Rabifast XL

Rabeprazole Sodium (GR) & Levosulpiride (PR) Capsules

Rabifast XL

Each hard gelatin capsule contains:

Rabeprazole Sodium IP……………………. 20 mg

(as Gastro-resistant pellets)

Colour: Red Oxide of Iron

Levosulpiride………………………………. 75 mg

(as prolonged release pellets)

Colour: Lake of Sunset Yellow

Approved colours used in hard gelatin capsule shells.

Capsule

Rabeprazole 20 mg and Levosulpiride 75 mg

4.1 Therapeutic Indication

For the treatment of Gastroesophageal Reflux Disease (GERD)

4.2 Posology and method of administration

Adults

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

Paediatric Use

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

Method of administration

Capsule should be swallowed whole & not to be opened, chewed or crushed.

4.3 Contraindications

• Hypersensitivity to the active substances or to any of the excipients
• Pregnancy and Breast feeding
• 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

4.4 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. Patients on long-term treatment (particularly those treated for more than a year) should be kept under regular surveillance.
• 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 (PPI) or substituted benzimidazoles cannot be excluded.
• 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 aetiology 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 authorisation. In the majority of cases where an alternative aetiology 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 PPIs, including rabeprazole, may possibly increase the risk of gastrointestinal infections such as Salmonella, Campylobacter and Clostridium difficile

Hypomagnesaemia

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.

PPIs, 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 PPIs 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.

Concomitant use of rabeprazole with methotrexate

Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum levels 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.

Influence on vitamin B12 absorption

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.

Subacute cutaneous lupus erythematosus (SCLE)

PPIs 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 PPI may increase the risk of SCLE with other PPIs.

Interference with laboratory tests

Increased Chromogranin A (CgA) level may interfere with investigations for neuroendocrine tumours. 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 PPI treatment.

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.

4.5 Drugs interactions

Rabeprazole

Rabeprazole sodium produces a profound and long lasting inhibition of gastric acid secretion. An interaction with compounds whose absorption is pH dependent may occur. Co-administration of rabeprazole sodium with ketoconazole or itraconazole may result in a significant decrease in antifungal plasma levels. Therefore, individual patients may need to be monitored to determine if a dosage adjustment is necessary when ketoconazole or itraconazole are taken concomitantly with rabeprazole.

In clinical trials, antacids were used concomitantly with the administration of rabeprazole and, in a specific drug-drug interaction study, no interaction with liquid antacids was observed.

Co-administration of atazanavir 300 mg/ritonavir 100 mg with omeprazole (40 mg once daily) or atazanavir 400 mg with lansoprazole (60 mg once daily) to healthy volunteers resulted in a substantial reduction in atazanavir exposure. The absorption of atazanavir is pH dependent. Although not studied, similar results are expected with other proton pump inhibitors. Therefore, PPIs, including rabeprazole, should not be co-administered with atazanavir

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 hydroxymethotrexate. However, no formal drug interaction studies of methotrexate with PPIs have been conducted.

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

Rabifast XL is not recommended in human pregnancy.

Breast-feeding

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, Rabifast XL must not be used during breast feeding.

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

4.8 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: 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)

1. Includes facial swelling, hypotension and dyspnoea

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

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

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to: medico@zuventus.com

Website: www.zuventus.co.in and click the tab “Safety Reporting” located on the top end of the home page.

Website link: https://www.zuventus.co.in/drug-safety-reporting

By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

Rabeprazole

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.

5.1 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.

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

5.2 Pharmacodynamic properties

Rabeprazole

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. 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.

Levosulpiride

Like its parent compound, levosulpiride shows antagonism at D3 and D2 receptors present pre-synaptically as well as post-synaptically 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.

5.3 Pharmacokinetic properties

Rabeprazole

Absorption: Rabeprazole, an enteric-coated (gastro-resistant) formulation of rabeprazole sodium. This presentation is necessary because rabeprazole is acid-labile. Absorption of rabeprazole therefore begins only after the capsule 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 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.

Renal dysfunction

In patients with stable, end-stage, renal failure requiring maintenance haemodialysis (creatinine clearance ≤ 5ml/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.

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 2-3 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.

Older people

Elimination of rabeprazole was somewhat decreased in older people. 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.

CYP2C19 polymorphism

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 metabolisers 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.

6.1 Animal Toxicology or Pharmacology

Rabeprazole

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.

Rabifast XL is a combination of Rabeprazole sodium and Levosulpiride.

Rabeprazole sodium is a proton pump inhibitor. It is a substituted benzimidazole that inhibits gastric acid secretion.

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.

8.1 Incompatibilities

Not applicable

8.2 Shelf-life

Refer to the pack

8.3 Packaging information

10 Blister Strips of capsules each

8.4 Storage and handing instructions

• Store protected from light and moisture at a temperature not exceeding 300 C.
• Keep out of reach of children.
• Capsule should be swallowed whole & not to be opened, chewed or crushed.

• Advice patient Not to take the medicine if the patient is
  • Are pregnant or think that you are pregnant.
  • Are breast-feeding.
  • Prolactin-releasing pituitary tumour (prolactinoma).
  • When stimulation of the gastric motility could be harmful e.g. in patients with gastro-intestinal haemorrhage, mechanical obstruction or perforation.
  • In patients with moderate or severe hepatic impairment oIn patients who have known existing prolongation of cardiac conduction intervals, particularly QTc, patients with significant electrolyte disturbances or underlying cardiac diseases such as congestive heart failure
  • Co-administration with QT-prolonging drugs, at the exception of apomorphine
  • Co-administration with potent CYP3A4 inhibitors (regardless of their QT prolonging effects 
• Acute Interstitial Nephritis Advise the patient or caregiver to call the patient’s healthcare provider immediately if they experience signs and/or symptoms associated with acute interstitial nephritis
• Clostridium difficile-Associated Diarrhea Advise the patient or caregiver to immediately call the patient’s healthcare provider if they experience diarrhea that does not improve
• Bone Fracture Advise the patient or caregiver to report any fractures, especially of the hip, wrist or spine, to the patient’s healthcare provider
• Cutaneous and Systemic Lupus Erythematosus Advise the patient or caregiver to immediately call the patient’s healthcare provider for any new or worsening of symptoms associated with cutaneous or systemic lupus erythematosus.
• Cyanocobalamin (Vitamin B-12) Deficiency Advise the patient or caregiver to report any clinical symptoms that may be associated with cyanocobalamin deficiency to the patient’s healthcare provider if they have been receiving rabeprazole sodium delayed-release tablets for longer than 3 years
• Hypomagnesemia Advise the patient or caregiver to report any clinical symptoms that may be associated with hypomagnesemia to the patient’s healthcare provider, if they have been receiving rabeprazole sodium delayed-release tablets for at least 3 months
• Drug Interactions Advise patients to report to their healthcare provider if they are taking rilpivirine-containing products, warfarin, digoxin or high-dose methotrexate, Diltiazem, Pregabalin, Sucralfate, Tramadol, Aluminium Hydroxide/Magnesium Hydroxide, Ipratropium
• 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.
• Administration: Capsule should be swallowed whole & not to be opened, chewed or crushed. Do not take this medicine, if you are allergic to Rabeprazole or Levosulpiride
• Signs of an allergic reaction include a rash, itching or shortness of breath.
• Advice patients to talk to your doctor or pharmacist, if you get any side effects. This includes any possible side effects not listed in this leaflet.
• Advice patients If they have any further questions, ask doctor or pharmacist.

07/2024