Repigut 20 and 40 mg Gastric-resistant tablets.

REPIGUT is indicated for the following (see sections 4.4 and 5.1):

• Gastro-Oesophageal Reflux Disease (GORD)
• Treatment of erosive reflux oesophagitis
• Long-term management of patients with healed oesophagitis to prevent relapse
• Symptomatic treatment of Gastro-Oesophageal Reflux Disease (GORD).
• Patients requiring continued NSAID therapy:
• prevention of gastric and duodenal ulcers associated with non-steroidal anti-inflammatory drug (NSAID) therapy in patients at risk.
• In combination with appropriate antibacterial therapeutic regimen for the eradication of Helicobacter pylori:
• healing of Helicobacter pylori associated duodenal ulcer
• prevention of relapse of peptic ulcers in patients with Helicobacter pylori associated ulcer disease.
• REPIGUT has been used in pathological hypersecretory conditions including Zollinger-Ellison syndrome and idiopathic hypersecretion.

Posology

• Gastro-Oesophageal Reflux Disease (GORD):
• Treatment of erosive reflux oesophagitis: 40 mg once daily for 4 weeks. An additional 4-week treatment is recommended for patients in whom oesophagitis has not healed or who have persistent symptoms. If gastro-oesophageal reflux disease (GORD) symptom control has not been achieved after four weeks of treatment with the prescribed daily dose, especially where differentiation of diagnosis of GORD with angina and congestive heart failure is present, further investigation is recommended.
• Long-term management of patients with healed oesophagitis to prevent relapse: 20 mg once daily.
• Symptomatic treatment of Gastro-oesophageal Reflux Disease (GORD): 20 mg once daily in patients without oesophagitis: If symptom control has not been achieved after 4 weeks, the patient should be further investigated. Once symptoms have resolved, subsequent symptom control can be achieved using an on-demand regimen, taking 20 mg once daily, when needed.
• Patients requiring continued NSAID therapy:
• Prevention of gastric and duodenal ulcers associated with NSAID therapy in patients at risk: 20 mg or 40 mg once daily.
• In combination with appropriate antibacterial therapeutic regimens for the eradication of Helicobacter pylori and healing of Helicobacter pylori associated duodenal ulcer and prevention of relapse of peptic ulcers in patients with Helicobacter pylori associated ulcer disease:
• 20 mg REPIGUT with 1 g amoxicillin and 500 mg clarithromycin, all twice daily for 7 days.
• Pathological hypersecretory conditions including Zollinger-Ellison syndrome and idiopathic hypersecretion:
• The recommended initial dosage is 40 mg twice daily. The dosage should then be individually adjusted, and treatment continued as long as clinically indicated. Doses up to 120 mg twice daily have been administered.

Adolescents 12-18 years

• Gastro-Oesophageal Reflux Disease (GORD):
• Treatment of erosive reflux oesophagitis: 40 mg once daily for 4 weeks. An additional 4-week treatment is recommended for patients in whom oesophagitis has not healed or who have persistent symptoms.
• Long-term management of patients with healed oesophagitis to prevent relapse: 20 mg once daily.
• Symptomatic treatment of Gastro-oesophageal Reflux Disease (GORD): 20 mg once daily in patients without oesophagitis. If symptom control has not been achieved after 4 weeks, the patient should be further investigated. Once symptoms have resolved, subsequent symptom control can be achieved using an on-demand regimen, taking 20 mg once daily, when needed.
• Doses over 1 mg/kg/day have not been studied.

Special populations

• Impaired renal function: Dose adjustment is not required in patients with impaired renal function. Due to limited experience in patients with severe renal insufficiency, such patients should be treated with caution.
• Impaired hepatic function: Dose adjustment is not required in patients with mild to moderate liver impairment. For patients with severe liver impairment, a maximum daily dose of 20 mg REPIGUT should be used.
• Elderly: Dose adjustment is not required in the elderly.
• Paediatric population: REPIGUT should not be used in children younger than 12 years since no data is available.

Method of administration

REPIGUT 20 mg and 40 mg tablets are for oral use. The tablets should be swallowed whole with liquid. The tablets should not be chewed or crushed.

• Known hypersensitivity to esomeprazole, substituted benzimidazoles or any other constituents of REPIGUT.
• Concomitant administration of REPIGUT with atazanavir or nelfinavir (see section 4.5).

REPIGUT is not indicated for mild gastrointestinal complaints such as nervous dyspepsia. Prior to treatment or in the presence of any alarm symptom (e.g., significant unintentional weight loss, recurrent vomiting, dysphagia, haematemesis or melaena) and when gastric ulcer is suspected or present, the possibility of malignancy of gastric ulcer or a malignant disease of the oesophagus should be excluded, as the treatment with REPIGUT may alleviate the symptoms of malignant ulcers and can thus delay diagnosis.

There is an increased risk of subclinical acute interstitial nephritis (AIN), associated with proton pump inhibitors (PPIs), such as REPIGUT which may progress to acute kidney injury and/or chronic renal failure. Symptoms of interstitial nephritis may persist even when treatment with the PPI is terminated.

Severe hypomagnesaemia has been reported in patients treated with proton pump inhibitors (PPIs) like REPIGUT 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 dysrhythmia 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, including REPIGUT, with digoxin or medicine that may cause hypomagnesaemia (e.g. diuretics), healthcare professionals should consider measuring magnesium levels before starting REPIGUT treatment and periodically during treatment.

Concomitant administration with REPIGUT and medicines such as atazanavir and nelfinavir is not recommended (see sections 4.3 and 4.5). Therapeutic medicine monitoring is recommended during concomitant treatment with warfarin (see section 4.5).

REPIGUT, as all acid-blocking medicines, may reduce the absorption of vitamin B12 (cyanocobalamin) due to hypo- or achlorhydria. This should be considered in patients with reduced body stores or risk factors for reduced vitamin B12 absorption on long-term therapy.

Concomitant administration of clopidogrel and esomeprazole resulted in decreased exposure to the active metabolite of clopidogrel by an average of 40 %. The maximum inhibition of (ADP induced) platelet aggregation decreased by an average of 14 %. Based on these data, concomitant use of REPIGUT and clopidogrel should be avoided.

During treatment with REPIGUT serum gastrin increases, in response to decreased acid secretion. During long-term oral treatment with esomeprazole gastric glandular cysts occur. These changes are a physiological consequence of pronounced inhibition of acid secretion, are benign, and appear to be reversible.

Proton pump inhibitors, including REPIGUT, especially if used in high doses and over long durations, 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 u2013 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.

Proton pump inhibitors are associated with very infrequent cases of sub-acute cutaneous lupus erythematosus (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 REPIGUT. SCLE after previous treatment with a proton pump inhibitor may increase the risk of SCLE with other proton pump inhibitors.

During treatment with antisecretory medicines, serum gastrin increases in response to the decreased acid secretion. Also, chromogranin A (CgA) increase due to decreased gastric acidity. The increased CgA level may interfere with investigations for neuroendocrine tumours. To avoid this interference, the esomeprazole treatment should be temporarily stopped 5 days before CgA measurements.

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

Decreased gastric acidity due to any means including proton pump inhibitors such as REPIGUT tablets, increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with REPIGUT may lead to increased risk of gastrointestinal infections such as Salmonella and Campylobacter and also Clostridium difficile in hospitalised patients. Clostridium difficile is a bacterium that can cause severe debilitating diarrhoea that does not improve. Symptoms may include watery stools, abdominal pain, fever, and patients may develop more serious intestinal conditions.

Excipient warning: REPIGUT tablets contain sucrose and lactose monohydrate which may have an effect on the glycaemic control of patients with diabetes mellitus. Patients with the rare hereditary conditions such of galactose intolerance, total lactase deficiency, glucose-galactose malabsorption, sucrase-isomaltase or fructose intolerance should not take REPIGUT.

Effects of REPIGUT on the pharmacokinetics of other medicines

The gastric acid suppression during treatment with REPIGUT, might decrease or increase the absorption of medicines with a gastric pH dependent absorption. The absorption of medicines such as ketoconazole, itraconazole and erlotinib can decrease while the absorption of medicines such as digoxin can increase during treatment with REPIGUT.

Concomitant treatment with omeprazole (20 mg daily) and digoxin in healthy subjects increased the bioavailability of digoxin by 10 % (up to 30 % in 2 out of 10 subjects). Digoxin toxicity has been reported. Caution should be exercised when REPIGUT is given at high doses in elderly patients. Therapeutic monitoring of digoxin levels should be done.

REPIGUT inhibits CYP2C19, the major REPIGUT metabolising enzyme. Concomitant administration of 30 mg REPIGUT resulted in a 45 % decrease in clearance of the CYP2C19 substrate diazepam. This interaction is unlikely to be of clinical relevance. Concomitant administration of 40 mg REPIGUT resulted in a 13 % increase in trough plasma levels of phenytoin in epileptic patients.

Concomitant administration of 40 mg REPIGUT to warfarin-treated patients showed that, despite elevation in the trough plasma concentration of the less potent R-isomer of warfarin, the coagulation times were within the accepted range. From post marketed use, cases of elevated INR of clinical significance have been reported during concomitant treatment with warfarin. Close monitoring is recommended when warfarin is co-administered with REPIGUT at initiation of treatment, during the treatment and at ending treatment.

Results from studies in healthy subjects have shown a pharmacokinetic/pharmacodynamic interaction between clopidogrel (300 mg loading dose/75 mg daily maintenance dose) and esomeprazole (40 mg p.o. daily) resulting in decreased exposure to the active metabolite of clopidogrel by an average of 40 % and resulting in decreased maximum inhibition of (ADP induced) platelet aggregation by an average of 14 %. Based on these data, concomitant use of REPIGUT and clopidogrel should be avoided.

Omeprazole as well as esomeprazole act as inhibitors of CYP 2C19. Omeprazole given in doses of 40 mg to healthy subjects in a cross-over study, increased C max and AUC for cilostazol by 18 % and 26 % respectively, and one of its metabolites by 29 % and 69 % respectively. REPIGUT can be suspected to have a similar effect.

In concomitant administration of 40 mg REPIGUT resulted in a 32 % increase in area under the plasma concentration-time curve (AUC) and a 31 % prolongation of elimination half-life (t u00bd) but no significant increase in peak plasma levels of cisapride. This interaction did not alter the influence of cisapride on cardiac electrophysiology.

When given together with proton pump inhibitors, methotrexate levels have been reported to increase in some patients. In high-dose methotrexate administration a temporary withdrawal of REPIGUT may need to be considered.

REPIGUT has been shown to have no clinically relevant effects on the pharmacokinetics of amoxicillin or quinidine. Studies evaluating concomitant administration of REPIGUT and either naproxen (nonselective NSAID) or rofecoxib (COX-2-selective NSAID) did not identify any clinically relevant interaction.

Concomitant administration of REPIGUT may significantly reduce the plasma levels of atazanavir. Omeprazole has been reported to interact with some antiretroviral medicines. Increased gastric pH during omeprazole treatment may change the absorption of the antiretroviral medicines. Other possible interaction mechanisms are via CYP2C19. For some antiretroviral medicines, such as atazanavir and nelfinavir, decreased serum levels have been reported when given together with omeprazole and concomitant administration is not recommended.

Co-administration of esomeprazole (40 mg once daily) reduced mean nelfinavir exposure by approximately 40 % and the mean exposure of the pharmacological active metabolite was reduced by approximately 75-90 %. REPIGUT substantially decreases the concentration of nelfinavir. Concomitant administration with esomeprazole and antiretroviral medicines such as atazanavir and nelfinavir is not recommended.

For other antiretroviral medicines, such as saquinavir, increased serum levels have been reported of 80-100 %. There are also some antiretroviral medicines for which unchanged serum levels have been reported when given with omeprazole. Close monitoring or dose alteration is recommended.

Tipranavir may decrease the concentration of REPIGUT. Co-administration is not recommended. However, if used concurrently, the dose of REPIGUT should be increased.

Concomitant administration of REPIGUT has been reported to increase the serum levels of tacrolimus. A reinforced monitoring of tacrolimus concentrations as well as renal function (creatinine clearance) should be performed, and dosage of tacrolimus adjusted if needed.

Effects of other medicines on the pharmacokinetics of REPIGUT

REPIGUT is metabolised by CYP2C19 and CYP3A4. Concomitant administration of REPIGUT and a CYP3A4 inhibitor, clarithromycin (500 mg twice a day), resulted in a doubling of the exposure (AUC) to REPIGUT. Concomitant administration of REPIGUT and a combined inhibitor of CYP2C19 and CYP3A4, such as voriconazole, may result in more than tripling of the REPIGUT exposure. Dose adjustment of REPIGUT is not required. Medicines known to induce CYP2C19 or CYP3A4 or both (such as rifampicin and St. John's wort) may lead to decreased esomeprazole serum levels by increasing the esomeprazole metabolism.

Pregnancy

Safety during pregnancy has not been established.

Breastfeeding

Safety during lactation has not been established.

REPIGUT may cause dizziness and blurred vision, thereby affecting the ability to drive or use machinery.

a. Summary of the safety profile

Headache, abdominal pain, diarrhoea and nausea are among those adverse reactions that have been most commonly reported in clinical trials (and also from post-marketing use). In addition, the safety profile is similar for different formulations, treatment indications, age groups and patient populations.

b. Tabulated summary of adverse reactions

Post marketing experience

Blood and lymphatic system disorders: Leukopenia, thrombocytopenia, agranulocytosis, pancytopenia

Immune system disorders: Hypersensitivity reactions e.g. angioedema and anaphylactic reaction/shock.

Metabolism and nutrition disorders: Peripheral oedema, hyponatraemia

Psychiatric disorders: Insomnia, agitation, confusion, depression, aggression, hallucination

Nervous system disorders: Headache, dizziness, paraesthesia, somnolence, taste disturbance

Eye disorders: Blurred vision

Ear and labyrinth disorders: Vertigo

Respiratory, thoracic, and mediastinal disorders: Bronchospasm

Gastrointestinal disorders: Abdominal pain, diarrhoea, flatulence, nausea/vomiting, constipation, dry mouth, stomatitis, gastrointestinal candidiasis.

Hepatobiliary disorders: Increased liver enzymes, hepatitis with or without jaundice, hepatic encephalopathy, hepatic failure.

Skin and subcutaneous tissue disorders: Dermatitis, pruritus, urticaria, rash, alopecia, photosensitivity, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN)

Musculoskeletal, connective tissue and bone disorders: Arthralgia, myalgia, muscular weakness

Renal and urinary disorders: Interstitial nephritis which may progress to kidney injury and/or chronic renal failure

Reproductive system and breast disorders: Gynaecomastia

General disorders and administration site conditions: Malaise, hyperhidrosis

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications https://www.sahpra.org.za/Publications/Index/8

No specific antidote is known. REPIGUT is extensively plasma protein bound and is therefore not readily dialysable. In any case of overdose, treatment should be symptomatic and general supportive measures should be utilised.