Pariet

Rabeprazole sodium.

Each light yellow, film-coated tablet (enteric coated tablet) contains 10 mg or 20 mg of rabeprazole sodium. (See Table 1.)

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Physicochemistry: Nonproprietary name: Sodium Rabeprazole(JAN).
Chemical name: (±)-sodium2-[[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl]-1H-benzimidazole.
Molecular formula: C₁₈H₂₀N₃O₃SNa.
Molecular weight: 381.43.
Sodium rabeprazole occurs as a white to pale yellowish white powder. It is odorless. It is very soluble in water and in methanol, freely soluble in dehydrated ethanol and in ethyl acetate, and practically insoluble in ether and in hexane.
It shows no optical rotation.
It is hygroscopic.
Melting point: 225°C (with decomposition).
Partition coefficient: about 214 (pH7.0, water:octanol).

Pharmacology: Mechanism of action: PARIET transforms to the activated form (sulfenamide form) at parietal cells in acidic conditions, and acts by modification of SH-groups of the proton pump (H⁺, K⁺-ATPase) causing inhibition of enzyme activity and consequents acid secretion suppression. It is believed that the recovery of enzyme activity is mainly due to drug elimination from the active site, or that glutathione may be involved in the elimination of the active drug. The involvement of glutathione in recovery of enzyme activity is also suspected.
Action in humans: Inhibition of gastric acid secretion: When PARIET was administered to healthy adult male volunteers at 10 mg or 20 mg once a day, gastrin-stimulated acid output was significantly decreased compared with the 1st day of administration. The mean percentages of acid output reduction compared with the day before starting administration on day 1 and on day 7 were, at 10 mg once a day, 73% and 80%, and at 20 mg once a day, 88-89% and 99%, respectively.
Increase reaction of intragastric pH: When PARIET was administered to healthy adult male volunteers at 10 mg or 20 mg once a day, intragastric pH was significantly increased. The percentage of holding times above pH 4 and pH 3 in 24 hr on day 4 after treatment with 10 mg was 73% and 80% respectively, and for treatment with 20 mg was 78% and 83%, respectively.
Action in animals: Inhibition of H⁺, K⁺-ATPase (in vitro): Sodium rabeprazole strongly inhibits H⁺, K⁺-ATPase in preparations made from pig gastric mucosa.
Inhibition of gastric acid secretion: Sodium rabeprazole inhibits gastric acid secretion stimulated by dibutyl cyclic-AMP in isolated rabbit gastric glands (in vitro).
Sodium rabeprazole exhibits strong inhibition of gastric acid secretion stimulated by histamine or pentagastrin in chronic gastric fistula dogs as well as basal gastric acid secretion and histamine-stimulated gastric acid secretion in rats.
Compared to other proton pump inhibitors, the reversal of the antisecretory effect is more rapid with sodium rabeprazole and the increase in blood gastrin levels is less in dogs and rats.
Antiulcer action: In rats, sodium rabeprazole demonstrated a strong antiulcer action against various experimental ulcers and therapeutic activity in experimental gastric mucosal lesions (induced by cold restraint stress, water immersion stress, pyloric ligation, cysteamine or ethanol-hydrochloride).
Adjunctive effect on Helicobacter pylori Eradication: Susceptibility testing of H. pylori isolates was performed for amoxicillin and clarithromycin using agar dilution methodology, and minimum inhibitory concentrations (MICs) were determined.
Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures.
Incidence of Antibiotic-Resistant Organisms Among Clinical Isolates: Pretreatment Resistance: Clarithromycin pretreatment resistance rate (MIC ≥ 1 mcg/mL) to H. pylori was 9% (51/560) at baseline in all treatment groups combined. A total of > 99% (558/560) of patients had H. pylori isolates which were considered to be susceptible (MIC ≤ 0.25 mcg/mL) to amoxicillin at baseline. Two patients had baseline H. pylori isolates with an amoxicillin MIC of 0.5 mcg/mL. (See Table 2.)

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Patients with persistent H. pylori infection following rabeprazole, amoxicillin, and clarithromycin therapy will likely have clarithromycin resistant clinical isolates. Therefore, clarithromycin susceptibility testing should be done when possible. If resistance to clarithromycin is demonstrated or susceptibility testing is not possible, alternative antimicrobial therapy should be instituted.
Amoxicillin Susceptibility Test Results and Clinical/Bacteriological Outcomes: In the U.S. multicenter study, a total of > 99% (558/560) of patients had H. pylori isolates which were considered to be susceptible (MIC ≤ 0.25 mcg/mL) to amoxicillin at baseline. The other 2 patients had baseline H. pylori isolates with an amoxicillin MIC of 0.5 mcg/mL, and both isolates were clarithromycin-resistant at baseline; in one case the H. pylori was eradicated. In the 7 and 10 day treatment groups 75% (107/145) and 79% (112/142), respectively, of the patients who had pretreatment amoxicillin susceptible MICs (≤ 0.25 mcg/mL) were eradicated of H. pylori. No patients developed amoxicillin-resistant H. pylori during therapy.
During treatment with antisecretory medicinal products, serum gastrin increases in response to the decreased acid secretion. Also, CgA increases due to decreased gastric acidity. The increased CgA level may interfere with investigations for neuroendocrine tumours.
Available published evidence suggests that proton pump inhibitors should be discontinued between 5 days and 2 weeks prior to CgA measurements. This is to allow CgA levels that might be spuriously elevated following PPI treatment to return to reference range.
Clinical Studies: Clinical efficacy: The results of open-labeled and double-blind clinical trials conducted with PARIET in patients with gastric ulcer, duodenal ulcer, reflux esophagitis and anastomotic ulcer are summarized in the following table. (See Table 3.)

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The overall improvement rate in 2 patients with Zollinger-Ellison syndrome was 100%.
It was demonstrated in clinical pharmacology studies that the increase in gastric pH was greater in the 20 mg group than in the 10 mg group, and the usefulness of PARIET in the treatment of intractable ulcer has been demonstrated using a dose of 20 mg once daily.
In addition, the clinical usefulness of PARIET in the treatment of gastric and duodenal ulcers has been demonstrated in double-blind clinical trials.
The following table shows endoscopic non-recurrence rate at week 52 in the Maintenance Period (Central Evaluation) with PARIET for patients with reflux esophagitis resistive to treatment ^note) with standard doses of proton pump inhibitors. (See Table 4.)

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Helicobacter pylori Eradication in Patients with Peptic Ulcer Disease or Symptomatic Non-Ulcer Disease in Adults: The U.S. multicenter study was a double-blind, parallel-group comparison of rabeprazole, amoxicillin, and clarithromycin for 3, 7, or 10 days vs. omeprazole, amoxicillin and clarithromycin for 10 days. Therapy consisted of rabeprazole 20 mg twice daily, amoxicillin 1000 mg twice daily, and clarithromycin 500 mg twice daily (RAC) or omeprazole 20 mg twice daily, amoxicillin 1000 mg twice daily, and clarithromycin 500 mg twice daily (OAC). Patients with H. pylori infection were stratified in a 1:1 ratio for those with peptic ulcer disease (active or a history of ulcer in the past five years) [PUD] and those who were symptomatic but without peptic ulcer disease [NPUD], as determined by upper gastrointestinal endoscopy. The overall H. pylori eradication rates, defined as negative 13C-UBT for H. pylori ≥ 6 weeks from the end of the treatment are shown in the following table. The eradication rates in the 7 day and 10 day RAC regimens were found to be similar to 10 day OAC regimen using either the Intent-to-Treat (ITT) or Per-Protocol (PP) populations. Eradication rates in the RAC 3 day regimen were inferior to the other regimens. (See Table 5.)

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Pharmacokinetics: Blood concentrations: The changes over time in the mean plasma sodium rabeprazole concentration when administered orally to healthy adult male volunteers at a dose of 20 mg during fasting or after a meal are shown in the following figure. Mean values of pharmacokinetic parameters determined for individual subjects during fasting and postprandial administration of PARIET are presented in the following table. T_max was prolonged by 1.7 hr after postprandial administration compared to administration during fasting, and inter-individual variations in absorption were observed. (See figure and Table 6.)

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The following table shows the mean values of pharmacokinetic parameters when sodium rabeprazole was administered orally to healthy adult male volunteers at doses of 10 mg and 20 mg during fasting. (See Table 7.)

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Metabolism: When PARIET was administered orally to healthy adult male volunteers at single doses of 10 mg and 20 mg, the main metabolite recognized in plasma was its thioether-form product produced by non-enzymatic reduction reaction. Other metabolites were the demethylated products due to demethylation which involving the hepatic enzymatic metabolism of cytochrome P450 2C19 (CYP2C19), and the sulfone-form products due to sulfonation involving 3A4 (CYP3A4).
Urinary excretion: No unchanged drug was detected in the urine of healthy adult male volunteers up to 24 hr after oral administration of 20 mg of sodium rabeprazole, and about 29-40% of the dose was excreted in the urine as the carboxylic acid form and its glucuronide, and about 13-19% of the dose was present as the mercapturate conjugated-form.

Healing of Erosive or Ulcerative Gastroesophageal Reflux Disease (GERD): PARIET is indicated for short-term (4 to 8 weeks) treatment in the healing and symptomatic relief of erosive or ulcerative gastroesophageal reflux disease (GERD). For those patients who have not healed after 8 weeks of treatment, an additional 8-week course of PARIET may be considered.
Maintenance of Healing of Erosive or Ulcerative Gastroesophageal Reflux Disease (GERD): PARIET is indicated for maintaining healing and reduction in relapse rates of heartburn symptoms in patients with erosive or ulcerative gastroesophageal reflux disease (GERD maintenance).
Healing of Duodenal Ulcers: PARIET is indicated for short-term (up to four weeks) treatment in the healing and symptomatic relief of duodenal ulcers. Most patients heal within four weeks.
Treatment of Pathological Hypersecretory Conditions, Including Zollinger-Ellison Syndrome: PARIET is indicated for the long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison Syndrome.
Symptomatic treatment of moderate to very severe Gastroesophageal reflux disease (symptomatic GERD): PARIET is indicated for the symptomatic treatment of moderate to very severe GERD.
Helicobacter pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence in Adults: PARIET in combination with amoxicillin and clarithromycin as a three drug regimen, is indicated for the treatment of patients with H. pylori infection and duodenal ulcer disease (active or history within the past 5 years) to eradicate H. pylori. Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence [see Pharmacology: Clinical Studies under Actions, and Dosage & Administration].
In patients who fail therapy, susceptibility testing should be done. If resistance to clarithromycin is demonstrated or susceptibility testing is not possible, alternative antimicrobial therapy should be instituted [see Pharmacology: Adjunctive effect on Helicobacter pylori Eradication under Actions].

The usual adult dose for oral use is 10 mg of sodium rabeprazole administered once daily. However, the dosage may be increased up to 20 mg orally once daily depending on the severity of symptoms.
Adults/elderly: Healing of Erosive or Ulcerative Gastro-Oesophageal Reflux Disease (GERD): The recommended oral dose for this condition is 20 mg to be taken once daily for four to eight weeks. Doses of 10 mg or 20 mg twice daily may be administered orally to reflux esophagitis patients for a further 8 weeks when proton pump inhibitor treatment is ineffective. However, a dose of 20 mg twice daily should only be administered to patients with severe mucosa injury.
Gastro-Oesophageal Reflux Disease Long-term Management (GERD Maintenance): For long-term management, a maintenance dose of PARIET 20 mg or 10 mg once daily can be used depending upon patient response.
For the maintenance therapy of reflux esophagitis when proton pump inhibitor treatment is ineffective, dose of 10 mg twice daily may be administered orally.
Zollinger-Ellison Syndrome: The recommended adult starting dose is 60 mg once a day. The dose may be titrated upwards to 120 mg/day based on individual patient needs. Single daily doses up to 100 mg/day may be given. 120 mg dose may require divided doses, 60 mg twice daily. Treatment should continue for as long as clinically indicated.
Symptomatic treatment of moderate to very severe gastro-oesophageal reflux disease (symptomatic GERD): 10 mg once daily in patients without oesophagitis. If symptom control has not been achieved during four weeks, the patient should be further investigated. Once symptoms have resolved, subsequent symptom control can be achieved using an on-demand regimen taking 10 mg once daily when needed.
Helicobacter pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence in Adults: See Table 8.

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For indications requiring once daily treatment PARIET tablets 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 rabeprazole sodium activity, this regimen will facilitate treatment compliance.
Patients should be cautioned that the PARIET tablets should not be chewed or crushed, but should be swallowed whole.
Renal and hepatic impairment: No dosage adjustment is necessary for patients with renal or hepatic impairment.
Children: PARIET is not recommended for use in children, as there is no experience of its use in this group.
<Precaution>: The patient should be carefully observed during administration and the cumulative dose should be kept to a minimum for the particular symptoms being treated.

Patients with known hypersensitivity to rabeprazole sodium, or to any excipient used in the formulation. PARIET is contra-indicated in pregnancy and during breast feeding.

Careful Administration: PARIET should be administered with care in the following patients: Patients with a history of drug hypersensitivity; Patients with hepatic function disorder [Psychoneurotic adverse reactions have been reported in patients with liver cirrhosis (see Adverse Reactions)]; Elderly patients (see Use in the Elderly as follows).
Important Precautions: PARIET can be administered at a dose of 20 mg once daily in the case of severe, recurrent and intractable conditions.
Precautions concerning Use: Regular Surveillance: Patients on proton pump inhibitor treatment (particularly those treated for long term) should be kept under regular surveillance.
Administration: Since PARIET is an enteric coated tablet, patients should be instructed not to chew or crush the tablet, but swallow it whole.
Caution in handing over drug: For drugs that are dispensed in a press-through package (PTP), instruct the patient to remove the drug from the package prior to use. [It has been reported that, if the PTP sheet is swallowed, the sharp corners of the sheet may puncture the esophageal mucosa, causing perforation and resulting in serious complications such as mediastinitis.]
Other Precautions: It has been reported that in a carcinogenicity study in which 5mg/kg/day or greater of sodium rabeprazole was administered orally to rats for 2 years, carcinoids were observed in the stomachs of female rats.
Increases in thyroid weight and blood thyroxine levels have been reported in animal studies (rats, oral administration of 25mg/kg/day or greater). Therefore, thyroid function should be carefully monitored during the administration of PARIET.
Benign gastric polyp has been reported during long-term administration of PARIET.
Fracture: Proton pump inhibitors, especially if used in high doses and over long durations (>1 year), may modestly increase the risk of hip, wrist and spine fracture, predominantly in older people or in presence of other recognised risk factors. Observational studies suggest that proton pump inhibitors may increase the overall risk of fracture by 10-40%. Some of this increase may be due to other risk factors. Patients at risk of osteoporosis should receive care according to current clinical guidelines and they should have an adequate intake of vitamin D and calcium.
Clostridium difficile Diarrhea: Published observational studies suggest that PPI therapy may be associated with an increased risk of Clostridium difficile associated diarrhea, especially in hospitalized patients. This diagnosis should be considered for diarrhea that does not improve.
Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.
Interference with laboratory test: Increased Chromogranin A (CgA) level may interfere with investigations for neuroendocrine tumours.
To avoid this interference, PARIET treatment should be stopped for at least 5 days before CgA measurements (see Pharmacology: Adjunctive effect on Helicobacter pylori Eradication under Actions). If CgA and gastrin levels have not returned to reference range after initial measurement, measurements should be repeated 14 days after cessation of proton pump inhibitor treatment.
Subacute cutaneous lupus erythematosus (SCLE): Proton pump inhibitors are associated with very infrequent cases of SCLE. If lesions occur, especially in sun-exposed areas of the skin, and if accompanied by arthralgia, the patient should seek medical help promptly and the health care professional should consider stopping PARIET. SCLE after previous treatment with a proton pump inhibitor may increase the risk of SCLE with other proton pump inhibitors.
Hypomagnesaemia: Severe hypomagnesaemia has been reported in patients treated with proton pump inhibitors like PARIET for at least three months, and in most cases for a year.
Serious manifestations of hypomagnesaemia such as fatigue, tetany, delirium, convulsions, dizziness and ventricular arrhythmia can occur but they may begin insidiously and be overlooked. In most affected patients, hypomagnesaemia improved after magnesium replacement and discontinuation of the PPI.
For patients expected to be on prolonged treatment or who take PPI with digoxin or drugs that may cause hypomagnesaemia (e.g., diuretics), health care professionals should consider measuring magnesium levels before starting PPI treatment and periodically during treatment.
Vitamin B12 Deficiency: Daily treatment with any acid-suppressing medications over a long period of time (e.g., longer than 3 years) may lead to malabsorption of cyanocobalamin (vitamin B-12) caused by hypo- or achlorhydria. Rare reports of cyanocobalamin deficiency occurring with acid-suppressing therapy have been reported in the literature. This diagnosis should be considered if clinical symptoms consistent with cyanocobalamin deficiency are observed.
Effects on ability to drive and use machines: 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 the Elderly: PARIET is metabolized mainly in the liver. Since the physiological functions of the liver are often reduced in the elderly, they are more likely to experience adverse reactions. Therefore, if adverse reactions such as gastrointestinal symptoms (see Adverse Reactions) occur, it is advisable to take measures such as instituting a drug-free interval with careful supervision.
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 foetus due to rabeprazole sodium, although low foeto-placental transfer occurs in rats. PARIET is contraindicated during pregnancy.
[Fetotoxicity (delayed ossification in rats, weight loss and delayed ossification in rabbits) has been reported with PARIET in animal studies (400 mg/kg p.o. in rats, 30 mg/kg i.v. in rabbits).]
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. Therefore PARIET should not be used during breast feeding.
[In an animal study (in rats), it has been reported that PARIET is excreted in breast milk.]
Use in Children: PARIET is not recommended for use in children, as there is no experience of its use in this group.

Use during Pregnancy, Delivery or 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 foetus due to rabeprazole sodium, although low foeto-placental transfer occurs in rats. PARIET is contraindicated during pregnancy.
[Fetotoxicity (delayed ossification in rats, weight loss and delayed ossification in rabbits) has been reported with PARIET in animal studies (400 mg/kg p.o. in rats, 30 mg/kg i.v. in rabbits).]
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. Therefore PARIET should not be used during breast feeding.
[In an animal study (in rats), it has been reported that PARIET is excreted in breast milk.]

Adverse reactions were reported in 22 of 1,244 patients (1.77%), and abnormal laboratory test values were reported in 82 (6.59%). (At the time of approval.)
Clinically significant adverse reactions: Shock: It has been reported that anaphylactic reactions or shock occurred with analogue compounds (omeprazole and lansoprazole). If any such abnormality is observed, treatment should be discontinued and appropriate measures taken.
Agranulocytosis, thrombocytopenia and pancytopenia: Agranulocytosis (incidence unknown), thrombocytopenia (5% > ≥0.1%) or pancytopenia (incidence unknown) may occur. If any such abnormality is observed, treatment should be discontinued and appropriate measures taken. It has been reported that hemolytic anemia occurred with analogous compounds (omeprazole and lansoprazole).
Hepatic function disorders: Hepatic function disorders (5% > ≥10%) or jaundice (incidence unknown) may occur. If any such abnormality is observed, treatment should be discontinued and appropriate measures taken.
Interstitial pneumonia: Interstitial pneumonia (incidence unknown) may occur. If symptoms such as fever, coughing, dyspnoea and abnormal lung sounds (crepitations) occur, thoracic radiography or other examination should be performed immediately. Administration should be discontinued, and appropriate measures should be taken, such as treatment with cortical steroid hormones.
Visual disturbance: Visual disturbance has been reported with an analogue compound (omeprazole).
Interstitial Nephritis.
Clostridium difficile associated diarrhea.
Vitamin B12 Deficiency.
Other adverse reactions: See Table 9.

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Post-Marketing Adverse Events: Additional adverse events reported from worldwide marketing experience with sodium rabeprazole are: sudden death, coma and hyperammonemia, jaundice, rhabdomyolysis, disorientation and delirium, bullous and other drug eruptions of the skin, interstitial pneumonia, interstitial nephritis, and TSH elevations. In most instances, the relationship to sodium rabeprazole 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.

It has been reported that the hepatic enzyme cytochromes P450 2C19 (CYP2C19) and 3A4 (CYP3A4) are involved in the metabolism of PARIET. [See Pharmacology: Pharmacokinetics under Actions.]
Precautions for coadministration: PARIET should be administered with care when coadministered with the following drugs. (See Table 10.)

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PARIET should be stored at room temperature not exceeding 30° C and protected from moisture after unsealing.
It is also recommended that PARIET be used as soon as possible 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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