Rabeprazole Sodium IP………………20 mg

(As enteric coated pellets)

Domperidone IP……………….………..30 mg

(As Sustained release pellets)

Rabeprazole After oral administration of 20 mg rabeprazole, peak plasma concentrations (C max ) of rabeprazole occur over a range of 2.0 to 5.0 hours (T max ). The rabeprazole C max and AUC are linear over an oral dose range of 10 mg to 40 mg. There is no appreciable accumulation when doses of 10 mg to 40 mg are administered every 24 hours; the pharmacokinetics of rabeprazole is not altered by multiple dosing. The plasma half-life ranges from 1 to 2 hours. 

Absorption:  Absolute bioavailability for a 20 mg oral tablet of rabeprazole (compared to intravenous administration) is approximately 52%. Rabeprazole may be taken without regard to timing of meals.Distribution:  Rabeprazole is 96.3% bound to human plasma proteins. 
Metabolism:  Rabeprazole is extensively metabolized. The thioether and sulphone are the primary metabolites measured in human plasma. In vitro studies have demonstrated that rabeprazole is metabolized in the liver primarily by cytochromes P450 3A (CYP3A) to a sulphone metabolite and cytochrome P450 2C19 (CYP2C19) to desmethyl rabeprazole. The thioether metabolite is formed non-enzymatically by reduction of rabeprazole. 
Excretion:  Following a single 20 mg oral dose of 14 C-labeled rabeprazole, approximately 90% of the drug was eliminated in the urine, primarily as thioether carboxylic acid; its glucuronide, and mercapturic acid metabolites. The remainder of the dose was recovered in the feces. No unchanged rabeprazole was recovered in the urine or feces. 
Domperidone
Absorption 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 gastro-intestinal 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 the oral drug is taken after a meal. 
Distribution
Oral domperidone does not appear to accumulate or induce its own metabolism; a peak plasma level after 90 minutes of 21 mg/ml after two weeks oral administration of 30 mg per day was almost the same as that of 18 mg/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. Small amounts of drug cross the placenta in rats.
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 P-450 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. 

Dyspepsia

GERD

Nausea associated with acid peptic disorders

Post-operative nausea and vomiting

Chronic gastritis

Duodenal Ulcers
 

Adults

One capsules a day after the morning meal for 4 wk; additional therapy may be required for some patients.

Short-Term Treatment of GERD
Adults and Children 12 y and older

One capsules daily for up to 8 wk.

Erosive or Ulcerative GERD
Adults

One capsules daily for 4 to 8 wk; an additional 8 wk may be considered for patients who do not heal.

For the maintenance healing of GERD, one capsule a day till heal.

Pathological Hypersecretory Conditions
 

 Adults

One capsule a day with 40 mg rabeprazole will control hyper secreation . Adjust dose to individual patient needs. Dosages up to 100 mg daily or 60 mg twice daily of rabeprazole have been administered.

Adverse events with rabeprazole are mild to moderate in intensity and included malaise, diarrhea, nausea, skin eruptions, headache and dizziness. Abnormal laboratory findings (increased hepatic enzymes, LDH, blood urea nitrogen) observed with rabeprazole were similar in incidence and severity with comparator agents and reversible with cessation of therapy. 
Domperidone has been found to be associated with Increased serum prolactin, which may be associated with galactorrhea, less frequently gynaecomastia, breast enlargement and soreness. Reduced libido has been reported. Occasional rashes and other allergenic phenomena are also reported. Domperidone does not readily cross the normally functioning blood brain barrier and is therefore less likely to interfere with the central dopaminergic function. However, acute extrapyramidal dystonic reactions have been reported with domperidone.

There has been no experience with large overdoses with Rabeprazole. In the event of overdosage, treatment should be symptomatic and supportive. There has been no experience with large overdoses with Domperidone.

The primary pathway of the metabolism of rabeprazole is nonenzymatic reduction to a thioether compound. Only an inappreciable percent is oxidated to demethylated rabeprazole or rabeprazole sulfone via CYP2C19 and CYP3A4. There are, however, notable differences among PPIs in the extent to which their degradation depends on the given CYP isoenzymes .Rabeprazole does not have clinically significant interactions with other drugs metabolized by the CYP450 system, such as warfarin, theophylline, diazepam and phenytoin.

Rabeprazole produces sustained inhibition of gastric acid secretion. An interaction with compounds which are dependent on gastric pH for absorption like ketoconazole may occur due to the magnitude of acid suppression observed with rabeprazole. Therefore, patients may need to be monitored when such drugs are taken concomitantly with rabeprazole. Co-administration of rabeprazole and antacids produced no clinically relevant changes in plasma rabeprazole concentrations.

While adverse interactions have not been reported in general clinical use, domperidone has the potential to interact with dopamine agonist (e.g. bromocriptine), antimuscarinics and opioid analgesics. It may also enhance the absorption of concomitantly administered drugs especially in cases of delayed gastric emptying.

Pregnancy

Category B.

Lactation

Undetermined.

Children

Safety and efficacy not established in the short-term treatment of GERD in children younger than 12 y. For other indications, safety and efficacy not established.

Hepatic Function

Use with caution in patients with severe hepatic impairment.

Bone fracture

Use may be associated with an increased risk of osteoporosis-related fractures of the hip, wrist, or spine.

Gastric malignancy

Symptomatic response to rabeprazole does not preclude gastric malignancy