Rablet-D

Rabeprazole sodium, domperidone.

Each capsule contains rabeprazole sodium 20 mg as enteric coated pellets and domperidone 30 mg as sustained release pellets.
Each capsule also contains the following inactive ingredients: Non pareil seeds, hypromellose, sodium hydroxide, light magnesium carbonate, purified talc, methacrylic acid copolymer dispersion, macrogol, titanium dioxide, ferric oxide (red, black, yellow), anhydrous colloidal silica, ethylcellulose, triacetin.
Rabeprazole sodium is 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]-methyl]sulfinyl]-1 H-benzimidazole sodium salt. It has a molecular formula of C₁₈H₂₀N₃NaO₃S and a molecular weight of 381.43.
Domperidone is 5-chloro-1-[1-[3-(2-oxo-2,3-dihydro-1H-benzimidazol-1yl)propyl]-piperidin-4-yl]-1,2-dihydro-2H-benzimidazol-2-one. It has a molecular formula of C₂₂H₂₄CIN₅O₂ and a molecular weight of 425.9.
Rabeprazole sodium is a substituted benzimidazole that inhibits gastric acid secretion. Domperidone is a dopamine-receptor blocking agent.

Pharmacology: 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 sulfonamide. When studied in vitro, rabeprazole is chemically activated at pH 1.2 with a half-life (t_½) of 78 sec. It inhibits acid transport in porcine gastric vesicles with a t_½ of 90 sec.
Antisecretory Activity: The antisecretory effect begins within 1 hr after oral administration of rabeprazole 20 mg. The median inhibitory effect of rabeprazole on 24 hr gastric acidity is 88% of maximal after the first dose. Rabeprazole 20 mg inhibits basal and peptone meal-stimulated acid secretion vs placebo by 86% and 95%, respectively, and increases the percent of a 24-hr period that the gastric pH >3 from 10-65%. This relatively prolonged pharmacodynamic action compared to the short pharmacokinetic t_½ (1-2 hr) reflects the sustained inactivation of the H⁺, K⁺ATPase.
Compared to placebo, rabeprazole 10, 20 and 40 mg administered once daily for 7 days significantly decreased intragastric acidity with all doses for each of 4 meal-related intervals and the 24-hr 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.
After administration of rabeprazole 20 mg once daily for 8 days, the mean percent of time that gastric pH >3 or gastric pH >4 alter a single dose (Day 1) and multiple doses (Day 8) was significantly greater than placebo.
Effects on Esophageal Acid Exposure: In patients with gastroesophageal reflux disease (GERD) and moderate to severe esophageal acid exposure, rabeprazole 20- and 40 mg/day decreased 24-hr esophageal acid exposure. After 7 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%, respectively. Normalization of 24-hr intraesophageal acid exposure was correlated to gastric pH >4 for at least 35% of the 24-hr period; this level was achieved in 90% of subjects receiving rabeprazole 20 mg and in 100% of subjects receiving rabeprazole 40 mg. With rabeprazole 20- and 40 mg/day, significant effects on gastric and esophageal pH were noted after 1 day of treatment and more pronounced after 7 days of treatment.
Effects on Serum Gastrin: In patients given daily doses of rabeprazole for up to 8 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 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 (ULN).
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.
In over 400 patients treated with rabeprazole (10 or 20 mg/day) for up to 1 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 1 year have not revealed clinically significant effects on the endocrine system. In healthy male volunteers treated with rabeprazole for 13 days, no clinically relevant changes have been detected in the following endocrine parameters examined: 17β-estradiol, thyroid-stimulating hormone, triiodothyronine, 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 rabeprazole for up to 1 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 rabeprazole and ocular effects.
Domperidone: It is a dopamine antagonist with anti-emetic properties. 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 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 oesophageal pressure, improve antroduodenal motility and accelerate gastric emptying. There is no effect on gastric secretion. 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.
Pharmacokinetics: Rablet D is enteric-coated to allow rabeprazole sodium to pass through the stomach relatively intact. After oral administration of rabeprazole 20 mg, peak plasma concentrations (C_max) of rabeprazole occur over a range of 2-5 hrs (T_max). The rabeprazole C_max and AUC are linear over an oral dose range of 10-40 mg. There is no appreciable accumulation when doses of 10-40 mg are administered every 24 hrs; the pharmacokinetics of rabeprazole is not altered by multiple dosing. The plasma half-life (t_½) ranges from 1-2 hrs. Absolute bioavailability for rabeprazole 20 mg oral tablet (compared to IV administration) is approximately 52%. When rabeprazole is administered with a high fat meal, its T_max is variable and may delay its absorption up to 5 hrs or longer, however, the C_max and the extent of rabeprazole absorption (AUC) are not significantly altered. Thus, rabeprazole may be taken without regard to timing of meals.
Rabeprazole is 96.3% bound to human plasma proteins.
Rabeprazole is extensively metabolized. 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 rabeprazole is metabolized in the liver primarily by cytochromes P-450 3A (CYP3A) to a sulphone metabolite and cytochrome P-450 2C19 (CYP2C19) to desmethyl rabeprazole. The thioether metabolite is formed non-enzymatically by reduction of rabeprazole. CYP2C19 exhibits a known genetic polymorphism due to its deficiency in some subpopulations (eg, 3-5% of Caucasians and 17-20% of Asians). Rabeprazole metabolism is slow in these subpopulations, therefore, they are referred to as poor metabolizers of the drug.
Following a single oral dose of 14C-labeled rabeprazole 20 mg, 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 rabeprazole was recovered in the urine or feces.
Special Populations: Geriatric: In 20 healthy elderly subjects administered rabeprazole 20 mg once daily for 7 days, AUC values approximately doubled and the C_max increased by 60% compared to values in a parallel younger control group. There was no evidence of drug accumulation after once daily administration (see Precautions).
Pediatric: The pharmacokinetics of rabeprazole in pediatric patients <18 years have not been studied.
Gender and Race: In analyses adjusted for body mass and height, rabeprazole pharmacokinetics showed no clinically significant differences between male and female subjects. In studies that used different formulations of rabeprazole, AUC values for healthy Japanese men were approximately 50-60% greater than values derived from pooled data from healthy men in the United States.
Renal Insufficiency: In 10 patients with stable end-stage renal disease requiring maintenance hemodialysis [creatinine clearance (CrCl) ≤5 mL/min/1.73 m²], no clinically significant differences were observed in the pharmacokinetics of rabeprazole after a single 20 mg oral dose when compared to 10 healthy volunteers.
Hepatic Insufficiency: In a single dose study of 10 patients with chronic mild to moderate compensated cirrhosis of the liver who were administered a dose of rabeprazole 20 mg, AUC_0-24 was approximately doubled, the elimination t_½ was 2- to 3-fold higher and the 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 rabeprazole 20 mg once daily for 8 days, AUC and C_max values increased approximately 20% compared to values in healthy age- and gender-matched subjects. These increases were not statistically significant.
No information exists on rabeprazole disposition in patients with severe hepatic impairment.
Domperidone: In fasting subjects, domperidone is rapidly absorbed after oral administration, with peak plasma concentrations at 30-60 min. 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 meal, patients with gastrointestinal complaints should take domperidone 15-30 min 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.
Oral domperidone does not appear to accumulate or induce its own metabolism; a peak plasma level after 90 min of 21 ng/mL after 2 weeks oral administration of 30 mg/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 radio-labeled drug in animals have shown wide tissue distribution, but low brain concentration. Small amounts of drug cross the placenta in rats.
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.
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 t_½ after a single oral dose is 7-9 hrs in healthy subjects but is prolonged in patients with severe renal insufficiency.

Short-term treatment of gastroesophageal reflux disease (GERD).

Adults and Adolescents >12 years: 1 cap once daily for 4-8 weeks.
Administration: Rablet-D should be swallowed whole and taken 15-30 min before meals.

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.
Rabeprazole: There has been no experience with large overdoses with rabeprazole. Seven reports of accidental overdosage with 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 rabeprazole up to 120 mg once daily. No specific antidote for rabeprazole is known. Rabeprazole is extensively protein bound and is not readily dialyzable. In the event of an overdosage, treatment should be symptomatic and supportive.
Single oral doses of rabeprazole at 786 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.
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, antiparkinson drugs may be helpful in controlling the extrapyramidal reactions.

Patients with known hypersensitivity to domperidone, rabeprazole or substituted benzimidazoles, or to any of the ingredients of Rablet-D.
Patients with prolactin-releasing pituitary tumour (prolactinoma).
Rablet-D should not be used in patients with severe hepatic impairment.
Domperidone should not be used when stimulation of gastric motility could be harmful, eg, gastrointestinal hemorrhage, mechanical obstruction or perforation.

General: Rabeprazole: Symptomatic response to therapy with rabeprazole does not preclude the presence of gastric malignancy.
Patients with healed gastroesophageal reflux disease (GERD) were treated for up to 40 months with rabeprazole and monitored with serial gastric biopsies. Patients with 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.
Steady-state interactions of rabeprazole and warfarin have not been adequately evaluated in patients. There have been reports of increased international normalized ratio (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 increase in INR and prothrombin time.
Domperidone: Hepatic Insufficiency: Since domperidone is highly metabolised in the liver, domperidone should not be used in patients with hepatic impairment.
Renal Insufficiency: In patients with severe renal insufficiency (serum creatinine >6 mg/100 mL, ie, >0.6 mmol/L), the elimination half-life (t_½) of domperidone was increased from 7.4-20.8 hrs, but plasma drug levels were lower than in healthy volunteers. Since very little unchanged drug is excreted via the kidneys, it is unlikely that the dose of a single administration needs to be adjusted in patients with renal insufficiency. However, on repeated administration, the dosing frequency should be reduced to once or twice daily depending on the severity of the impairment and the dose may need to be reduced. Such patients on prolonged therapy should be reviewed regularly.
Use with Ketoconazole: A slight increase of QT interval (mean <10 msec) was reported in a drug interaction study with oral ketoconazole. Even if the significance of this study is not fully clear, alternative therapeutic options should be considered if antifungal treatment is required.
Effects on the Ability to Drive or Operate Machinery: Domperidone has no or negligible influence on the ability to drive and use machines.
Use in pregnancy: Rabeprazole: Teratology studies have been performed in rats at IV doses up to 50 mg/kg/day (plasma AUC of 11.8 mcg•hr/mL, about 13 times the human exposure at the recommended dose for GERD) and rabbits at IV doses up to 30 mg/kg/day (plasma AUC of 7.3 mcg•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 rabeprazole. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Rablet-D should be used during pregnancy only if clearly needed.
Domperidone: There are limited post-marketing data on the use of domperidone in pregnant women. Domperidone should only be used during pregnancy when justified by the anticipated therapeutic benefit. A study in rats has shown reproductive toxicity at a high, maternally toxic dose. The potential risk for humans is unknown.
Use in lactation: Rabeprazole: Following IV administration of 14C-labeled rabeprazole 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 rabeprazole is excreted in human breast milk. Administration of 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 rabeprazole, a decision should be made to discontinue nursing or Rablet-D, taking into account the importance of the drug to the mother.
Domperidone: Domperidone is excreted in breast milk of lactating rats (mostly as metabolites: peak concentration of 40 and 800 ng/mL after oral and IV administration of 2.5 mg/kg, respectively). Domperidone concentrations in breast milk of lactating women are 10-50% of the corresponding plasma concentrations and expected not to exceed 10 ng/mL. The total amount of domperidone excreted in human breast milk is expected to be <7 mcg/day at the highest recommended dosing regimen. It is not known whether this is harmful to the newborn. Therefore, breastfeeding is not recommended for mothers who are taking domperidone.
Use in children: Rabeprazole: The safety and effectiveness of rabeprazole in pediatric patients have not been established.
Domperidone: Neurological side effects are rare (see Adverse Reactions). Since metabolic functions and the blood-brain barrier are not fully developed in the first months of life, the risk of neurological side effects is higher in young children.
Overdosing may cause extrapyramidal symptoms in children but other causes should be taken into consideration.
Use in the elderly: Rabeprazole: Of the total number of subjects in clinical studies of rabeprazole, 19% were ≥65 years, while 4% were ≥75 years. 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.

Use in pregnancy: Rabeprazole: Teratology studies have been performed in rats at IV doses up to 50 mg/kg/day (plasma AUC of 11.8 mcg•hr/mL, about 13 times the human exposure at the recommended dose for GERD) and rabbits at IV doses up to 30 mg/kg/day (plasma AUC of 7.3 mcg•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 rabeprazole. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Rablet-D should be used during pregnancy only if clearly needed.
Domperidone: There are limited post-marketing data on the use of domperidone in pregnant women. Domperidone should only be used during pregnancy when justified by the anticipated therapeutic benefit. A study in rats has shown reproductive toxicity at a high, maternally toxic dose. The potential risk for humans is unknown.
Use in lactation: Rabeprazole: Following IV administration of 14C-labeled rabeprazole 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 rabeprazole is excreted in human breast milk. Administration of 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 rabeprazole, a decision should be made to discontinue nursing or Rablet-D, taking into account the importance of the drug to the mother.
Domperidone: Domperidone is excreted in breast milk of lactating rats (mostly as metabolites: peak concentration of 40 and 800 ng/mL after oral and IV administration of 2.5 mg/kg, respectively). Domperidone concentrations in breast milk of lactating women are 10-50% of the corresponding plasma concentrations and expected not to exceed 10 ng/mL. The total amount of domperidone excreted in human breast milk is expected to be <7 mcg/day at the highest recommended dosing regimen. It is not known whether this is harmful to the newborn. Therefore, breastfeeding is not recommended for mothers who are taking domperidone.

Rabeprazole: Worldwide, over 2900 patients have been treated with rabeprazole in Phase II-III clinical trials involving various dosages and durations of treatment. In general, rabeprazole treatment has been well tolerated in both short- and long-term trials. The adverse events rates were generally similar between the 10 and 20 mg doses.
In short- and long-term studies, the following adverse events, regardless of causality, were reported in rabeprazole-treated patients. Rare events are those reported in ≤1/1000 patients.
Body as a Whole: Asthenia, fever, allergic reaction, chills, malaise, substernal chest pain, neck rigidity, photosensitivity reaction.
Cardiovascular System: Hypertension, myocardial infarct, abnormal electrocardiogram (ECG), migraine, syncope, angina pectoris, bundle branch block, palpitation, sinus bradycardia, tachycardia. Rare: Bradycardia, pulmonary embolus, supraventricular tachycardia, thrombophlebitis, vasodilation, QT prolongation and ventricular tachycardia.
Digestive System: Diarrhea, nausea, vomiting, abdominal pain, dyspepsia, flatulence, constipation, dry mouth, eructation, gastroenteritis, rectal hemorrhage, melena, anorexia, cholelithiasis, mouth ulceration, stomatitis, dysphagia, gingivitis, cholecystitis, increased appetite, abnormal stools, colitis, esophagitis, glossitis, pancreatitis, proctitis. Rare: Bloody diarrhea, cholangitis, duodenitis, gastrointestinal hemorrhage, hepatic encephalopathy, hepatitis, hepatoma, liver fatty deposit, salivary gland enlargement, thirst.
Endocrine System: Hyperthyroidism, hypothyroidism.
Hemic and Lymphatic System: Anemia, ecchymosis, lymphadenopathy, hypochromic anemia.
Metabolic & Nutritional Disorders: Peripheral edema, edema, weight gain, gout, dehydration, weight loss.
Musculoskeletal System: Myalgia, arthritis, leg cramps, bone pain, arthrosis, bursitis. Rare: Twitching.
Nervous System: Insomnia, anxiety, dizziness, depression, nervousness, somnolence, hypertonia, neuralgia, vertigo, convulsion, abnormal dreams, decreased libido, neuropathy, paraesthesia, tremor. Rare: Agitation, amnesia, confusion, extrapyramidal syndrome, hyperkinesia.
Respiratory System: Dyspnea, asthma, epistaxis, laryngitis, hiccup, hyperventilation. Rare: Apnea, hypoventilation.
Skin and Appendages: Rash, pruritus, sweating, urticaria, alopecia. Rare: Dry skin, herpes zoster, psoriasis, skin discoloration.
Special Senses: Cataract, amblyopia, glaucoma, dry eyes, abnormal vision, tinnitus, otitis media. Rare: Corneal opacity, blurred vision, diplopia, deafness, eye pain, retinal degeneration, strabismus.
Urogenital System: Cystitis, urinary frequency, dysmenorrhea, dysuria, kidney calculus, metrorrhagia, polyuria. Rare: Breast enlargement, hematuria, impotence, leukorrhea, menorrhagia, orchitis, urinary incontinence.
Laboratory Values: The following changes in laboratory parameters were reported as adverse events: Abnormal platelets, albuminuria, increased creatinine phosphokinase, abnormal erythrocytes, hypercholesterolemia, hyperglycemia, hyperlipemia, hypokalemia, hyponatremia, leukocytosis, leukorrhea, abnormal liver function tests, increase prostatic specific antigen and SGPT, urine abnormality, abnormal WBC.
Combination Treatment with Amoxicillin and Clarithromycin: In clinical trials using combination therapy with rabeprazole plus amoxicillin and clarithromycin (RAC), no adverse events unique to this drug combination were observed. In the U.S. multicenter study, the most frequently reported drug-related adverse events 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.
Post-Marketing Adverse Events: Additional adverse events reported from worldwide marketing experience with rabeprazole sodium are: Sudden death, coma and hyperammonemia, jaundice, rhabdomyolysis, disorientation and delirium , anaphylaxis, angioedema, bullous and other drug eruptions of the skin, interstitial pneumonia and nephritis; and TSH elevations. In most instances, the relationship to rabeprazole sodium was unclear. 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.
Domperidone: The frequency of adverse reactions listed as follow is defined using the following convention: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare <1/10,000).
Immune System Disorder: Very Rare: Allergic reaction.
Endocrine Disorder: Rare: Increased prolactin levels.
Nervous System Disorders: Very Rare: Extrapyramidal side effects.
Gastrointestinal Disorders: Rare: GI disorders, including very rare transient intestinal cramps.
Skin and Subcutaneous Tissue Disorders: Very Rare: Urticaria.
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 hyperprolactinaemia may lead to neuro-endocrinological side effects eg, galactorrhea, gynaecomastia and amenorrhea.
Extrapyramidal side effects are very rare in neonates and infants, and exceptional in adults. These side effects reverse spontaneously and completely as soon as the treatment is stopped.

Rabeprazole: Drugs Metabolized by CYP450 System: Rabeprazole is metabolized by the cytochrome P-450 (CYP-450) drug metabolizing enzyme system. Studies in healthy subjects have shown that rabeprazole does not have clinically significant interactions with other drugs metabolized by the CYP-450 system eg, warfarin and theophylline given as singe oral dose, diazepam as a single IV dose and phenytoin given as a single IV 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 international normalized ratio (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 C_max in healthy volunteers following 14 days of dosing with rabeprazole 20 mg. 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 once daily resulted in an approximately 30% decrease in the bioavailability of ketoconazole and increase in the AUC and C_max for digoxin of 19% and 29%, respectively. Therefore, patients may need to be monitored when such drugs are taken concomitantly with rabeprazole.
Domperidone: CYP3A4 Inhibitors: 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. In vivo interaction studies with ketoconazole revealed a marked inhibition of domperidone's CYP3A4-mediated first pass metabolism by ketoconazole.
A pharmacokinetic study has demonstrated that the AUC and the peak plasma concentration of domperidone is increased by a factor 3 when oral ketoconazole is administered concomitantly (at steady state). A slight QT prolonging effect (mean <10 msec) of this combination was detected, which was greater than the 1 seen with ketoconazole alone. A QT prolonging effect could not be detected when domperidone was given alone in patients with no co-morbidity, even at high oral doses (up to 160 mg/day).
The results of this interaction study should be taken into account when prescribing domperidone concomitantly with strong CYP3A4 inhibitors eg, ketoconazole, ritonavir and erythromycin.

Store below 25°C. Protect from light and moisture.
Shelf-Life: 24 months.

Antacids, Antireflux Agents & Antiulcerants

A02BC54 - rabeprazole, combinations ; Belongs to the class of proton pump inhibitors. Used in the treatment of peptic ulcer and gastro-oesophageal reflux disease (GERD).

POM

Cap 10's, 30's.