Rabeprazole Sodium (EC) & Levosulpride (SR) Capsules Taj Pharma

Quantitative and Qualitative Composition

Each hard gelatin capsule contains:

Rabeprazole Sodium   20 mg
(as enteric-coated pellets)

Levosulpiride       75 mg
(as sustained-release pellets)

Colour: Titanium Dioxide IP, Ferric Oxide (Red) USP-NF & Ferric Oxide (Black) USP-NF

Approved colours used in capsule shell: Titanium Dioxide, Brilliant Blue, Carmoisine, Sunset Supra Yellow & Ponceau 4R

Dosage Form and Strength

Rabeprazole Sodium 20mg Enteric-Coated pellets and Levosulpiride 75mg Sustained release pellets in hard gelatin capsule

Clinical Particulars

Therapeutic Indication

For the treatment of Gastroesophageal Reflux Disease (GERD)

Posology and Method of Administration

One capsule per day on an empty stomach or as directed by Physician

Contraindications

Rabeprazole

Hypersensitivity to the active substance or to any of the excipients listed in section

Pregnancy.

Breast feeding

Levosulpiride

The following are the conditions where the drug should either be used cautiously or is contraindicated:

Elderly people

Children less than 14 years of age

Parkinson disease

Severe renal or hepatic insufficiency

History of epilepsy

Porphyrias

Breast cancer

Alcohol intoxication

Certain tumors like phaeochromocytoma and pituitary prolactinoma

Hypokalemia

Special Warnings and Precautions for Use

Rabeprazole

Symptomatic response to therapy with rabeprazole sodium does not preclude the presence of gastric or oesophageal malignancy, therefore the possibility of malignancy should be excluded prior to commencing treatment with Rabeprazole

Patients on long-term treatment (particularly those treated for more than a year) should be kept under regular surveillance.

A risk of cross-hypersensitivity reactions with other proton pump inhibitor or substituted benzimidazoles cannot be excluded.

Patients should be cautioned that Rabeprazole should not be chewed or crushed but should be swallowed whole.

Rabeprazole is not recommended for use in children due to a lack of data on safety and efficacy.

There have been post marketing reports of blood dyscrasias (thrombocytopenia and neutropenia). In the majority of cases where an alternative etiology cannot be identified, the events were uncomplicated and resolved on discontinuation of rabeprazole.

Hepatic enzyme abnormalities have been seen in clinical trials and have also been reported since market authorization. In the majority of cases where an alternative etiology cannot be identified, the events were uncomplicated and resolved on discontinuation of rabeprazole.

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 rabeprazole in the treatment of patients with severe hepatic dysfunction the prescriber is advised to exercise caution when treatment with Rabeprazole is first initiated in such patients.

Co-administration of atazanavir with rabeprazole is not recommended.

Treatment with proton pump inhibitors, including rabeprazole, may possibly increase the risk of gastrointestinal infections such as Salmonella, Campylobacter and Clostridium difficile

Severe hypomagnesaemia has been reported in patients treated with PPIs like rabeprazole 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 PPIs 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.

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 the elderly 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.

Rabeprazole sodium, as all acid-blocking medicines, may reduce the absorption of vitamin B12 (cyanocobalamin) due to hypo- or a- chlorhydria. This should be considered in patients with reduced body stores or risk factors for reduced vitamin B12 absorption on long-term therapy or if respective clinical symptoms are observed.

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 Rabeprazole. SCLE after previous treatment with a proton pump inhibitor may increase the risk of SCLE with other proton pump inhibitors.

Increased Chromogranin A (CgA) level may interfere with investigations for neuroendocrine tumors. To avoid this interference, Rabeprazole treatment should be stopped for at least 5 days before CgA measurements. 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.

Steady state interactions of rabeprazole and warfarin have not been adequately evaluated in patients. There have been reports of increased 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 rabeprazole sodium and warfarin concomitantly may need to be monitored for increases in INR and prothrombin time.

Acute interstitial nephritis has been observed in patients taking 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

Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum concentrations of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities. In high-dose methotrexate administration, a temporary withdrawal of the PPI may be considered in some patients.

PPI use is associated with an increased risk of fundic gland polyps that increases with long-term use, especially beyond one year. Most PPI users who developed fundic gland polyps were asymptomatic and fundic gland polyps were identified incidentally on endoscopy. Use the shortest duration of PPI therapy appropriate to the condition being treated.

Levosulpiride

Caution should be exercised in patients with history of neuroendocrine tumor, epilepsy, manic states, abnormally-high levels of prolactin in the blood, painful, lumpy breasts, heart disease, any allergy, during pregnancy and breastfeeding.

Drug Interactions

Rabeprazole

Clinically Relevant Interactions Affecting Drugs Co-Administered with Rabeprazole Sodium and Interactions with Diagnostics:

Antiretrovirals
Clinical Impact:The effect of PPI on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known.

•  Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir, and nelfinavir) when used concomitantly with rabeprazole may reduce antiviral effect and promote the development of drug resistance.

•  Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with rabeprazole may increase toxicity.

•  There are other antiretroviral drugs which do not result in clinically relevant interactions with rabeprazole.

Intervention:Rilpivirine-containing products: Concomitant use with rabeprazole sodium is contraindicated

Atazanavir: See prescribing information for atazanavir for dosing information.

Nelfinavir: Avoid concomitant use with rabeprazole sodium. See prescribing information for nelfinavir.

Saquinavir: See the prescribing information for saquinavir and monitor for potential saquinavir toxicities.

Other antiretrovirals: See prescribing information.

Warfarin
Clinical Impact:Increased INR and prothrombin time in patients receiving PPIs, including rabeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death
Intervention:Monitor INR and prothrombin time. Dose adjustment of warfarin may be needed to maintain target INR range. See prescribing information for warfarin.
Methotrexate
Clinical Impact:Concomitant use of rabeprazole with methotrexate (primarily at high dose) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of methotrexate with PPIs have been conducted
Intervention:A temporary withdrawal of rabeprazole sodium may be considered in some patients receiving high dose methotrexate administration.
Digoxin
Clinical Impact:Potential for increased exposure of digoxin.
Intervention:Monitor digoxin concentrations. Dose adjustment of digoxin may be needed to maintain therapeutic drug concentrations. See prescribing information for digoxin.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole, itraconazole)
Clinical Impact:Rabeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
Intervention: Mycophenolate mofetil (MMF): Co-administration of PPIs in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving rabeprazole sodium and MMF. Use rabeprazole sodium with caution in transplant patients receiving MMF.

See the prescribing information for other drugs dependent on gastric pH for absorption.

Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact:Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated.
Intervention:See Contraindications and Warnings and Precautions in prescribing information for clarithromycin.
Tacrolimus
Clinical Impact:Potentially increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.
Intervention:Monitor tacrolimus whole blood trough concentrations. Dose adjustment of tacrolimus may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact:Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors.
Intervention:Temporarily stop rabeprazole sodium  treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g. for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
Interaction with Secretin Stimulation Test
Clinical Impact:Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Intervention:Temporarily stop treatment with rabeprazole sodium at least 14 days before assessing to allow gastrin levels to return to baseline.
False Positive Urine Tests for THC
Clinical Impact:There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs.
Intervention:An alternative confirmatory method should be considered to verify positive results.

 

Levosulpiride

Antacids and Sucralfate: They can decrease the absorption of the drug from the intestine. So, these medicines should not be taken along with levosulpiride. There should be a minimum 2 hour time lag between the two medicines.

Alcohol : there is increased chance of sedation.

Smoking: increased metabolism of the drug may require higher dose.

Antihypertensive medications: concomitant use may enhance the hypotensive effect seen with the drug.

Anticholinergics: increased incidence of anticholinergic side effects.

Levo dopa: It may oppose the antipsychotic action of the drug, conversely levosulpiride can cause decrease the efficacy of levo-dopa in the management of Parkinsonism.

Arrhythmia especially prolonged QT interval with the concurrent use of

Atomoxetine

Antiarrhythmics

Terfenadine

Chloroquine, quinine

Cisapride

Drugs causing hypokalemia (corticosteroids, laxatives, diuretics like furosemide)

Use in Special Populations

Pregnancy

There are no data on the safety of Rabicip L in human pregnancy.

Lactation

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, Rabicip must not be used during breast feeding.

Paediatric Use

Rabeprazole are not recommended for use in children due to a lack of data on safety and efficacy.

Effects on Ability to Drive and Use Machines

Based on the pharmacodynamic properties and the adverse events profile, it is unlikely that Rabeprazole 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.

Do not drive a car or operate machinery while Levosulpiride may cause dizziness or drowsiness.

Undesirable Effects

Rabeprazole

The most commonly reported adverse drug reactions, during controlled clinical trials with rabeprazole were headache, diarrhoea, abdominal pain, asthenia, flatulence, rash and dry mouth. The majority of adverse events experienced during clinical studies were mild or moderate in severity, and transient in nature.

The following adverse events have been reported from clinical trial and post-marketed experience.

Frequencies are defined as: 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), not known (cannot be estimated from the available data)

System Organ ClassCommonUncommonRareVery RareNot known
Infections and infestationsInfection
Blood and lymphatic system disordersNeutropenia

Leucopenia

Thrombocytopenia

Leucocytosis

Immune system disordersHypersensitivity1,2
Metabolism and nutrition disordersAnorexiaHyponatremia

Hypomagnesaemia4

Psychiatric disordersInsomniaNervousnessDepressionConfusion
Nervous system disordersHeadache

Dizziness

Somnolence
Eye disordersVisual disturbance
Vascular disordersPeripheral oedema
Respiratory, thoracic and mediastinal disordersCough

Pharyngitis

Rhinitis

Bronchitis

Sinusitis

Gastrointestinal disordersDiarrhoea

Vomiting

Nausea

Abdominal pain

Constipation

Flatulence

Fundic gland polyps (benign)

Dyspepsia

Dry mouth

Eructation

Gastritis

Stomatitis

Taste disturbance

Microscopic colitis
Hepatobiliary disordersHepatitis

Jaundice

Hepatic encephalopathy3

Skin and subcutaneous tissue disordersRash

Erythema2

Pruritus

Sweating

Bullous reactions2

Erythema multiforme, toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS)Subacute cutaneous lupus erythematosus
Musculoskeletal and connective tissue disordersNon-specific pain

Back pain

Myalgia

Leg cramps

Arthralgia

Fracture of the hip,wrist or spine

Renal and urinary disordersUrinary tract infectionInterstitial nephritis
Reproductive system and breast disordersGynecomastia
General disorders and administration site conditionsAsthenia

Influenza like illness

Chest pain

Chills

Pyrexia

InvestigationsIncreased hepatic enzymes3Weight increased

 

1 Includes facial swelling, hypotension and dyspnea

2 Erythema, bullous reactions and hypersensitivity reactions have usually resolved after discontinuation of therapy.

3 Rare reports of hepatic encephalopathy have been received in patients with underlying cirrhosis. In treatment of patients with severe hepatic dysfunction the prescriber is advised to exercise caution when treatment with Rabeprazole is first initiated in such patients

4 See Special warnings and precautions for use

Proton pump inhibitor use was found to be associated with increased risks for acute kidney injury and chronic kidney disease.

Levosulpiride

The following side effects can occur with the use of this drug;

Acute muscular dystonia characterized by abnormal movements (twitching, tremor etc.) of hands, leg, tongue and facial muscles.

Sedation or drowsiness (because of decrease in sensory inputs to reticular activating system)

Increase in plasma prolactin levels manifested by breast enlargement, production

of milk and stopping of menstrual periods. This can be taken care of with the use of lower dose of this drug.

Neuroleptic malignant syndrome (characterized by hyperpyrexia, muscle rigidity,

increased myoglobin and creatine kinase; the last two suggestive of muscle damage.

Akathisia (uncontrollable desire to move about without any anxiety).

Tardive dyskinesia, it occurs late in the therapy and its features include involuntary rhythmical movements of face, mouth and jaw. The reason for tardive dyskinesia is synthesis of newer DA receptors which are supersensitive to even a small amount of DA. This causes a decrease in cholinergic activity in the striatum followed by decrease in GABA release. This decreased in inhibitory GABA is responsible for increased involuntary motor activity.

Postural hypotension (because of autonomic blockade), tolerance develops to this effect after some time.

Weight gain.

Elevated liver transaminases.

Reporting of suspected adverse reactions

If you experience any side effects, talk to your doctor or pharmacist. By reporting side effects, you can help provide more information on the safety of this product.

Overdose

Experience to date with deliberate or accidental overdose is limited. The maximum established exposure has not exceeded 60 mg twice daily, or 160 mg once daily. Effects are generally minimal, representative of the known adverse event profile and reversible without further medical intervention. No specific antidote is known. Rabeprazole sodium is extensively protein bound and is, therefore, not dialysable. As in any case of overdose, treatment should be symptomatic and general supportive measures should be utilised.

Pharmacological Properties

Mechanism of Action

Rabeprazole

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 cysteines on the proton pump.

Levosulpiride

Levosulpride is an atypical antipsychotic agent that blocks the presynaptic dopaminergic D2 receptors.

Pharmacodynamic Properties

Rabeprazole

Anti-secretory activity: After oral administration of a 20 mg dose of rabeprazole sodium the onset of the anti-secretory effect occurs within one hour, with the maximum effect occurring within two to four hours. Inhibition of basal and food stimulated acid secretion 23 hours after the first dose of rabeprazole sodium are 69 % and 82 % respectively and the duration of inhibition lasts up to 48 hours. The inhibitory effect of rabeprazole sodium on acid secretion increases slightly with repeated once-daily dosing, achieving steady state inhibition after three days. When the drug is discontinued, secretory activity normalises over 2 to 3 days.

Decreased gastric acidity due to any means, including proton pump inhibitors such as rabeprazole, increases counts of bacteria normally present in the gastrointestinal tract. Treatment with proton pump inhibitors may possibly increase the risk of gastrointestinal infections such as Salmonella, Campylobacter and Clostridium difficile.

Serum gastrin effects: In clinical studies patients were treated once daily with 10 or 20 mg rabeprazole sodium, for up to 43 months duration. Serum gastrin levels increased during the first 2 to 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 to 2 weeks after discontinuation of 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.

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.

Human gastric biopsy specimens from the antrum and the fundus from over 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 H. pylori infection. In over 250 patients followed for 36 months of continuous therapy, no significant change in findings present at baseline was observed.

Other effects: Systemic effects of rabeprazole sodium in the CNS, cardiovascular and respiratory systems have not been found to date. Rabeprazole sodium, 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, oestrogen, testosterone, prolactin, cholecystokinin, secretin, glucagon, follicle stimulating hormone (FSH), luteinising hormone (LH), renin, aldosterone or somatotrophic hormone.

Studies in healthy subjects have shown that rabeprazole sodium does not have clinically significant interactions with amoxicillin. Rabeprazole does not adversely influence plasma concentrations of amoxicillin or clarithromycin when co-administered for the purpose of eradicating upper gastrointestinal H. pylori infection.

Levosulpiride

Like its parent compound, levosulpiride shows antagonism at D3 and D2 receptors present presynaptically as well as postsynaptically in the rat striatum or nucleus accumbens. The preferential binding of the presynaptic dopamine receptors decreases the synthesis and release of dopamine at low doses whereas it causes postsynaptic D2 receptor antagonism at higher dose. This receptor profile of the drug along with its limbic selectivity explains its effectiveness in the management of both positive and negative symptoms of schizophrenia.

Pharmacokinetic Properties

Rabeprazole

Rabeprazole 20 mg is an enteric-coated pellet formulation of rabeprazole sodium. This presentation is necessary because rabeprazole is acid-labile. Absorption of rabeprazole therefore begins only after the pellet 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.

Rabeprazole is approximately 97 % bound to human plasma proteins.

Rabeprazole sodium, as is the case with other members of the proton pump inhibitor (PPI) class of compounds, is metabolised through the cytochrome P450 (CYP450) hepatic drug metabolising system. In vitro studies with human liver microsomes indicated that rabeprazole sodium is metabolised 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.

Following a single 20 mg 14C labelled oral dose of rabeprazole sodium, no unchanged drug was excreted in the urine. Approximately 90 % of the dose was eliminated in urine mainly as the two metabolites: a mercapturic acid conjugate (M5) and a carboxylic acid (M6), plus two unknown metabolites. The remainder of the dose was recovered in faeces.

Adjusted for body mass and height, there are no significant gender differences in pharmacokinetic parameters following a single 20 mg dose of rabeprazole.

In patients with stable, end-stage, renal failure requiring maintenance haemodialysis (creatinine clearance ≤5 ml/min/1.73 m2), the disposition of rabeprazole was very similar to that in healthy volunteers. The AUC and the Cmax in these patients was about 35 % lower than the corresponding parameters in healthy volunteers. The mean half-life of rabeprazole was 0.82 hours in healthy volunteers, 0.95 hours in patients during haemodialysis and 3.6 hours post dialysis. The clearance of the drug in patients with renal disease requiring maintenance haemodialysis was approximately twice that in healthy volunteers.

Following a single 20 mg dose of rabeprazole to patients with chronic mild to moderate hepatic impairment the AUC doubled and there was a 2-3-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 Cmax to only 1.2-fold. The half-life of rabeprazole in patients with hepatic impairment was 12.3 hours compared to 2.1 hours in healthy volunteers. The pharmacodynamic response (gastric pH control) in the two groups was clinically comparable.

Elimination of rabeprazole was somewhat decreased in the elderly. Following 7 days of daily dosing with 20 mg of rabeprazole sodium, the AUC approximately doubled, the Cmax increased by 60 % and t½ increased by approximately 30 % as compared to young healthy volunteers. However, there was no evidence of rabeprazole accumulation.

Following a 20 mg daily dose of rabeprazole for 7 days, CYP2C19 slow metabolisers, had AUC and t½ which were approximately 1.9 and 1.6 times the corresponding parameters in extensive metabolizers whilst Cmax had increased by only 40 %.

Levosulpiride

The parent drug is given in a dose of 400-1800 mg orally daily although a much lower dose is effective for producing antidepressant effect (about 50-300 mg).The plasma t1/2 of the drug is about 6-8 hours. The drug is chiefly excreted through the renal route.

Non-Clinical Properties

Animal Toxicology or Pharmacology

Non-clinical 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.

Description

Rabeprazole and Levosulpride Capsule contains Rabeprazole and Levosulpiride.

Rabeprazole

Rabeprazole sodium, which is a proton pump inhibitor. It is a substituted benzimidazole known chemically as 2–methyl]sulfinyl]-1H–benzimidazole sodium salt. It has a molecular formula of C18H20N3NaO3S and a molecular weight of 381.42. Rabeprazole sodium is a white to off-white, hygroscopic powder. It is freely soluble in methanol and methylene chloride. The stability of rabeprazole sodium is a function of pH; it is rapidly degraded in acid media and is more stable under alkaline conditions.

Levosulpiride

Levosulpiride is the levo enantiomer of sulpiride. It is a substituted benzamide which is meant to be used for several indications: depression, psychosis, somatoform disorders, emesis and dyspepsia. It is physically present as a white crystalline powder.

Pharmaceutical Particulars

Incompatibilities

NA

Shelf-Life

As on Pack

Packaging Information

Strip pack containing 10 capsules

Storage and Handling Instructions

Store protected from light & moisture, at a temperature not exceeding 30○ C

Manufactured in India by:

TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com

Rabeprazole Sodium (EC) & Levosulpride (SR) Capsules Taj Pharma

Patient Counselling Information

 What Rabeprazole and Levosulprideare and what they are used for

Rabeprazole and Levosulpride is a medicine which contains Rabeprazole and Levosulpiride

Rabeprazole

Rabeprazole belong to a group of medicines called Proton Pump Inhibitors (PPIs). Rabeprazole act by reducing the amount of acid made by the stomach. Rabeprazole are used to treat:

  • ulcer in the upper part of the intestine (duodenal ulcer)
  • gastro-esophageal reflux disease (GERD) with or without ulcer.

GERD is commonly referred to as inflammation of the gullet caused by acid and associated with heartburn. Heartburn is a burning feeling rising from the stomach or lower chest up towards the neck. Rabeprazole may be used as a long term treatment of GERD (GORD maintenance). Rabeprazole may also be used for the symptomatic treatment of moderate to very severe gastro-oesophageal reflux disease (symptomatic GERD).

  • Zollinger-Ellison Syndrome, which is a condition when the stomach makes extremely high amounts of acid.

Levosulpiride 

Levosulpiride belongs to the class of antipsychotic medicines. However, it is primarily used for its gut motility properties i.e to improve food movement and treats disorders of the stomach and intestines. This medicine works by inhibiting the action of certain specific neurotransmitters in the brain and specific regions of the stomach and the intestine.

Do not take if you have an allergy to the drug

Do not take this medicine if you

  • are allergic to rabeprazole sodium, Levosulpiride or any of the other ingredients of this medicine

Before you take this drug, tell your healthcare practitioner about other medications you may be taking

Rabeprazole

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. This is especially important in case you are taking any of the following medicines:

  • atazanavir (used to treat HIV); it is not recommended to take Rabeprazole if you are taking atazanavir.
  • ketoconazole or itraconazole (used to treat infections caused by a fungus).

Levosulpiride

All drugs interact differently for person to person. You should check all the possible interactions with your doctor before starting any medicine.

Interaction with Alcohol: Consumption of alcohol while taking this medicine can cause CNS depression characterized by confusion, lack of focus, anxiety, drowsiness etc.

Avoid or limit the uptake of alcohol while taking this medicine as the risk of adverse effects are increasingly high. Contact your doctor if an excess of drowsiness is experienced.

Interaction with Medicine

  • Diltiazem
  • Pregabalin
  • Sucralfate
  • Tramadol
  • Aluminium Hydroxide/Magnesium Hydroxide
  • Ipratropium

Disease interactions

  • Heart Disease: This medicine should be used with caution in patients suffering from a disease of the heart and blood vessels. You may require an adjusted dose and safety monitoring to safely use this medicine.
  • Gastro-intestinal bleeding: This medicine should be used with extreme caution in patients suffering from perforation and bleeding of the stomach and the intestine. Report any instance of fever with chills, nausea, vomiting, presence of blood in stool to the doctor.
  • Prolactin imbalance: This medicine should not be used in patients having an abnormal level of the hormone prolactin. Breast cancer due to a high level of prolactin should be ruled out before treatment with this medicine is initiated.
  • Neuroleptic Malignant Syndrome (NMS): Use of this medicine is not recommended if the patient suffers from Neuroleptic malignant syndrome. Introduction or reintroduction of this medicine should be done with caution in patients having a known history of this syndrome.
  • Asthma: This medicine should be used with caution if you have asthma. Report any instances of difficulty in breathing, wheezing, chest pain etc to the doctor immediately.

Lab interactions

Prolactin test: Report the use of this medicine before undergoing a laboratory test to determine the levels of the hormone prolactin in the body. This medicine can interfere with the test and yield false positive results.

This is not an exhaustive list of possible drug interactions. You should consult your doctor about all the possible interactions of the drugs you’re taking.

How should you take this medicine?

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.

The recommended dose is: Once capsule once daily

If you take more this medicine than you should:

If you have taken more this medicine than prescribed by your doctor, seek medical advice.

If you forget to take this medicine

Do not take a double dose to make up for a forgotten dose. If you forget to take a dose, take it as soon as you remember. If it is almost time to take the next dose, wait until then.

What are the possible side effects?

Rabeprazole

Like all medicines, this medicine can cause side effects, although not everybody gets them. If you notice any of the following serious side effects, stop taking Rabeprazole and contact a doctor immediately:

  • sudden wheezing, swelling of your lips, face or body, rash, fainting or difficulties swallowing (severe allergic reaction).
  • yellow skin, dark urine and tiredness which can be symptoms of liver problems.
  • reddening of the skin with blisters or peeling and may be associated with a high fever and joint pains. There may also be severe blisters and bleeding in the lips, eyes, mouth, nose and genitals. This could be erythema multiforme, Stevens-Johnson syndrome or toxic epidermal necrolysis.

Common side effects (may affect up to 1 in 10 people):

  • cough, sore throat (inflammation of the pharynx), runny nose.
  • nausea, vomiting, abdominal pain, diarrhoea, constipation, wind (flatulence).
  • back pain, non-specific pain. • weakness or loss of strength, flu like symptoms.
  • sleeplessness.
  • headache, dizziness.
  • infection.
  • benign polyps in the stomach.

Uncommon side effects (may affect up to 1 in 100 people):

  • nervousness.
  • sleepiness. • inflammation of the bronchial tubes (bronchitis), inflammation of the sinuses (sinusitis).
  • indigestion, dry mouth, belching.
  • rash, skin redness (erythema).
  • muscle pains, joint pains, leg cramps.
  • urinary tract infection.
  • chest pain, chills, fever.
  • increased liver enzymes, which is measured by blood tests.
  • fracture of the hip, wrist or spine.

Rare side effects (may affect up to 1 in 1,000 people):

  • blood problems such as reduced number of white cells or platelets. This can cause weakness, bruising or make infections more likely.
  • increased number of white blood cells.
  • allergic reactions including facial swelling, low blood pressure and breathing difficulties.
  • loss of appetite.
  • depression.
  • visual disturbance.
  • inflammation of the stomach, inflammation of the mouth, taste disturbance.
  • inflammation of the liver, jaundice (yellowing of the skin or eyes), brain disturbance associated with liver failure (hepatic encephalopathy).
  • itching, sweating, skin blisters.
  • kidney inflammation (interstitial nephritis).
  • increased weight.

Very rare side effects (may affect up to 1 in 10,000 people):

  • sudden onset of severe rash or blistering or peeling skin. This may be associated with a high fever and joint pains (erythema multiforme, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN)). Not known (frequency cannot be estimated from the available data):
  • low levels of sodium in the blood.
  • confusion.
  • swelling of the feet and ankles.
  • enlarged breasts in men.
  • If you are on Rabeprazole for more than three months it is possible that the levels of magnesium in your blood may fall. Low levels of magnesium can be seen as fatigue, involuntary muscle contractions, disorientation, convulsions, dizziness, increased heart rate. If you get any of these symptoms, please tell your doctor promptly. Low levels of magnesium can also lead to a reduction in potassium or calcium levels in the blood. Your doctor may decide to perform regular blood tests to monitor your levels of magnesium.
  • rash, possibly with pain in the joints.
  • inflammation of the gut (leading to diarrhoea).

Levosulpiride

Major & minor side effects for Levosulpiride

Drowsiness

Breast tenderness

Irregular menstrual periods

Gynacomastia

Cosntipation

Abdominal pain and cramps

Weight gain

Sleeplessness

Unusual tiredness and weakness

Increased salivation

Decrease in libido

Fever

Excessive sweating

Change in heart rate

How should I store this medicine?

Keep this medicine out of the sight and reach of children.

Store protected from light & moisture, at a temperature not exceeding 30○ C

Store in the original package in order to protect from moisture. Do not use this medicine after the expiry date which is stated on the carton and blister after EXP. The expiry date refers to the last day of that month. Do not throw away any medicines via wastewater or household waste.

Ask your pharmacist how to throw away medicines you no longer use. These measures will help to protect the environment.

General information about the safe and effective use of this medicine.

Rabeprazole

Do not take Rabeprazole if you

  • are pregnant or breast-feeding.

Warnings and precautions

Talk to your doctor, pharmacist or nurse before taking Rabeprazole if you

  • are allergic to other proton pump inhibitors.
  • have or have had any liver problems.
  • are taking a medicine called atazanavir (used to treat HIV).
  • have reduced body stores or risk factors for reduced vitamin B12 and receive long term treatment with rabeprazole sodium. As with all acid reducing agents, rabeprazole sodium may lead to a reduced absorption of vitamin B12.
  • if you are due to have a specific blood test (Chromogranin A).
  • if you have ever had a skin reaction after treatment with a medicine similar to

Rabeprazole that reduces stomach acid. If you get a rash on your skin, especially in areas exposed to the sun, tell your doctor as soon as you can, as you may need to stop your treatment with Rabeprazole. Remember to also mention any other ill effects like pain in your joints.

If the above applies to you, consult your doctor before taking Rabeprazole. Your doctor may perform or have performed an additional investigation called an endoscopy in order to diagnose your condition and/or exclude malignant disease.

The possibility of stomach and oesophageal tumours should be excluded before the treatment is started. If you take Rabeprazole on a long-term basis (longer than one year) your doctor will probably monitor, you regularly. You should report any new or different symptoms whenever you see your doctor. Taking a proton pump inhibitor like Rabeprazole, especially over a period of more than one year, may slightly increase your risk of fracture of the hip, wrist or spine. Tell your doctor if you have osteoporosis or if you are taking corticosteroids (which can increase the risk of osteoporosis).

Talk to your doctor straight away if you experience severe (watery or bloody) or persistent diarrhoea with symptoms such as fever, abdominal pain or tenderness, as rabeprazole has been associated with a small increase in infectious diarrhoea

Some abnormal blood values have been reported during treatment with Rabeprazole. Usually, the values become normal when the treatment is discontinued. Children Rabeprazole are not recommended for use in children.

Pregnancy and breast-feeding

Rabeprazole must not be used during pregnancy and breast-feeding. If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

Driving and using machines

It is unlikely that Rabeprazole would affect your ability to drive or operate machinery. However, occasionally rabeprazole can cause sleepiness. Therefore, driving and operating complex machinery should be avoided if you are affected

Levosulpiride

Warnings for special population

Pregnancy

Use of this medicine during pregnancy is not recommended unless absolutely necessary. It is advised to use this medicine only when the benefits outweigh the risks involved.

Breast-feeding

Use of this medicine by breastfeeding women is not recommended. However, if it is absolutely necessary to use this medicine, then breastfeeding should be discontinued. Consult your doctor before using this medicine.

General warnings

  • Heart disease: This medicine should be used with caution in patients having a history of stroke, blood clotting disorders or other ailments of the heart and blood vessels.
  • Diabetes: This medicine should be used with caution in patients who are suffering from diabetes or are exposed to the risk factors.
  • Hypokalemia: This medicine should be used with caution in patients having low potassium levels in the body. It is recommended to initiate treatment with Levosulpiride only after the potassium deficit is corrected.
  • Breast cancer: This medicine is not recommended for use if the patient is suspected to have breast cancer associated with abnormally high levels of prolactin in the body.
  • Drowsiness: This medicine is known to cause moderate to severe drowsiness and may the ability to perform tasks that require a high level of mental alertness. It is advised to refrain from driving or operating any heavy machinery after consuming this medicine.
  • Leukopenia: This medicine is not recommended for use in patients who have a decreased white blood cell count characterized by frequent infections, fever with chills, sore throat, and mouth ulcers.
  • Use in elderly: This medicine should be used with caution in the elderly as the risk of side effects are increasingly high. Appropriate dose adjustments should be made based on the response of the patients.
  • Menstrual abnormalities: Use of this medicine has been associated with abnormalities in menstrual period. Contact your doctor if the regular periods are excessively delayed.

Miscellaneous

  • To be taken before food
  • To be taken as instructed by doctor
  • May cause sleepiness
  • Avoid or limit the uptake of alcohol while taking this medicine as the risk of adverse effects are increasingly high. Contact your doctor if an excess of drowsiness is experienced.
  • No habit forming tendencies were reported.

What are the ingredients in this medicine?

Each hard gelatin capsule contains:

Rabeprazole Sodium       20mg
(as enteric-coated pellets)

Levosulpiride                  75mg
(as sustained-release pellets)

Colour: Titanium Dioxide IP, Ferric Oxide (Red) USP-NF & Ferric Oxide (Black) USP-NF

Approved colours used in capsule shell: Titanium Dioxide, Brilliant Blue, Carmoisine, Sunset Supra Yellow & Ponceau 4R.

Any other information

None.

Manufactured in India by:

TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com