Pariet

Sodium rabeprazole.

Sodium rabeprazole is (±)-sodium 2-[[4-(3-methoxypropoxy)-3-methylpyridin-2-yl] methylsulfinyl]-1H-benzimidazole. It has a molecular formula of C₁₈H₂₀N₃O₃S·Na and a molecular weight of 381.43.
Sodium rabeprazole occurs as a white to pale yellowish white powder. It is odorless; very soluble in water and methanol, freely soluble in dehydrated ethanol and ethyl acetate, and practically insoluble in ether and hexane.
Sodium rabeprazole shows no optical rotation. It is hygroscopic. Melting point: 225°C (with decomposition). Partition coefficient: About 214 (pH 7, water-octanol system).

Pharmacology: Mechanism of Action: Sodium rabeprazole belongs to the class of antisecretory 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, sodium rabeprazole 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 sulfonamide form through protonation and it subsequently reacts with the available cysteines on the proton-pump.
Antisecretory Activity: After oral administration of a 20-mg dose of sodium rabeprazole, the onset of antisecretory effect occurs within 1 hr, with the maximum effect occurring within 2-4 hrs. Inhibition of basal and food-stimulated acid secretion 23 hrs after the 1st dose of sodium rabeprazole are 69% and 82%, respectively, and the duration of inhibition lasts up to 48 hrs. The inhibitory effect of sodium rabeprazole on acid secretion increases slightly with repeated once-daily dosing, achieving steady-state inhibition after 3 days. When the drug is discontinued, secretory activity normalizes over 2-3 days.
Serum Gastrin Effects: In clinical studies, patients were treated once daily with 10 or 20 mg sodium rabeprazole, for up to 43 months duration. Serum gastrin levels increased during the first 2-8 weeks reflecting the inhibitory effects on acid secretion and remained stable while treatment was continued. Gastrin values returned to pre-treatment levels, usually within 1-2 weeks after discontinuation of therapy.
Human gastric biopsy specimens from the antrum and the fundus from >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 Helicobacter pylori infection. In >250 patients followed for 36 months of continuous therapy, no significant change in findings present at baseline was observed.
Other Effects: Systemic effects of sodium rabeprazole in the central nervous, cardiovascular and respiratory systems have not been found to date. Sodium rabeprazole, 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), luteinizing hormone (LH), renin, aldosterone or somatotrophic hormone.
Pharmacokinetics: Absorption: Pariet is an enteric-coated (gastro-resistant) tablet formulation of sodium rabeprazole. This presentation is necessary because rabeprazole is acid-labile. Absorption of rabeprazole, therefore, begins only after the tablet leaves the stomach. Absorption is rapid, with peak plasma levels of rabeprazole occurring approximately 3.5 hrs after a 20-mg dose. Peak plasma concentrations (C_max) of rabeprazole and AUC are linear over the dose range of 10-40 mg. Absolute bioavailability of an oral 20-mg dose (compared to IV administration) is about 52% due in large part to presystemic metabolism. Additionally, the bioavailability does not appear to increase with repeat administration. In healthy subjects, the plasma half-life is approximately 1 hr (range 0.7-1.5 hrs), and the total body clearance is estimated to be 283±98 mL/min. Neither food nor the time of day of administration of the treatment affects the absorption of sodium rabeprazole.
Distribution: Rabeprazole is approximately 97% bound to human plasma proteins.
Metabolism and Excretion: In humans, the thioether (M1) and carboxylic acid (M6) are the main plasma metabolites with the sulfone (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 antisecretory activity, but it is not present in plasma.
Following a single 20-mg ¹⁴C-labeled oral dose of sodium rabeprazole, no unchanged drug was excreted in the urine. Approximately 90% of the dose was eliminated in urine mainly as the 2 metabolites: A mercapturic acid conjugate (M5) and a carboxylic acid (M6), plus 2 unknown metabolites. The remainder of the dose was recovered in feces.
Gender: Adjusted for body mass and height, there are no significant gender differences in pharmacokinetic parameters following a single 2-mg dose of rabeprazole.
Renal Dysfunction: In patients with stable, end-stage renal failure requiring maintenance hemodialysis (creatinine clearance ≤5 mL/min/1.73 m²), the disposition of rabeprazole was very similar to that in healthy volunteers. The AUC and the C_max in these patients was about 35% lower than the corresponding parameters in healthy volunteers. The mean half-life of rabeprazole was 0.82 hrs in healthy volunteers, 0.95 hrs in patients during hemodialysis and 3.6 hrs 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- to 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 C_max to only 1.2-fold. The half-life of rabeprazole in patients with hepatic impairment was 12.3 hrs compared to 2.1 hrs in healthy volunteers. The pharmacodynamic response (gastric pH control) in the 2 groups was clinically comparable.
Elderly: Elimination of rabeprazole was somewhat decreased in the elderly. Following 7 days of daily dosing with 20 mg of sodium rabeprazole, the AUC approximately doubled, the C_max increased by 60% and t_½ 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 metabolizers had AUC and t_½ which were approximately 1.9 and 1.6 times the corresponding parameters in extensive metabolizers whilst C_max had increased by only 40%.
Toxicology: Preclinical Safety Data: Preclinical 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 vivo and in vitro DNA repair tests were negative. Carcinogenicity studies revealed no special hazard for humans.

Treatment of active duodenal ulcer, active benign gastric ulcer, symptomatic erosive or ulcerative gastroesophageal reflux disease (GERD).
Long-term management and symptomatic treatment of moderate to severe GERD.
Eradication of H. pylori in patients with peptic ulcer disease in combination with appropriate antibacterial therapeutic regimens.

Adults: Active Duodenal Ulcer and Active Benign Gastric Ulcer: Recommended Dose: 20 mg once daily in the morning. Some patients with active duodenal ulcer may respond to 10 mg once daily.
Most patients with active duodenal ulcer heal within 4 weeks. However, a few patients may require an additional 4 weeks of therapy to achieve healing. Most patients with active benign gastric ulcer heal within 6 weeks. However, again a few patients may require an additional 6 weeks of therapy to achieve healing.
Erosive or Ulcerative Gastroesophageal Reflux Disease (GERD): Recommended Dose: 20 mg once daily for 4-8 weeks.
Gastroesophageal Reflux Disease Long-Term Management (GERD Maintenance): 10 or 20 mg once daily depending upon patient response.
Symptomatic Treatment of Moderate to Very Severe Gastroesophageal Reflux Disease (Symptomatic GERD): 10 mg once daily in patients without esophagitis. If symptom control has not been achieved during 4 weeks, the patient should be further investigated.
Eradication of H. pylori: Patients with H. pylori infection should be treated with eradication therapy. The following combination given for 7 days is recommended: 20 mg twice daily + clarithromycin 500 mg twice daily and amoxicillin 1 g twice daily.
For indications requiring once-daily treatment, Pariet should be taken in the morning before eating, and although neither the time of day nor food intake was shown to have any effect on sodium rabeprazole activity, this regimen will facilitate treatment compliance.
Renal and Hepatic Impairment: No dosage adjustment is necessary for patients with renal or hepatic impairment. See precautions in the treatment of patients with severe hepatic impairment.

There is no experience to date with deliberate overdose. Dosages of up to 80 mg/day have been well tolerated. No specific antidote is known. Sodium rabeprazole is extensively protein-bound and is, therefore, not readily dialysable. As in any case of overdose, treatment should be symptomatic, and general supportive measures should be utilized.

Patients with known hypersensitivity to sodium rabeprazole, substituted benzimidazoles or to any excipient used in Pariet.
Use in pregnancy & lactation: 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 sodium rabeprazole, although low feto-placental transfer occurs in rats. Pariet is contraindicated during pregnancy.
It is not known whether sodium rabeprazole is excreted in human breast milk. No studies in lactating women have been performed. Sodium rabeprazole is, however, excreted in rat mammary secretions. Therefore, Pariet should not be used during breastfeeding.

Symptomatic response to therapy with sodium rabeprazole does not preclude the presence of gastric or esophageal malignancy, therefore, the possibility of malignancy should be excluded prior to commencing treatment with Pariet.
Patients on long-term treatment (particularly those treated for >1 year) should be kept under regular surveillance. Patients should be carefully observed during administration and the cumulative dose should be kept to a minimum in accordance with the disease condition.
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. However, because there are no clinical data on the use of Pariet in the treatment of patients with severe hepatic dysfunction, the prescriber is advised to exercise caution when treatment with Pariet is first initiated in such patients.
Increases in thyroid weight and blood thyroxine levels have been reported in animal experiments (rats ≥25 mg/kg/day orally), therefore thyroid function should be carefully monitored during administration of Pariet.
Carcinogenicity: It has been reported that in a carcinogenicity study in which ≥5 mg/kg/day of sodium rabeprazole was given to rats by oral administration for 2 years, carcinoids in the stomach were observed in female rats.
Effects on the Ability to Drive or Operate Machinery: Based on the pharmacodynamic properties and the adverse events profile, it is unlikely that Pariet would cause an impairment of driving performance or compromise the ability to use machinery. If however, alertness is impaired due to somnolence, it is recommended that driving and operating complex machinery be avoided.
Use in children: Pariet is not recommended for use in children, as there is no experience of its use in this group.
Use in the elderly: Pariet is metabolized mainly in the liver. Since the elderly often have a physiologic hepatic hypofunction, they are liable to experience adverse drug reactions. Therefore, it is advisable to take such measures as having a drug-free interval under careful supervision if adverse reactions eg, gastrointestinal symptoms (see Adverse Reactions) occur.

Pariet was generally well tolerated during clinical trials. The observed undesirable effects have generally been mild/moderate and transient in nature.
In clinical trials, the most common adverse events (incidence ≥5%) were headache, diarrhea and nausea. Other adverse events (incidence <5% and ≥2%) were rhinitis, abdominal pain, asthenia, flatulence, pharyngitis, vomiting, nonspecific pain/back pain, dizziness, flu-like syndrome, infection, cough, constipation and insomnia. Further less frequent adverse events (incidence ≤1%) were rash, myalgia, chest pain, dry mouth, dyspepsia, nervousness, somnolence, bronchitis, sinusitis, chills, eructation, leg cramps, urinary tract infection, arthralgia and fever.
In isolated cases, anorexia, gastritis, weight gain, depression, pruritus, vision or taste disturbances, stomatitis, sweating, leukocytosis have been observed.
However, only headaches, diarrhea, abdominal pain, asthenia, flatulence, rash and dry mouth have been associated with the use of Pariet.
Clinically Significant (Analogous Compounds):
Shock: It has been reported that anaphylactic reaction or shock occurred rarely with analogous compounds (omeprazole and lansoprazole). If any abnormality is observed, Pariet should be discontinued and appropriate treatment should be given.
Hematology: It has been reported that pancytopenia, thrombocytopenia, agranulocytosis and hemolytic anemia occurred rarely and granulocytopenia and anemia occurred infrequently with omeprazole and lansoprazole. If any abnormality is observed, Pariet should be discontinued and appropriate treatment should be given.
Post-Marketing Experience: Erythema and rarely bullous reactions have been reported in patients treated with Pariet which have usually resolved after discontinuation of therapy. Thrombocytopenia, neutropenia and leukopenia have been reported rarely. There have been reports of increased hepatic enzymes.

Sodium rabeprazole, as is the case with other members of the proton-pump inhibitor (PPI) class of compounds, is metabolized through the cytochrome P-450 (CYP450) hepatic drug metabolizing system. Studies in healthy subjects have shown that sodium rabeprazole does not have clinically significant interactions with the drugs studied including warfarin, phenytoin, theophylline or diazepam metabolized by the CYP450 system.
Sodium rabeprazole produces a profound and long lasting inhibition of gastric acid secretion. An interaction with compounds whose absorption is pH-dependent may occur, therefore, the potential for such interaction was investigated. Co-administration of sodium rabeprazole results in a 33% decrease in ketoconazole levels and a 22% increase in trough digoxin levels in normal subjects. Therefore, individual patients may need to be monitored to determine if a dosage adjustment is necessary when such drugs are taken concomitantly with Pariet. Rabeprazole does not adversely influence plasma concentrations of amoxicillin or clarithromycin when co-administered for the purpose of eradicating upper gastrointestinal H. pylori infection.
In clinical trials, antacids were used concomitantly with the administration of Pariet and, in a specific study designed to define this interaction. It has been reported that the mean plasma AUC decreases by 8% and 6% after simultaneous Pariet-antacid containing aluminium hydroxide gel/magnesium hydroxide co-administration and Pariet administration 1 hr after antacid containing aluminium hydroxide gel/magnesium hydroxide administration respectively, compared to Pariet administration alone. There was no clinically relevant interaction with food.
In vitro studies with human liver microsomes indicated that sodium rabeprazole is metabolized by isoenzyme 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.

Pariet should not be chewed nor crushed, but should be swallowed whole.

Store at room temperature (not exceeding 25°C). Protect from moisture after unsealing.

Antacids, Antireflux Agents & Antiulcerants

A02BC04 - rabeprazole ; Belongs to the class of proton pump inhibitors. Used in the treatment of peptic ulcer and gastro-oesophageal reflux disease (GERD).

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