CLINICAL PHARMACOLOGY

Pharmacodynamics properties

• Pharmacotherapeutic Group: Drugs for Peptic Ulcer and Gastro-Oesophageal Reflux Disease (GORD), Proton Pump Inhibitors.
• Mechanism of Action: Rabeprazole Sodium belongs to the class of Anti-Secretory 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, Rabeprazole Sodium 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 Sulphenamide form through Protonation and it subsequently reacts with the available Cysteine on the Proton Pump.

Pharmacokinetic properties

• Absorption: Rabeprazole 20mg Gastro-Resistant Tablet is an Enteric-Coated (Gastro-Resistant) Tablet formulation of Rabeprazole Sodium. 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 hours after a 20 mg dose. Peak plasma concentrations (Cmax) of Rabeprazole and AUC are linear over the dose range of 10 mg to 40 mg. Absolute bioavailability of an oral 20 mg dose (compared to intravenous administration) is about 52 % due in large part to pre-systemic metabolism. Additionally the bioavailability does not appear to increase with repeat administration. In healthy subjects the plasma half-life is approximately one hour (range 0.7 to 1.5 hours), and the total body clearance is estimated to be 283 ± 98 ml/min. There was no clinically relevant interaction with food. Neither food nor the time of day of administration of the treatment affect the absorption of Rabeprazole Sodium.
• Distribution: Rabeprazole is approximately 97 % bound to human plasma proteins.
• Biotransformation and elimination: Rabeprazole sodium, as is the case with other members of the Proton Pump Inhibitor (PPI) class of compounds, is Metabolized through the Cytochrome P450 (CYP450) Hepatic Drug Metabolizing system. In vitro studies with human Liver Microsomes indicated that Rabeprazole Sodium is metabolized by Isoenzymes 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. In humans the Thioether (M1) and Carboxylic Acid (M6) are the main plasma metabolites with the Sulphone (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 anti-secretory activity, but it is not present in plasma.

DRUG –DRUG INTERACTIONS

• Effect of Rabeprazole Sodium on other Medicines – Demonstrated Interactions In vitro studies with human liver Microsomes indicated that Rabeprazole Sodium is metabolized by Isoenzymes of CYP450 (CYP2C19 and CYP3A4). Patients may need to be monitored when these drugs are taken together with Rabeprazole.
• Cyclosporine: In vitro incubations Employing Human Liver Microsomes indicated that Rabeprazole inhibited Cyclosporin metabolism with an IC50 of 62 micro molar, a concentration that is over 50 times higher than the Cmax in healthy volunteers following 14 days dosing with 20 mg Rabeprazole. Although in vitro studies may not always be predictive of an in vivo status, these findings indicate that no interaction is expected between Rabeprazole and Cyclosporin.
• Methotrexate: Case reports, published population pharmacokinetic studies and retrospective analyses suggest that concomitant administration of PPIs and Methotrexate (primarily at high dose; may elevate and prolong serum levels of methotrexate and/or its metabolite Hydroxy methotrexate. However, no formal drug interaction studies of Methotrexate with PPIs have been conducted.
• Digoxin: A 22% increase in trough Digoxin levels was observed in normal subjects given both drugs concomitantly.
• Ketoconazole: A 33% decrease in Ketoconazole levels was observed in normal subjects given both drugs concomitantly.
• Atazanavir: Co-administration of Atazanavir with other Proton Pump Inhibitors resulted in a substantial reduction in Atazanavir exposure. The absorption of Atazanavir is pH dependent. Therefore, Rabeprazole should not be co-administered with Atazanavir.
• Mycophenolate Mofetil: Co-administration of Proton-Pump Inhibitors with Mycophenolate Mofetil in healthy and transplant patients has been reported to reduce the exposure to the active metabolite, Mycophenolic Acid. This is possibly due to a decrease in Mycophenolate Mofetil solubility at an increased Gastric PH. The clinical relevance of reduced Mycophenolic Acid exposure on organ rejection has not been established in transplant patients receiving Proton-Pump Inhibitors and Mycophenolate Mofetil. Use Rabeprazole Sodium with caution in transplant patients receiving Mycophenolate Mofetil.
• Clopidogrel: Clopidogrel is metabolized to its active metabolite by CYP2C19. Inhibition of CYP2C19 by Rabeprazole would be expected to result in reduced drug levels of the active metabolite of Clopidogrel and a reduction in its Antiplatelet activity and therefore its clinical efficacy. Concomitant use of Rabeprazole with Clopidogrel should be discouraged.
• Effect of Rabeprazole sodium on other Medicines – Theoretical Interactions Rabeprazole Sodium produces sustained inhibition of Gastric Acid Secretion. An interaction with compounds whose absorption depends on Gastric pH may occur due to the magnitude of acid suppression seen with Rabeprazole Sodium.
• Effect of Rabeprazole Sodium on other Medicines – Potential Interactions that have been Excluded Studies in healthy subjects have shown that Rabeprazole Sodium does not have clinically significant interactions with other drugs metabolized by the CYP450 system. These studies included the drugs Warfarin and Theophylline (as single oral doses), Phenytoin (as a single intravenous dose with supplemental oral dosing), Diazepam (as a single intravenous dose) and Amoxicillin (as single and multiple oral doses).
• Taking Rabeprazole with Antacids produces no clinically relevant changes in plasma Rabeprazole Sodium concentrations. Plasma concentrations of Rabeprazole and the active metabolite of Clarithromycin are increased by 24% and 50% respectively during concomitant administration. This is considered to be a useful interaction during H. pylori eradication.

INDICATIONS

Rabeprazole tablet is indicated for:

• Treatment and prevention of relapse of Gastro-Esophageal Reflux Disease.
• Symptomatic treatment of Gastro-Esophageal Reflux Disease
• Treatment of Duodenal Ulcers
• Treatment of Gastric Ulcers.

Patients whose Gastric and Duodenal Ulceration is not associated with ingestion of Non-steroidal anti-inflammatory drugs (NSAIDs) usually require treatment with Antimicrobial agents in addition to Antisecretory drugs whether on first presentation or on recurrence.

Rabeprazole tablet is also indicated, in combination with Clarithromycin and Amoxicillin, for:

• Eradication of Helicobacter pylori in patients with Peptic Ulcer Disease or Chronic Gastritis
• Healing of Peptic Ulcers in patients with Helicobacter Pylori associated Ulcers.

DOSAGE AND METHOD OF ADMINISTRATION

• Rabeprazole enteric-coated tablets are intended for oral administration. Dosage Rabeprazole tablets should not be chewed or crushed, but should be swallowed whole and should be taken at the same time each day to facilitate treatment compliance. Rabeprazole was taken with or without food in the pivotal clinical trials.
• Adults Treatment of active Gastro-Esophageal Reflux Disease (GORD): The recommended oral dose for this condition is one 20 mg tablet to be taken once daily for four to eight weeks.
• Prevention of Relapse of Gastro-esophageal Reflux Disease (GORD): The recommended oral dose for preventing relapse of GORD, once healing is achieved, is one 10 mg tablet to be taken once daily. If needed this dose should be increased to one 20 mg tablet to be taken once daily.
• Symptomatic Treatment of Gastro-esophageal Reflux Disease (GORD): Treatment should commence at 10 mg once daily in patients without Esophagitis. If no response, the dose should be increased to 20 mg once daily for four weeks. If symptom control has not been achieved within four weeks, the patient should be further investigated.
• Once symptoms have resolved, subsequent symptom control can be achieved using an on demand regimen of one 10 mg tablet to be taken once daily, when needed.
• Treatment of active Duodenal Ulcer and Gastric Ulcer: The recommended oral dose for both Duodenal Ulcer and Gastric Ulcer is one 20 mg tablet to be taken once daily. Some patients with Duodenal Ulcer may respond to one 10 mg tablet taken once daily. Most patients with active Duodenal Ulcer heal within four weeks. However a few patients may require an additional four weeks of therapy to achieve healing. Most patients with Gastric Ulcer heal within six weeks. However, again a few patients may require an additional six weeks of therapy to achieve healing.
• Eradication of H. pylori: Patients with Gastro-Duodenal Ulcers or Chronic Gastritis due to H. pylori infection should be treated with: Rabeprazole 20 mg twice daily + Clarithromycin 500 mg twice daily and Amoxicillin 1 g twice daily for seven days. Eradication of H. pylori with this regimen has been shown to result in the healing of Duodenal or Gastric Ulcers without the need for continued Ulcer therapy.
• Pediatrics Use: Rabeprazole tablet is not recommended for use in children as there is no experience of its use in this group.
• Use in Elderly Patients: No dosage adjustment is necessary in Elderly Patients.
• Use in Patients with Hepatic or Renal Impairment: No dosage adjustment is necessary for patients with Renal Impairment. Patients with mild to moderate Hepatic Impairment experience higher exposure to Rabeprazole Sodium at a given dose than do healthy patients. Caution should be exercised in patients with severe Hepatic Impairment .There are no data on the use of Rabeprazole in combination with Antibiotic Regimens in patients with Renal or Hepatic Impairment.

SIDE EFFECTS

• Headache, Dizziness
• Stomach complaints, such as Diarrhea, Constipation, Stomach Pain, Flatulence (Wind), Nausea, Vomiting.
• Dry mouth
• Runny or Blocked Nose, Sore Throat and discomfort when Swallowing, Cough
• Back pain, Muscle Weakness
• Insomnia
• breast enlargement in men If you experience any of the following, stop taking Rabeprazole and tell your doctor immediately or go to Accident and Emergency at your nearest hospital:
• shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue, throat or other parts of the body; rash, itching, blisters or hives on the skin (signs of an allergic reaction)
• Chest pain
• Bleeding or bruising more easily than normal
• Signs of frequent infections such as fever, severe chills, sore throat or mouth ulcers
• The above list includes serious side effects and you may need medical attention or hospitalization. Other problems are more likely to arise from the ulcer itself rather than the treatment. Contact your doctor immediately if you notice any of the following:
• Pain or indigestion
• vomiting blood or food
• Black (blood-stained) motions under rare circumstances supervised by the doctor, proton pump inhibitors (PPIs) might be used for long periods of time. Some side effects that may occur after prolonged use include:
• Low magnesium. Symptoms can include seizures, dizziness, spasms, cramps or muscle weakness
• Increased risk of fractures of the hip, wrist, or spine
• Vitamin B-12 deficiency Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

WARNING AND PRECAUTIONS

• Symptomatic response to therapy with Rabeprazole does not preclude the presence of Gastric Malignancy, therefore the possibility of Malignancy should be excluded prior to commencing treatment with Rabeprazole. Patients using an on-demand regimen for symptomatic GORD should be further reviewed and/or investigated if symptoms persist beyond 6 months.
• Acute Interstitial Nephritis: Acute interstitial Nephritis has been observed in patients taking Proton-Pump Inhibitors (PPIs) including Rabeprazole Sodium. Acute Interstitial Nephritis may occur at any point during PPI therapy and is generally attributed to an Idiopathic Hypersensitivity Reaction. Discontinue Rabeprazole Sodium if Acute Interstitial Nephritis develops.
• Cyanocobalamin (vitamin B-12) Deficiency: Daily treatment with acid-suppressing medicines over a long period of time (e.g. longer than 3 years) may lead to Mal absorption of Cyanocobalamin (vitamin B-12) caused by Hypo- or Achlorhydria.
• Hypomagnesaemia: Hypomagnesaemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs. Serious adverse events include Tetany, Arrhythmias, and Seizures. In most patients, treatment of Hypomagnesaemia required Magnesium replacement and discontinuation of the PPI.
• For patients expected to be on prolonged treatment or who take PPIs with medications such as Digoxin or drugs that may cause Hypomagnesaemia (e.g. Diuretics), Health Care Professionals may consider monitoring Magnesium levels prior to initiation of PPI treatment and then periodically while treatment continues .
• Fractures: Observational studies suggest that Proton Pump Inhibitor (PPI) therapy may be associated with an increased risk for Osteoporosis-related fractures of the Hip, Wrist, or Spine. The risk of fracture was increased in patients who received high-dose, and long-term PPI therapy (a year or longer).
• Concomitant use of Rabeprazole with Methotrexate: Literature suggests that concomitant use of PPIs with Methotrexate may elevate and prolong serum levels of Methotrexate and/or its metabolite, possibly leading to Methotrexate toxicities. In such high doses Methotrexate administration, a temporary withdrawal of the PPI may be considered in some patients.
• Clostridium Difficile: Treatment with Proton Pump Inhibitors may possibly increase the risk of Gastrointestinal Infections such as Clostridium difficile.
• Sub-Acute cutaneous lupus Erythematous: Sub-Acute Cutaneous Lupus Erythematous (SCLE) has been reported with the use of PPIs. 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 healthcare professionals should consider stopping Rabeprazole. The occurrence of SCLE with previous PPI treatment may increase the risk of SCLE with other PPIs.
• Use in Hepatic Impairment: No dosage adjustment is necessary for patients with Hepatic Impairment. While no evidence of significant drug related safety problems was observed in patients with Hepatic Impairment, it is advised to exercise caution when treatment with Rabeprazole is first initiated in patients with severe Hepatic Dysfunction.
• Effects on laboratory tests: Increased Chromogranin a (CgA) level may interfere with investigations for Neuroendocrine Tumors. CgA increases due to decreased Gastric Acidity. To avoid this interference, Proton Pump Inhibitors should be stopped 14 days before CgA measurements.
• Effects on fertility: Rabeprazole at intravenous doses up to 30 mg/kg/day (plasma AUC of 8.8 µg.h/mL, about 10 times the human exposure at 20 mg/day) was found to have no effect on fertility and reproductive performance of male and female rats.
• Use in pregnancy: Category B1: Rabeprazole sodium should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.
• Use in lactation: Following Intravenous Administration of Rabeprazole to Lactating rats, Radioactivity in milk reached levels that were about 2- to 7-fold higher than levels in the blood. Administration of Rabeprazole to rats in Gestation and during Lactation at doses of 400 mg/kg/day (about 195- or 85times a 20 mg or 40 mg human dose based on mg/m2) resulted in decreases in body weight gain of the pups.
• It is not known whether Rabeprazole Sodium is excreted in human breast milk and there are no studies in Lactating women. Since many drugs are excreted in milk and because of the potential for adverse reactions to nursing infants from Rabeprazole Sodium, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

CONTRAINDICATIONS

• Rabeprazole tablet is contraindicated in patients with known Hypersensitivity to Rabeprazole Sodium, Proton Pump Inhibitors, or any ingredient of this product.