORM

Capsules for oral use

CLINICAL PARTICULARS

Therapeutic Indications: Treatment of gastroesophageal reflux disease (GERD) not responding to rabeprazole alone.

Posology and Method of Administration: For Adults and Children over 16 years of age:

• One PARIT-D Capsule is to be taken once daily for 4 to 8 weeks.

• PARIT-D Capsule should be swallowed whole, before breakfast in the morning.

Contraindications

PARIT-D is contraindicated in patients with known hypersensitivity to rabeprazole, domperidone or substituted benzimidazoles or to any excipient used in the formulation.

PARIT-D is contraindicated in patients with hepatic and/or renal impairment, prolactin-releasing pituitary tumour (prolactinoma).

PARIT-D should not be used when stimulation of the gastric motility could be harmful, like gastro-intestinal hemorrhage, mechanical obstruction or perforation.

PARIT-D is contraindicated in pregnancy and during breast feeding.

Special Warnings and Special Precautions for Use

Patients should be cautioned that PARIT-D capsules should not be chewed or crushed, but should be swallowed whole. Co-administration of PARIT-D with atazanavir, ketoconazole, erythromycin or other potent CYP3A4 inhibitors are not recommended. (See Section on Interactions with Other Medications and other Forms of Interaction).

Symptomatic response to therapy with rabeprazole sodium does not preclude the presence of gastric or esophageal malignancy, therefore the possibility of malignancy should be excluded prior to commencing treatment with PARIT-D. A risk of cross-hypersensitivity reactions with other proton pump inhibitor or substituted benzimidazoles cannot be excluded. There have been reports of blood dyscrasias

Enteric Coated Rabeprazole Sodium and Domperidone Sustained Release Capsules

3. Prescribing information of Parit-D

21

(thrombocytopenia and neutropenia) and hepatic enzyme abnormalities with use of rabeprazole. In the majority of cases where an alternative etiology cannot be identified, the events were uncomplicated and resolved on discontinuation of rabeprazole.

Patients with Severe Hepatic Dysfunction: Although no evidence of significant drug related safety problems was seen in a study of patients with mild to moderate hepatic impairment versus normal age and sex matched controls, the prescriber is advised to exercise caution when treatment with rabeprazole sodium is first initiated in patients with severe hepatic dysfunction. The exposure to rabeprazole sodium (AUC) in patients with significant hepatic dysfunction is approximately two-fold that of healthy patients.

Pediatrics: PARIT-D is not recommended for use in children under 16 years of age, as there is no experience of its use in this group.

Geriatrics: No overall differences in safety or effectiveness were observed between elderly subjects and younger subjects in the clinical studies with rabeprazole. 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.

Interaction with Other Medications and Other Forms of Interaction

Rabeprazole

Drugs metabolized by CYP450 system: Rabeprazole is metabolized by the cytochrome P450

(CYP450) drug metabolizing enzyme system. Studies in healthy subjects have shown that rabeprazole does not have clinically significant interactions with other drugs metabolized by the CYP450 system, such as warfarin and theophylline given as single oral doses, diazepam as a single intravenous dose, and phenytoin given as a single intravenous dose (with supplemental oral dosing). Steady state interactions of rabeprazole and other drugs metabolized by this enzyme system have not been studied in patients. There have been reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including rabeprazole and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.

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

Antacids:Co-administration of rabeprazole and antacids produced no clinically relevant changes in plasma rabeprazole concentrations.

Other: Rabeprazole produces sustained inhibition of gastric acid secretion. An interaction with compounds which are dependent on gastric pH for absorption may occur due to the magnitude of acid suppression observed with rabeprazole. For example, in normal subjects, co-administration of rabeprazole 20 mg OD resulted in an approximately 30% decrease in the bioavailability of ketoconazole and increases in the AUC and Cmax for digoxin of 19% and 29%, respectively. Therefore, patients may need to be monitored when such drugs are taken concomitantly with rabeprazole.

AmoxicillinorClarithromycin: Studies in healthy subjects have shown that rabeprazole sodium does not have clinically significant interactions with amoxicillin. Rabeprazole does not adversely influence plasma concentrations of amoxicillin or clarithromycin when co-administered for the purpose of eradicating upper gastrointestinal H. pylori infection.

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Domperidone

The main metabolic pathway of domperidone is through CYP3A4. In vitro data suggest that the concomitant use of drugs that significantly inhibit this enzyme may result in increased plasma levels of domperidone.

Separate in-vivo pharmacokinetic/pharmacodynamic interaction studies with oral ketoconazole or oral erythromycin in healthy subjects confirmed a marked inhibition of domperidone’s CYP3A4 mediated first pass metabolism by these drugs. With the combination of oral domperidone 10 mg four times daily and ketoconazole 200 mg twice daily, a mean QTc prolongation of 9.8 msec was seen over the observation period, with changes at individual time points ranging from 1.2 to 17.5 msec. With the combination of domperidone 10 mg four times daily and oral erythromycin 500 mg three times daily, mean QTc over the observation period was prolonged by 9.9 msec, with changes at individual time points ranging from 1.6 to 14.3 msec. Both the Cmax and AUC of domperidone at steady state were increased approximately three-fold in each of these interaction studies. In these studies domperidone monotherapy at 10 mg given orally four times daily resulted in increases in mean QTc of 1.6 msec (ketoconazole study) and 2.5 msec (erythromycin study), while ketoconazole monotherapy (200 mg twice daily) and erythromycin monotherapy (500 mg three times daily) led to increases in QTc of 3.8 and 4.9 msec, respectively, over the observation period.

Pregnancy and Lactation: PARIT-D is contraindicated during pregnancy and should not be used during breast feeding.

Rabeprazole: There are no data on the safety of rabeprazole in human pregnancy. Reproduction studies performed in rats and rabbits have revealed no evidence of impaired fertility or harm to the fetus due to rabeprazole sodium, although low foeto-placental transfer occurs in rats. It is not known whether rabeprazole sodium is excreted in human breast milk. No studies in lactating women have been performed. Rabeprazole sodium is however excreted in rat mammary secretions.

Domperidone: There are limited post-marketing data on the use of domperidone in pregnant women. Studies have shown that domperidone enters breast milk. It is not known whether this is harmful to the newborn. Therefore, breast feeding is not recommended for mothers who are taking domperidone.

Effects on Ability to Drive and Use Machines: PARIT-D has no or negligible influence on the ability to drive machines or operate machinery.

Undesirable Effects

Rabeprazole

ClinicalStudies

Rabeprazole sodium tablets were generally well tolerated during clinical trials. The observed adverse events have generally been mild/moderate and transient in nature.

The table below contains a subset of adverse events reported in placebo-controlled North American clinical trials. Data is broken down to show both total numbers of the listed ADEs reported as treatment-emergent signs and symptoms (TESS) and to show the number of reports considered possibly or probably related to study drug treatment by the reporter.

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Moderate persistent• Table I. Adverse Events Reported in Placebo-controlled North American Clinical Trials

BODY SYSTEM Rabeprazole Placebo Rabeprazole Placebo n=749 n=89 n=749 n=89

WHOLE BODY Headache 96 (13%) 9 (10%) 22 (3%) 3 (3%)

GASTROINTESTINAL Abdominal Pain 39 (5%) 5 (6%) 6 (1%) 1 (1%)Diarrhea 77 (10%) 8 (9%) 20 (3%) 5 (6%)Flatulence 36 (5%) 1 (1%) 6 (1%) 0 (0%)Constipation 15 (2%) 1 (1%) 4 (1%) 0 (0%)Dry Mouth 8 (1%) 0 (0%) 7 (1%) 0 (0%)

NEUROLOGICAL Dizziness 23 (3%) 5 (6%) 4 (1%) 1 (1%)

SKIN & APPENDAGES Rash 8 (1%) 4 (4%) 3 (0%) 2 (2%)Peripheral edema 5 (1%) 0 (0%) N/A N/A

Total Reported TESS TESS considered Possibly or Probably Related to Study Drug

Post-Marketing Experience

There have been reports of hepatic enzyme increase, and rarely reports of hepatitis and jaundice. Rare reports of hepatic encephalopathy have been received in patients with underlying cirrhosis. There have also been rare reports of thrombocytopenia, neutropenia, leukopenia, bullous or urticarial skin eruptions, and acute systemic allergic reactions, myalgia and arthralgia. There have been very rare reports of interstitial nephritis, gynecomastia, erythema multiforme, toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome.

There has been no other notable abnormality in laboratory values attributable to treatment with rabeprazole sodium.

Domperidone

Domperidone is generally very well tolerated with few undesirable effects when used within recommended dosages and duration.

Immune system disorder: Very rare; allergic reactions including anaphylaxis, anaphylactic shock, anaphylactic reaction, urticaria and angioedema.

Endocrine disorder: Rare; increased prolactin levels.

Nervous system disorders: Very rare; extrapyramidal side effects.

Cardiac disorders: QTc prolongation (frequency not known). Very rare; ventricular arrhythmias.

Gastrointestinal disorders: Rare; gastrointestinal disorders, including very rare transient intestinal cramps. Very rare: diarrhea.

Skin and subcutaneous tissue disorders: Very rare; pruritus, rash.

Reproductive system and breast disorders: Rare; galactorrhea, gynecomastia, amenorrhea.

As the hypophysis is outside the blood brain barrier, domperidone may cause an increase in prolactin

24

levels. In rare cases, this hyperprolactinemia may lead to neuro endocrinological side effects such as galactorrhea, gynecomastia and amenorrhea. Extrapyramidal side effects are exceptional in adults. These side effects reverse spontaneously and completely as soon as treatment is stopped.

Overdose

Clinical data on overdose with PARIT-D is not available. Treatment should be symptomatic with general supportive measures.

Rabeprazole:Experience to date with deliberate or accidental overdose is limited. The maximum established exposure has not exceeded 60 mg twice daily, or 160 mg once daily. Effects are generally minimal, representative of the known adverse event profile and reversible without further medical intervention. No specific antidote is known. Rabeprazole sodium is extensively protein bound and is, therefore, not dialysable. As in any case of overdose, treatment should be symptomatic and general supportive measures should be utilized.

Domperidone: Symptoms of overdosage may include drowsiness, disorientation and extrapyramidal reactions, especially in children. There is no specific antidote to domperidone, but in the event of overdose, gastric lavage as well as the administration of activated charcoal, may be useful. Close medical supervision and supportive therapy is recommended. Anticholinergic, anti-parkinson drugs may be helpful in controlling the extrapyramidal reactions.

PHARMACOLOGICAL PROPERTIES

Some GERD patients refractory to Proton Pump Inhibitors (PPIs) monotherapy have dyspeptic (dysmotility) symptoms. Clinical studies have shown that most of them respond to the addition of a prokinetic agent.

Pharmacodynamic Properties

Rabeprazole

MechanismofAction:Rabeprazole sodium belongs to the class of anti-secretory compounds, the substituted benzimidazoles, that do not exhibit anticholinergic or H2 histamine antagonist properties, but suppress gastric acid secretion by the specific inhibition of the H+/K+-ATPase enzyme (the acid or proton pump) The effect is dose-related and leads to inhibition of both basal and stimulated acid secretion irrespective of the stimulus. Animal studies indicate that after administration, rabeprazole sodium rapidly disappears from both the plasma and gastric mucosa. As a weak base, rabeprazole is rapidly absorbed following all doses and is concentrated in the acid environment of the parietal cells. Rabeprazole is converted to the active sulphenamide form through protonation and it subsequently reacts with the available cysteines on the proton pump.

Anti-secretoryActivity: After oral administration of a 20 mg dose of rabeprazole sodium the onset of the anti-secretory effect occurs within one hour, with the maximum effect occurring within two to four hours. Inhibition of basal and food stimulated acid secretion 23 hours after the first dose of rabeprazole sodium are 69% and 82% respectively and the duration of inhibition lasts up to 48 hours. The inhibitory effect of rabeprazole sodium on acid secretion increases slightly with repeated once-daily dosing, achieving steady state inhibition after three days. When the drug is discontinued, secretory activity normalises over 2 to 3 days.

SerumGastrinEffects: In clinical studies patients were treated once daily with 10 or 20 mg rabeprazole sodium, for up to 43 months duration. Serum gastrin levels increased during the first 2 to 8 weeks reflecting the inhibitory effects on acid secretion and remained stable while treatment was continued. Gastrin values returned to pre-treatment levels, usually within 1 to 2 weeks after discontinuation of therapy.

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Human gastric biopsy specimens from the antrum and the fundus from over 500 patients receiving rabeprazole or comparator treatment for up to 8 weeks have not detected changes in ECL cell histology, degree of gastritis, incidence of atrophic gastritis, intestinal metaplasia or distribution of H. pylori infection. In over 250 patients followed for 36 months of continuous therapy, no significant change in findings present at baseline was observed.

Other Effects:Systemic effects of rabeprazole sodium in the CNS, cardiovascular and respiratory systems have not been found to date. Rabeprazole sodium, given in oral doses of 20 mg for 2 weeks, had no effect on thyroid function, carbohydrate metabolism, or circulating levels of parathyroid hormone, cortisol, estrogen, testosterone, prolactin, cholecystokinin, secretin, glucagon, follicle stimulating hormone (FSH), luteinising hormone (LH), renin, aldosterone or somatotrophic hormone.

Domperidone

Domperidone is a dopamine antagonist with antiemetic properties. Domperidone does not readily cross the blood-brain barrier. In domperidone users, especially adults, extrapyramidal side effects are very rare, but domperidone promotes the release of prolactin from the pituitary. Its antiemetic effect may be due to a combination of peripheral (gastrokinetic) effects and antagonism of dopamine receptors in the chemoreceptor trigger zone, which lies outside the blood-brain barrier in the area postrema. Animal studies, together with the low concentrations found in the brain, indicate a predominantly peripheral effect of domperidone on dopamine receptors.

Studies in man have shown oral domperidone to increase lower esophageal pressure, improve antroduodenal motility and accelerate gastric emptying. There is no effect on gastric secretion.

Pharmacokinetic Properties

Rabeprazole

Absorption: Rabeprazole available in PARIT-D capsules is in the form of enteric-coated pellets. This presentation is necessary because rabeprazole is acid-labile. Absorption of rabeprazole therefore begins only after the enteric coated pellets leave the stomach. Absorption is rapid, with peak plasma levels of rabeprazole occurring approximately 3.5 hours after a 20 mg dose. Peak plasma concentrations (Cmax) of rabeprazole and AUC are linear over the dose range of 10 mg to 40 mg. Absolute bioavailability of an oral 20 mg dose (compared to intravenous administration) is about 52% due in large part to pre-systemic metabolism. Additionally the bioavailability does not appear to increase with repeat administration. In healthy subjects the plasma half-life is approximately one hour (range 0.7 to 1.5 hours), and the total body clearance is estimated to be 283 ± 98 mL/min. There was no clinically relevant interaction with food. Neither food nor the time of day of administration of the treatment affect the absorption of rabeprazole sodium.

Distribution: Rabeprazole is approximately 97% bound to human plasma proteins.

Metabolism and excretion: Rabeprazole sodium, as is the case with other members of the proton pump inhibitor (PPI) class of compounds, is metabolized through the cytochrome P450 (CYP450) hepatic drug metabolizing system. In vitro studies with human liver microsomes indicated that rabeprazole sodium is metabolized by isoenzymes of CYP450 (CYP2C19 and CYP3A4). In these studies, at expected human plasma concentrations rabeprazole neither induces nor inhibits CYP3A4; and although in vitro studies may not always be predictive of in vivo status these findings indicate that no interaction is expected between rabeprazole and cyclosporin. In humans the thioether (M1) and carboxylic acid (M6) are the main plasma metabolites with the sulphone (M2), desmethyl-thioether (M4) and mercapturic acid conjugate (M5) minor metabolites observed at lower levels. Only the desmethyl metabolite (M3) has a small amount of anti-secretory activity, but it is not present in plasma.

26

Following a single 20 mg 14C labelled oral dose of rabeprazole sodium, no unchanged drug was excreted in the urine. Approximately 90% of the dose was eliminated in urine mainly as the two metabolites: a mercapturic acid conjugate (M5) and a carboxylic acid (M6), plus two unknown metabolites. The remainder of the dose was recovered in faeces.

Gender: Adjusted for body mass and height, there are no significant gender differences in pharmacokinetic parameters following a single 20 mg dose of rabeprazole.

Renal dysfunction: In patients with stable, end-stage, renal failure requiring maintenance hemodialysis (creatinine clearance ≤5ml/min/1.73m2), the disposition of rabeprazole was very similar to that in healthy volunteers. The AUC and the Cmax in these patients was about 35% lower than the corresponding parameters in healthy volunteers. The mean half-life of rabeprazole was 0.82 hours in healthy volunteers, 0.95 hours in patients during hemodialysis and 3.6 hours post dialysis. The clearance of the drug in patients with renal disease requiring maintenance hemodialysis was approximately twice that in healthy volunteers.

Hepatic dysfunction: Following a single 20 mg dose of rabeprazole to patients with chronic mild to moderate hepatic impairment the AUC doubled and there was a 2 - 3 fold increase in half-life of rabeprazole compared to the healthy volunteers. However, following a 20 mg dose daily for 7 days the AUC had increased to only 1.5-fold and the Cmax to only 1.2-fold. The half-life of rabeprazole in patients with hepatic impairment was 12.3 hours compared to 2.1 hours in healthy volunteers. The pharmacodynamic response (gastric pH control) in the two groups was clinically comparable.

Elderly: Elimination of rabeprazole was somewhat decreased in the elderly. Following 7 days of daily dosing with 20 mg of rabeprazole sodium, the AUC approximately doubled, the Cmax increased by 60% and t½ increased by approximately 30% as compared to young healthy volunteers. However there was no evidence of rabeprazole accumulation.

CYP2C19 Polymorphism: Following a 20 mg daily dose of rabeprazole for 7 days, CYP2C19 slow metabolisers, had AUC and t½ which were approximately 1.9 and 1.6 times the corresponding parameters in extensive metabolisers whilst Cmax had increased by only 40%.

Domperidone

Domperidone available in PARIT-D capsules is in the form of controlled-release pellets, facilitating the use of PARIT-D as once daily dosage

Absorption: In vitro dissolution test using 0.1 N HCl at 37±50C demonstrated a release of 15 - 40%, 30-60% and 55 - 85% of domperidone from PARIT - D at 1, 4 and 8 hours respectively. In fasting subjects, domperidone is rapidly absorbed after oral administration, with peak plasma concentrations at 30 to 60 minutes. The low absolute bioavailability of oral domperidone (approximately 15%) is due to an extensive first-pass metabolism in the gut wall and liver. Although domperidone’s bioavailability is enhanced in normal subjects when taken after a meal, patients with gastrointestinal complaints should take domperidone 15 - 30 minutes before a meal. Reduced gastric acidity impairs the absorption of domperidone. Oral bioavailability is decreased by prior concomitant administration of cimetidine and sodium bicarbonate. The time of peak absorption is slightly delayed and the AUC somewhat increased when domperidone is taken after a meal.

Distribution: Oral domperidone does not appear to accumulate or to induce its own metabolism; a peak plasma level after 90 minutes of 21 ng/mL after two weeks oral administration of 30 mg per day was almost the same as that of 18 ng/mL after the first dose. Domperidone is 91-93% bound to plasma proteins. Distribution studies with radiolabelled drug in animals have shown wide tissue distribution, but low brain concentration. Studies in rats have shown that small amounts of drug cross the placenta.

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Metabolism: Domperidone undergoes rapid and extensive hepatic metabolism by hydroxylation and N-dealkylation. In vitro metabolism experiments with diagnostic inhibitors revealed that CYP3A4 is a major form of cytochrome P450 involved in the N-dealkylation of domperidone, whereas CYP3A4, CYP1A2 and CYP2E1 are involved in domperidone aromatic hydroxylation.

Excretion: Urinary and faecal excretions amount to 31 and 66 % of the oral dose respectively. The proportion of the drug excreted unchanged is small (10% of faecal excretion and approximately 1% of urinary excretion). The plasma half-life after a single oral dose is 7 - 9 hours in healthy subjects but is prolonged in patients with severe renal insufficiency.

Preclinical Safety Data

Rabeprazole:Non-clinical effects were observed only at exposures sufficiently in excess of the maximum human exposure that make concerns for human safety negligible in respect of animal data. Studies on mutagenicity gave equivocal results. Tests in mouse lymphoma cell line were positive, but in vivo micronucleus and in vitro DNA repair tests were negative. Carcinogenicity studies revealed no special hazard for humans.

Domperidone:Electrophysiological in vitro and in vivo studies indicate an overall moderate risk of domperidone to prolong the QT interval in humans. In in vitro experiments on isolated cells transfected with HERG and on isolated guinea pig myocytes, exposure ratios ranged between 5 and 30 fold based on IC50 values inhibiting currents through IKr ion channels in comparison to the free plasma concentrations in humans after administration of the maximum daily dose of 20 mg q.i.d. Exposure margins for prolongation of action potential duration in in vitro experiments on isolated cardiac tissues exceeded the free plasma concentrations in humans at maximum daily dose (20 mg q.i.d.) by 17 fold. However, safety margins in in vitro and in vivo pro-arrhythmic models (isolated Langendorff perfused heart) and in in vivo models (dog, guinea pig, rabbits sensitized for torsades de points) exceeded the free plasma concentrations in humans at maximum daily dose (20 mg q.i.d.) by more than 17-fold. In the presence of inhibition of the metabolism via CYP3A4 free plasma concentrations of domperidone can rise up to 10-fold.

At a high, maternally toxic dose (more than 40 times the recommended human dose), teratogenic effects were seen in the rat. No teratogenicity was observed in mice and rats.

PHARMACEUTICAL PARTICULARS

List of Excipients: Non pareil seeds, Methanol, Methylene chloride, Triacetin, Cellulose derivatives, Colloidal silicon dioxide, Polyethylene glycol, Sodium hydroxide, Methacrylic acid copolymer, Magnesium salts, Purified talc, Ferric oxide (red), Ferric oxide (yellow), Black oxide of iron, Titanium dioxide, Purified water

Incompatibilities: None known.

Shelf Life: 24 months. The expiry date is indicated on the label.

Special Precautions for Storage: PARIT-D should be stored below 25°C protected from light and moisture. Keep out of reach of children.

Nature and Specification of Container: Aluminium foil strip packs

Instructions for Use/Handling: Capsule should be swallowed whole.

28

Manufactured by:

Inventia Healthcare Private Limited,

F1- F1/1, Additional Ambernath M.I.D.C.,

Ambernath (East) - 421 506,

District Thane, Maharashtra

Co-promoted by:

Eisai Pharmaceuticals India Private Limited,

Marwah Centre, B Wing, Krishanlal Marwah Marg,

Andheri (East), Mumbai 400 072

&

GlaxoSmithKline Pharmaceuticals Limited,

Dr. Annie Besant Road, Mumbai 400 030.

PARITis a trademark of the Eisai Co. Ltd., Japan

PAR-D/PI/IN/2009/01dated21Dec2009

29

4. REFERENCES

30

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2007.2. Kumar HR, Thomas V. Gastro Esophageal Reflux Disease – An Update. Calicut Medical Journal.2004;2(1):e133. Medina WC. Nonverbal Individuals with Intellectual/Developmental Disabilities Experiencing GERD: From Infants to Older Adults.

International Journal of Nursing. Vol 2(1).4. Goyal RK. Diseases of the oesophagus. In: Kasper DL, Braunwald E, Fauci A, Hauser S, Longo D, Jameson JL editors. Harrison’s

Principles of Internal Medicine; Vol 2, 16th edition, New York: McGraw-Hill. 2004:1742-44.5. Gastroesophageal reflux disease. 2008.Otolaryngology.com 6. Clark CL, Horwitz B. Complications of Gastroesophageal Reflux Disease: Oesophagitis, acid laryngitis, and beyond. Postgraduate

Medicine. 1996:100(5).7. O¨ berg S, Wenner J, Johansson J, Walther B, Wille´n R. Barrett Esophagus. Risk Factors for Progression to Dysplasia and Adenocarcinoma.

Ann Surg. 2005;242(1): 49–54.8. Bruce TV and Rundsarah M. Proton Pump Inhibitors: An Update. American Family Physician. 2002;66:273-80.9. McCarthy DM, Caspi A. Proton Pump Inhibitors in the Management of Patients with Acid-Peptic Disorders: A Managed Care Perspective.

P & T. 2005; Vol 30 (5): 282-291.10. Reddymasu S et al. Domperidone: Review of Pharmacology and clinical applications in Gastroenterology.Am J Gastroenterol.

2007;102:2036-2045.11. American Gastroenterological Association medical position statement on the management of gastroesophageal reflux disease.

Gastroenterology. 2008;135:1383-91.12. Goh KL. Changing epidemiology of gastroesophageal reflux disease in the asian pacific region: An overview. Journal of gastroenterology

and hepatology. 2004; Vol. 19 (suppl 3): S22-S25.13. Richter JE. The Many Manifestations of Gastroesophageal Reflux Disease: Presentation, Evaluation and Treatment. Gastroenterol Clin N

Am. 2007;36:577-599.14. Rai RR, Sharma M. Prevalence and clinical spectrum of GERD - healthy population. Indian J Gastroenterol. 2004;23 (Suppl 2):A12.15. Sharma PK, Ahuja V, Madan K, Raizada A, Sharma MP. Prevalence of symptomatic GERD: Interim analysis of an adult community-based

cross-sectional study. Indian J Gastroenterol. 2004;23 (Suppl 2):A11. 16. Kumar PS, Selvaraj MK, Jayanthi V. Prevalence of symptoms of gastroesophageal reflux amongst medical students. Indian J

Gastroenterology. 2006;25(3):168-9.17. Castell DO. Acid Suppression Therapy for GERD: The Devil’s in the Details, Part I. Practical Gastroenterology. 2006: 30-39.18. Desai CA, Samant BD. Rabeprazole. J Postgrad Med. 2002;48:80.19. Singhal S, Dhawan P, Bhatt A, Pokharna R, Sharma D, Kumar G et al. Evaluation of safety and efficacy of Pantoprazole and Domperidone

combination in patients with gastroesophageal reflux disease. The Internet Journal of Gastroenterology. 2006; Vol 4(2): ISSN 1528-8323.20. Rabeprazole sodium. Drug Monograph. RxList. 2010.21. Brogden RN, Carmine AA, Heel RC, Speight TM, Avery GS. Domperidone: A review of its pharmacological activity, pharmacokinetics and

therapeutic efficacy in the symptomatic treatment of chronic dyspepsia and as an antiemetic. Drugs. 1982;24(5):360-400.22. Domperidone Maleate. Drug Monograph. RxMed. 23. Rabeprazole. Drug Monograph. UK Drug Information Pharmacists Group. 1998.24. OTC Domperidone. The Pharmaceutical Journal Checklist. September 1998.25. Pariet. The electronic Medicines Compendium (eMC). Summary of product characteristics. 2010 Datapharm Communications Ltd.26. Domperidone. Data Sheet. Medsafe- Information for Health Care Professionals. New Zealand Medicines and Medical devices Safety

Authority.27. Domperidone: Drug Monograph. Inhouse Pharmacy.28. OD-PEP Product monograph29. Cutler A, Robinson M, Murthy A, Delemos B. Rabeprazole 20 mg for erosive esophagitis-associated symptoms in a large, community-

based study: Additional results. Dig Dis Sci. 2010;55(2):338-45. 30. Pace F, Annese V, Prada A, Zambelli A, Casalini S, Nardini P, Bianchi Porro G; Italian Rabeprazole Study Group. Rabeprazole is equivalent

to omeprazole in the treatment of erosive gastro-esophageal reflux disease. A randomised, double-blind, comparative study of rabeprazole and omeprazole 20 mg in acute treatment of reflux esophagitis, followed by a maintenance open-label, low-dose therapy with rabeprazole. Dig Liver Dis. 2005;37(10):741-50.

31. Pace F, Pallotta S, Casalini S, Porro GB. A review of rabeprazole in the treatment of acid-related diseases. Therapeutics and Clinical Risk Management. 2007:3(3) 363–379.

32. Caos A, Breiter J, Perdomo C, et al. Long-term prevention of erosive or ulcerative gastro-oesophageal reflux disease relapse with rabeprazole 10 or 20 mg vs. placebo: Results of a 5-year study in the United States. Aliment Pharmacol Ther. 2005;22:193–202.

33. Ofman JJ, Yamashita BD, Siddique RM, et al. Cost-effectiveness of rabeprazole versus generic ranitidine for symptom resolution in patients with erosive esophagitis. Am J Manag Care. 2000;6:905–16.

34. Heidelbaugh JJ, Wamsteker E, Pernicano PG, Nostrant TT. Chapter 49 - Gastroenterology. In: Rakel RE (editor) Rakel: Textbook of Family Medicine. 7th edition;2007. Philadelphia: Saunders Elseviers.

35. Boeckxstaens GEE. Review article: The pathophysiology of gastro-oesophageal reflux Disease. Aliment Pharmacol Ther. 2007;26:149-60.

36. Veloz D. Veloz D training manual. 37. Shahani S, Sawant P, Dabholkar P. Rabeprazole plus domperidone: The answer for gastro-oesophageal reflux disease. J Indian Med

Assoc. 2008;106(4):264, 266, 268.

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Notes

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Disclaimer

The matter published herein has been developed by clinicians and medical writers and is validated by experts. The same is strictly meant for Medical

Practioners only. Although great care has been taken in compiling and checking the information, GlaxoSmithKline Pharmaceuticals Ltd. and Hansa MedCell

shall not be held responsible or liable for errors, omission or inaccuracies in this publication arising from negligence or otherwise, nor for consequences

arising thereform.

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