APR ROBESEC ADVANCE DSR CAPSULE

G-09A:

INFORMATION FOR THE USER

Rabeprazole sodium20mg (enteric coated)& Domperidone 30mg (sustained release)Capsules

Read all of this information carefully before you start taking this medicine because it contains important information for you.
• Keep this information. You may need to read it again.
• If you have any further questions, ask your doctor, pharmacist or nurse.
• This medicine is prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this information.

1. COMPOSITION:
Each capsule contains:
Rabeprazole sodium(enteric coated) – 40mg
Domperidone (sustained release) – 30mg

For oral use only.

2. DESCRIPTION:
Rabeprazole is an antacid drug. It belongs to a class of drugs known as proton pump inhibitors (PPI’s).
Domperidone is a drug that is useful as an antiemetic & a gastro prokinetic agent. It falls under the category of dopamine D2 receptor antagonist.

3. PHARMACOLOGICAL 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 effect is dose-related & leads to inhibition of both basal & stimulated acid secretion irrespective of the stimulus. It is rapidly disappears from both the plasma & gastric mucosa. As a weak base it is rapidly absorbed following all doses & is concentrated in the acid environment of the parietal cells. It is converted to the active sulphenamide form through protonation & it subsequently reacts with the available cysteines on the proton pump.
Domperidone is a dopamine antagonist with anti-emetic properties. It does not readily cross the blood brain barrier. Extrapyramidal side effects are very rare, but it promotes the release of prolactin from the pituitary. Its anti-emetic effect may be due to a combination of peripheral (gastrokinetic) effects & antagonism of dopamine receptors in the chemoreceptor trigger zone which lies outside the blood-brain barrier in the area postrema. Studies together with the low conc. found in the brain indicate a predominantly peripheral effect on dopamine receptors. It increases lower oesophageal pressure, improves antroduodenal motility & accelerates gastric emptying. There is no effect on gastric secretion.
4. CLINICAL PHARMACOKINETICS:
Absorption begins only after the capsule leaves the stomach. Absorption is rapid with peak plasma levels occurring approx. 3.5 hrs after a 20mg dose. Peak plasma conc. (Cmax) & AUC are linear over the dose range of 10-40mg. Absolute bioavailability is about 52% due in large part to pre-systemic metabolism. Bioavailability does not appear to increase with repeat administration. The plasma half-life is approx. 1 hr (range 0.7-1.5 hrs) & 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. It is approx. 97% bound to human plasma proteins. As is the case with other members of the PPI class it is metabolised through the cytochrome P450 system. It is metabolised by isoenzymes of CYP450. It neither induces nor inhibits CYP3A4 & although. The thioether (M1) & carboxylic acid (M6) are the main plasma metabolites with the sulphone (M2), desmethyl-thioether (M4) & 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. No unchanged drug was excreted in the urine. Approx. 90% was eliminated in urine mainly as the 2 metabolites: a mercapturic acid conjugate (M5) & a carboxylic acid (M6) plus two unknown metabolites. The remainder of the dose was recovered in faeces.
Domperidone is rapidly absorbed after oral administration with peak plasma conc. occurring at approx. 1 hr after dosing. The Cmax& AUC values increased proportionally with dose in the 10mg-20mg range. A 2-3 fold accumulation of AUC was observed with repeated 4 times daily (every 5 hr) dosing for 4 days. The low absolute bioavailability (approx. 15%) is due to an extensive first-pass metabolism in gut wall & liver. Although bioavailability is enhanced when taken after a meal patients with GI complaints should take domperidone 15-30 minbefore a meal. Reduced gastric acidity impairs the absorption. Bioavailability is decreased by prior concomitant administration of cimetidine & sodium bicarbonate. The time of peak absorption is slightly delayed & the AUC somewhat increased when taken after a meal. It does not appear to accumulate/induce its own metabolism; a peak plasma level after 90 min of 21ng/ml after 2 weeks. It is 91-93% bound to plasma proteins. Studies have shown wide tissue distribution, but low brain conc. It undergoes rapid & extensive hepatic metabolism by hydroxylation & N-dealkylation. Urinary & faecal excretions amount to 31 & 66%. The proportion of the drug excreted unchanged is small (10% of faecal excretion & approx. 1% of urinary excretion). Plasma half life is 7-9 hrs but is prolonged in patients with severe renal insufficiency.
5. INDICATIONS:
Rabeprazole& domperidonecapsules are indicated for the relief of:
– short-term treatment of reflux symptoms (e.g. heartburn, acid regurgitation) in adults.

6. CONTRAINDICATIONS:
Rabeprazole& domperidonecapsules are contraindicated in the following cases:

– Hypersensitivity to the active substance/any of the excipients.
– Moderate/severe hepatic impairment.
– Known existing prolongation of cardiac conduction intervals, particularly QTc patients with significant electrolyte disturbances/underlying cardiac diseases such as congestive heart failure.
– Co-administration with QT-prolonging drugs, at the exception of apomorphine.
– Co-administration with potent CY3A4 inhibitors (regardless of their QT prolonging effects).
– Prolactin-releasing pituitary tumour (prolactinoma).
– Renal impairment & hepatic impairment

7. WARNINGS AND PRECAUTIONS:
Symptomatic response to therapy with rabeprazole does not preclude the presence of gastric/oesophageal malignancy. Possibility of malignancy should be excluded prior to commencing treatment.
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/substituted benzimidazoles cannot be excluded.
Patients should be cautioned that capsules should not be chewed or crushed but should be swallowed whole.
Not recommended for use in children as there is no experience of its use in this group.
There have been post marketing reports of blood dyscrasias (thrombocytopenia & neutropenia).
Hepatic enzyme abnormalities have been seen in clinical trials & have also been reported since market authorisation.
Prescriber is advised to exercise caution when treatment is first initiated in such patients with hepatic impairement
Co-administration of atazanavir is not recommended.
Treatment with PPI’s may possibly increase the risk of GI infections such as Salmonella, Campylobacter & Clostridium difficile.
PPIs, especially if used in high doses & over long durations may modestly increase the risk of hip, wrist & spine fracture, predominantly in older people or in presence of other recognised risk factors.
Severe hypomagnesaemia has been reported in patients treated with PPIs for at least 3 months & in most cases for a year. Serious manifestations of hypomagnesaemia such as fatigue, tetany, delirium, convulsions, dizziness & ventricular arrhythmia can occur.
For patients expected to be on prolonged treatment or drugs that may cause hypomagnesaemia (e.g., diuretics), health care professionals should consider measuring magnesium levels before starting PPI treatment.
Concomitant use with methotrexate: May elevate & prolong serum levels of methotrexate &/or its metabolite possibly leading to methotrexate toxicities.
Influence on vitamin B12 absorption: May reduce the absorption of vitamin B12 due to hypo- or a- chlorhydria.
Subacute cutaneous lupus erythematosus (SCLE): Associated with very infrequent cases of SCLE.
Interference with laboratory tests: Increased Chromogranin A level may interfere with investigations for neuroendocrine tumours.
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Use in infants: Since metabolic functions & the blood-brain barrier are not fully developed in the first months of life the risk of neurological side effects is higher in young children. Overdosing may cause extrapyramidal symptoms in children, but other causes should be taken into consideration.
Renal Impairment: Elimination half-life is prolonged in severe renal impairment.
Cardiovascular effects: Has been associated with prolongation of the QT interval on the ECG.
Use with apomorphine: Domperidone is contra-indicated with QT prolonging drugs including apomorphine, unless the benefit of the co-administration with apomorphine outweighs the risks.

8. ADVERSE EFFECTS:
Common side effects include:
– Anxiety, sleep disorders, insomnia
– Headache/dizziness
– Diarrhoea, nausea, vomiting, abdominal distension, bloating
– Increased liver enzymes
– Pruritis, rash
– Asthenia, fatigue, malaise
– Agranulocytosis
– Taste disorders, dry mouth
– Peripheral oedema
– Gallactorrhoea
– Breast pain & tenderness
9. DRUG INTERACTIONS:
May reduce the absorption of active substances whose bioavailability is dependent on the gastric pH (e.g. ketoconazole).
Co-administration of atazanavir/ritonavir with omeprazole resulted in a substantial reduction in the bioavailability of atazanavir. The absorption is pH-dependent. Must not be co-administered with atazanavir.
No interaction during concomitant administration of phenprocoumon/warfarin has been observed in clinical pharmacokinetic studies. A few isolated cases of changes in INR have been reported during concomitant treatment.
Concomitant use of high dose methotrexate &PPI’s has been reported to increase methotrexate levels.
There were no interactions with concomitantly administered antacids.
Concomitant use of the following substances is contraindicated:
• anti-arrhythmics class IA (e.g. disopyramide, hydroquinidine, quinidine)
• anti-arrhythmics class III (e.g. amiodarone, dofetilide, dronedarone, ibutilide, sotalol)
• certain antipsychotics (e.g. haloperidol, pimozide, sertindole)
• certain antidepressants (e.g., citalopram, escitalopram)
• certain antibiotics (e.g. erythromycin, levofloxacin, moxifloxacin, spiramycin)
• certain antifungal agents (e.g. pentamidine)
• certain antimalarial agents (in particular halofantrine, lumefantrine)
• certain gastro-intestinal medicines (e.g. cisapride, dolasetron, prucalopride)
• certain antihistaminics (e.g. mequitazine, mizolastine)
• certain medicines used in cancer (e.g. toremifene, vandetanib, vincamine)
• certain other medicines (e.g. bepridil, diphemanil, methadone)
• apomorphine, unless the benefit of the co-administration outweighs the risks, & only if the recommended precautions for co-administration are strictly fulfilled. Please refer to the apomorphine SmPC.
Potent CYP3A4 inhibitors (regardless of their QT prolonging effects), i.e :
• protease inhibitors
• systemic azole antifungals
• some macrolides (erythromycin, clarithromycin & telithromycin)
Concomitant use of the following substances is not recommended: Moderate CYP3A4 inhibitors i.e. diltiazem, verapamil & some macrolides.
Concomitant use of the following substances requires caution in use: Caution with bradycardia & hypokalaemia-inducing drugs as well as with the following macrolides involved in QT-interval prolongation: azithromycin & roxithromycin (clarithromycin is contraindicated as it is a potent CYP3A4 inhibitor).
Ketoconazole or oral erythromycin: marked inhibition of domperidone’s CYP3A4 mediated first pass metabolism.
10. DOSAGE:
The recommended dose is 1capsule per day.
It might be necessary to take the capsules for 2-3 consecutive days to achieve improvement of symptoms. Once complete relief of symptoms has occurred, treatment should be discontinued.
The treatment should not exceed 4 weeks without consulting a doctor.
If no symptom relief is obtained within 2 weeks of continuous treatment, the patient should be instructed to consult a doctor.

11. ADMINISTRATION:
Rabeprazole & domperidonecapsules are supplied for oral administration & should be swallowed whole with a sufficient quantity of liquid. Do not crush or chew the capsules. Never change the dose of your medicine without talking to your doctor first. Continue to take your capeules for as long as your doctor recommends.
12. PRESENTATION:
13. STORAGE:
Store below 25°C in a cool & dry pace. Protect from direct sunlight. Keep away from the reach of children.

14. MANUFACTURED BY:
15. MARKETED BY:

This leaflet was last revised on October 2020.