Nexiam 20 mg, 40 mg Gastric resistant tablet.

NEXIAM 20 mg and 40 mg tablets are indicated for:

• 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 nonsteroidal 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 and
• prevention of relapse of peptic ulcers in patients with Helicobacter pylori associated ulcer disease
• NEXIAM has been used in pathological hypersecretory conditions including Zollinger-Ellison syndrome and idiopathic hypersecretion.

Posology

Adults:

• Gastro-oesophageal reflux disease (GORD):
• treatment of erosive reflux oesophagitis 40 mg once daily for 4 weeks. An additional 4 weeks 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.
• 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 NEXIAM 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 NEXIAM 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 u2013 18 years:

• Gastro-oesophageal reflux disease (GORD):
• treatment of erosive reflux oesophagitis 40 mg once daily for 4 weeks. An additional 4 weeks 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 20 mg once daily under medical supervision.

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 NEXIAM should be used.
• Elderly: Dose adjustment is not required in the elderly.

Method of administration

The tablets should be swallowed whole with liquid. The tablets should not be chewed or crushed. The tablets can also be dispersed in half a glass of non-carbonated water. No other liquids should be used. Stir until the tablets disintegrate and drink the liquid with the pellets immediately or within 30 minutes. Rinse the glass with half a glass of water and drink. The pellets must not be chewed or crushed. For patients who cannot swallow, the tablets can be dispersed in non-carbonated water and administered through a gastric tube.

• Known hypersensitivity to esomeprazole, to substituted benzimidazoles or to any of the excipients of NEXIAM listed in section 6.1.
• Concomitant administration of NEXIAM with atazanavir or nelfinavir (see section 4.5).

NEXIAM 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 NEXIAM may alleviate the symptoms of malignant ulcers and can thus delay diagnosis. Patients on long-term treatment (particularly those treated for more than a year) should be kept under regular surveillance.

Concomitant administration of clopidogrel and esomeprazole results 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 NEXIAM and clopidogrel should be avoided.

Proton pump inhibitor (PPI) therapy has a potential association with an increased risk of osteoporosis-related fractures, particularly with long-term use, potentially impacting the hip, spine, and wrist bones. The risk is more apparent in patients with secondary risk factors of osteoporosis, such as renal dysfunction. In AstraZenecau2019s randomised, double-blind and controlled clinical studies on omeprazole and esomeprazole (including two open long-term studies of up to more than 12 years) there are no indications that PPIs are associated with osteoporotic fractures. Patients at risk for developing osteoporosis or osteoporotic fractures are advised to have appropriate clinical monitoring in accordance with current clinical guidelines for these conditions.

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. Literature reports indicate that proton pump inhibitor treatment should be stopped 5 to 14 days before CgA measurement. Measurements should be repeated if levels have not normalised by this time.

Decreased gastric acidity increases gastric contents counts of bacteria normally present in the gastrointestinal tract. Treatment with proton pump inhibitors may lead to increased risk of gastrointestinal infections such as Salmonella and Campylobacter and, in hospitalised patients, possibly also Clostridium difficile. Clostridium difficile is a bacteria 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.

Serious cutaneous adverse reactions (SCARs) such as erythema multiforme (EM), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening, have been reported very rarely in association with esomeprazole treatment. Patients should be advised of the signs and symptoms of the severe skin reaction EM/SJS/TEN/DRESS and should seek medical advice from their medical practitioner immediately when observing any indicative signs or symptoms. NEXIAM should be discontinued immediately upon signs and symptoms of severe skin reactions and additional medical care/close monitoring should be provided as needed. Re-challenge should not be undertaken in patients with EM/SJS/TEN/DRESS.

Hypomagnesaemia: Severe hypomagnesaemia has been reported in patients treated with PPIs like esomeprazole 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 with medicines that may cause hypomagnesaemia (e.g. diuretics, digoxin), the medical practitioner should consider measuring magnesium serum levels before starting PPI treatment and periodically during treatment.

NEXIAM contains sucrose and is not suitable for patients with glucose-galactose malabsorption syndrome, fructose intolerance, or sucrose isomaltase deficiency.

Effects of NEXIAM on the pharmacokinetics of other medicines: The gastric acid suppression during treatment with NEXIAM, 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 NEXIAM. 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 NEXIAM is given at high doses in elderly patients. Therapeutic monitoring of digoxin levels should be done.

NEXIAM inhibits CYP2C19, the major NEXIAM metabolising enzyme. Concomitant administration of 30 mg NEXIAM 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 NEXIAM resulted in a 13 % increase in trough plasma levels of phenytoin in epileptic patients; dose adjustment was not required in this study.

Concomitant administration of 40 mg NEXIAM 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 of the INR is recommended when warfarin is co-administered with NEXIAM 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 NEXIAM 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. NEXIAM can be suspected to have a similar effect.

In healthy volunteers, concomitant administration of 40 mg NEXIAM resulted in a 32 % increase in area under the plasma concentration-time curve (AUC) and a 31 % prolongation of elimination half-life (tu03a9) but no significant increase in peak plasma levels of cisapride. This interaction did not alter the influence of cisapride on cardiac electrophysiology.

Concomitant administration of esomeprazole has been reported to increase the serum levels of tacrolimus. When given together with PPIs, methotrexate levels have been reported to increase in some patients. In high-dose methotrexate administration a temporary withdrawal of NEXIAM may need to be considered.

NEXIAM has been shown to have no clinically relevant effects on the pharmacokinetics of amoxicillin or quinidine. Esomeprazole, as all gastric 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.

Studies evaluating concomitant administration of NEXIAM and either naproxen (non-selective NSAID) or rofecoxib (COX-2-selective NSAID) did not identify any clinically relevant interaction.

Concomitant administration of NEXIAM 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 inhibition of 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. For other antiretroviral medicines, such as saquinavir, increased serum levels of 80 u2013 100 % have been reported. 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. Concomitant administration with esomeprazole and antiretroviral medicines such as atazanavir and nelfinavir is not recommended. NEXIAM substantially decreases the concentration of atazanavir and nelfinavir (see section 4.3). Co-administration of esomeprazole (40 mg once daily) reduced mean nelfinavir exposure by approximately 40 % and the mean exposure of the pharmacologically active metabolite was reduced by approximately 75 u2013 90 %. Tipranavir may decrease the concentration of NEXIAM. Co-administration is not recommended. However, if used concurrently, the dose of NEXIAM should be increased.

Effects of other medicines on the pharmacokinetics of NEXIAM: NEXIAM is metabolised by CYP2C19 and CYP3A4. Concomitant administration of NEXIAM and a CYP3A4 inhibitor, clarithromycin (500 mg b.i.d.), resulted in a doubling of the exposure (AUC) to NEXIAM. Concomitant administration of NEXIAM and a combined inhibitor of CYP2C19 and CYP3A4, such as voriconazole, may result in more than tripling of the NEXIAM exposure. Dose adjustment of NEXIAM is not required.

Voriconazole: Omeprazole (40 mg once daily) increased voriconazole (a CYP2C19 substrate) C max and AUC t by 15 % and 41 %, respectively. Medicines known to induce CYP2C19 or CYP3A4 or both (such as rifampicin and St. Johnu2019s wort (Hypericum perforatum)) may lead to decreased esomeprazole serum levels by increasing the esomeprazole metabolism.

Interference with laboratory tests: Increased Chromogranin A (CgA) level may interfere with investigations for neuroendocrine tumours. To avoid this interference, esomeprazole treatment should be stopped for at least 5 days before CgA measurements (see section 5.1). 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.

Safety during pregnancy and lactation has not been established.

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

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. No dose-related adverse reactions have been identified.

Tabulated summary of adverse reactions

The following definitions of frequency are used: Common: uf0b3 1/100 Uncommon: uf0b3 1/1000 and uf03c 1/100 Rare: uf0b3 1/10 000 and uf03c 1/1000 Very rare: uf03c 1/10 000

Clinical trials: The following adverse reactions have been identified or suspected in the clinical trials programme for NEXIAM. None, however, were found to be dose-related.

MedDRA system organ class Frequency Adverse reactions

Blood and lymphatic system disorders Rare Leukopenia, thrombocytopenia

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

Metabolism and nutrition disorders Uncommon Peripheral oedema

Rare Hyponatraemia

Very rare Hypomagnesaemia (see section 4.4)

Psychiatric disorders Uncommon Insomnia

Rare Agitation, confusion, depression

Very rare Aggression, hallucination

Nervous system disorders Common Headache

Uncommon Dizziness, paraesthesia, somnolence

Rare Taste disturbance

Eye disorders Rare Blurred vision

Ear and labyrinth disorders Uncommon Vertigo

Respiratory, thoracic and mediastinal disorders Rare Bronchospasm

Gastrointestinal disorders Common Abdominal pain, diarrhoea, flatulence, nausea/vomiting, constipation

Uncommon Dry mouth

Rare Stomatitis, gastrointestinal candidiasis, gastrointestinal infections

Very rare Microscopic colitis

Hepatobiliary disorders Uncommon Increased liver enzymes

Rare Hepatitis with or without jaundice

Very rare Hepatic encephalopathy

Skin and subcutaneous tissue disorders Uncommon Dermatitis, pruritus, urticaria, rash

Rare Alopecia, photosensitivity

Musculoskeletal and connective tissue disorders Uncommon Fracture of the hip, wrist or spine (see section 4.4)

Rare Arthralgia, myalgia

Reproductive system and breast disorders Very rare Gynaecomastia

General disorders and administration site conditions Rare Malaise, hyperhidrosis

Post marketing experience: The following adverse events have been reported during the post marketing use of NEXIAM. Because these are spontaneous reports from a population of uncertain size, it is not possible to reliably estimate their frequency.

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, hypomagnesaemia, severe hypomagnesaemia may result in hypocalcaemia. Hypomagnesaemia may also result in hypokalaemia.

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), acute generalised exanthematous pustulosis (AGEP), drug rash with eosinophilia and systemic symptoms (DRESS).

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

Renal and urinary disorders: Interstitial nephritis

Reproductive system and breast disorders: Gynaecomastia

General disorders and administration site conditions: Malaise, hyperhydrosis

Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of NEXIAM is important. It allows continued monitoring of the benefit/risk balance of NEXIAM. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website.

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