COMPOSITION :
Each capsule contains |
Rabeprazole sodium IP |
Equivalent to Rabeprazole (As enteric coated pellets) |
…………. |
20 mg |
Domperidone (As sustained release pellets) |
…………. |
q.s |
DESCRIPTION :
Rabeprazole 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, rabeprazole has been characterized
as a gastric proton pump inhibitor. Rabeprazole blocks the final step of
gastric acid secretion. In gastric parietal cells, rabeprazole is protonated,
accumulates, and is transformed to an active sulfenamide.
Domperidone is a derivative of benzimidazole that possesses both prokinetic
and antiemetic properties due to its inhibitory action at dopamine D2 receptors.
PHARMACOLOGY :
Pharmacodynamics:
Mechanism of Action
Rabeprazole
Rabeprazole 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, rabeprazole has been characterized
as a gastric proton-pump inhibitor. Rabeprazole blocks the final step of
gastric acid secretion. In gastric parietal cells, rabeprazole is protonated,
accumulates, and is transformed to an active sulfenamide.
When studied in vitro, 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.
Antisecretory Activity
The antisecretory effect begins within one hour after oral administration of
20 mg rabeprazole. The median inhibitory effect of rabeprazole on 24 hour
gastric acidity is 88% of maximal after the first dose. 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% (see table below). This relatively prolonged Pharmacodynamics action
compared to the short pharmacokinetic half-life (1-2 hours) reflects the sustained
inactivation of the H+, K+ ATPase.
Domperidone
Domperidone is a dopamine antagonist with anti-emetic properties domperidone does
not readily cross the blood-brain barrier. In domperidone users, especially in adults,
extrapyramidal side effects are very rare, but domperidone promotes the release of
prolactin from the pituitary. Its anti-emetic 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 esophaegeal pressure, improve antroduodenal motility and accelerate gastric
emptying. There is no effect on gastric secretion.
Pharmacokinetics:
Rabeprazole
After oral administration of 20 mg rabeprazole, peak plasma concentrations (Cmax) of rabeprazole
occur over a range of 2.0 to 5.0 hours (Tmax). 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 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. 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 fecal excretions amount to 31 and 66% of the oral dose respectively.
The proportion of the drug excreted unchanged is small (10% of fecal 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.
INDICATIONS :
RAZOCER-DSR is indicated for the relief of symptoms of
1. Dyspepsia.
2. GERD.
3. Nausea associated with acid peptic disorders.
4. Post-operative nausea and vomiting.
5. Chronic gastritis.
DOSAGE AND ADMINISTRATION :
One capsule a day or as directed by the physician.
CONTRAINDICATIONS :
RAZOCER-DSR is contraindicated in patients with known hypersensitivity to
rabeprazole, substituted benzimidazole, Domperidone or to any component of
the formulation. It should not be used whenever stimulation of gastric
motility is to be avoided or could be harmful, e.g. in the presence of gastro-intestinal
hemorrhage, obstruction or perforation. It is also contra-indicated in patients with a
prolactin-releasing pituitary tumor (prolactinoma).
ADVERSE EFFECTS :
Adverse effects 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.
SHELF-LIFE :
2 years.
PACKAGING INFORMATION :
RAZOCER- DSR is available in an Alu - Alu pack of 10 capsules.