APR PENTAMAAT ADVANCE DSR CAPSULE

G-04A:

INFORMATION FOR THE USER

Pantoprazole sodium 40mg (extended release)& Domperidone (sustained release)40mgCapsules

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:
Pantoprazole sodium (extended release)– 40mg
Domperidone (sustained release) – 10mg

For oral use only.

2. DESCRIPTION:
Pantoprazole 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:
Pantoprazole is a substituted benzimidazole which inhibits the secretion of hydrochloric acid in the stomach by blockade of the proton pumps of the parietal cells. It is converted to its active form in the acidic environment in the parietal cells where it inhibits the H+, K+-ATPase enzyme (final stage in the production of hydrochloric acid).The inhibition is dose-dependent & affects both basal & stimulated acid secretion. Freedom from heartburn & acid reflux symptoms is achieved in 1 week. It reduces acidity in the stomach & thereby increases gastrin in proportion to the reduction in acidity. Increase in gastrin is reversible. Since it binds to the enzyme distal to the receptor level it can inhibit hydrochloric acid secretion independently of stimulation by other substances. The effect is the same whether the active substance is given orally/IV.It increases fasting gastrin levels. They do not exceed the upper limit of normal. During long-term treatment gastrin levels double in most cases. An excessive increase occurs only in isolated cases. Mild-moderate increase in the number of specific endocrine cells in the stomach is observed in a minority of cases during long-term treatment. The formation of carcinoid precursors (atypical hyperplasia)/gastric carcinoids have not been observed.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.Should be discontinued between 5 days & 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.
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:
Pharmacokinetics do not vary after single/repeated administration. In the dose range of 10-80 mg the plasma kinetics are linear after both oral &IV administration.It is completely & rapidly absorbed after oral administration. Absolute bioavailability was found to be about 77%. On average at about 2.0- 2.5 h post administration (tmax) of a single 20mg oral dose, the max. serum conc. (Cmax) of about 1-1.5 µg/ml are achieved. These values remain constant after multiple administration. Concomitant intake of food had no influence on bioavailability (AUC or Cmax), but increased the variability of the lag-time (tlag).Volume of distribution is about 0.15 l/kg & serum protein binding is ~98%. It is almost exclusively metabolized in the liver.Clearance is about 0.1 l/h/kg& terminal half-life (t1/2) about 1 h. There were a few cases of subjects with delayed elimination. Due to specific binding to the proton pumps within the parietal cell the elimination half-life does not correlate with the much longer duration of action.Renal elimination represents the major route of excretion (~ 80%) for the metabolites; the rest is excreted with the faeces. The main metabolite in both serum & urine is desmethylpantoprazole, which is conjugated with sulphate. The half-life of the main metabolite (~ 1.5 h) is not much longer than that of pantoprazole.
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 minutes before 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 are 31 & 66%. The proportion excreted unchanged is small (10% of faecal excretion & approx. 1% of urinary excretion). Plasma half-life is 7-9 hours but is prolonged in patients with severe renal insufficiency.
5. INDICATIONS:
Pantoprazole& domperidonecapsules are indicated for the relief of:
– short-term treatment of reflux symptoms (e.g. heartburn, acid regurgitation) in adults.

6. CONTRAINDICATIONS:
Pantoprazole& 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:
Patients should be instructed to consult a doctor if:
• They have unintentional weight loss, anaemia, GI bleeding, dysphagia, persistent vomiting/vomiting with blood, since it may alleviate symptoms & delay diagnosis of a severe condition. In these cases, malignancy should be excluded.
• They have had previous gastric ulcer/GI surgery.
• They are on continuous symptomatic treatment of indigestion/heartburn for 4/more weeks.
• They have jaundice, hepatic impairment/ liver disease.
• They have any other serious disease affecting general well-being.
• They are aged over 55 years with new/recently changed symptoms.
Patients with long-term recurrent symptoms of indigestion/heartburn should see their doctor at regular intervals. Especially, patients over 55 years taking any non-prescription indigestion/heartburn remedy on a daily basis should inform their pharmacist or doctor.
Patients should not take another proton pump inhibitor or H2 antagonist concomitantly.
Patients should consult their doctor before taking this medicine if they are due to have an endoscopy/urea breath test.
Patients should be advised that the capsules are not intended to provide immediate relief.
Patients may start to experience symptomatic relief after approximately 1 day of treatment but it might be necessary to take it for 7 days to achieve complete heartburn control. Patients should not take pantoprazole as a preventive medicinal product.
Decreased gastric acidity increases gastric counts of bacteria normally present in the GI tract. Treatment with acid-reducing medicinal products leads to a slightly increased risk of GI infections such as Salmonella, Campylobacter, or Clostridium difficile.
PPI’s are associated with very infrequent cases of SCLE. If lesions occur in sun-exposed areas of the skin& if accompanied by arthralgia the patient should seek medical help promptly & the health care professional.
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: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
– 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 & proton-pump inhibitors 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:
Pantoprazole & 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 capsules 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.