Nexiam 5 mg, 2,5 mg Sachets

NEXIAM granules for oral suspension are indicated for:

• the reduction in intra-oesophageal pH, by reducing the acidity of the gastric reflux in neonates and infants
• the treatment of Gastro Oesophageal Reflux Disease (GORD) confirmed by pH probe or endoscopy

Known hypersensitivity to NEXIAM, substituted benzimidazoles or any other constituents of NEXIAM.

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.

Concomitant administration with esomeprazole and medicines such as atazanavir and nelfinavir is not recommended (see u201cInteractionsu201d).

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, increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with proton pump inhibitors may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter.

NEXIAM is not likely to affect the ability to drive or use machines.

Interaction with other medicinal products and other forms of interaction:

Effects of NEXIAM on the pharmacokinetics of other medicines: The gastric acid suppression during treatment with NEXIAM and other PPIs might decrease or increase the absorption of medicines with a gastric pH dependent absorption. Like with other medicines that decrease the intragastric acidity, 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).

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 a slight elevation in the trough plasma concentration of the less potent R-isomer of warfarin, the coagulation times were within the accepted range. However from post-marketed use cases of elevated INR of clinical significance have been reported during concomitant treatment with warfarin. Close monitoring is recommended when initiating and ending treatment with warfarin or other coumarine derivatives.

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 (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 esomeprazole may need to be considered.

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 active metabolites by 29 % and 69 % respectively.

Omeprazole has been reported to interact with some antiretroviral medicines. The clinical importance and the mechanisms behind these reported interactions are not always known. Increased gastric pH during omeprazole treatment may change the absorption of the antiretroviral medicine. 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. For other antiretroviral medicines, such as saquinavir, increased serum levels have been reported. There are also some antiretroviral medicines for which unchanged serum levels have been reported when given with omeprazole. Due to the similar pharmacodynamic effects and pharmacokinetic properties of omeprazole and esomeprazole, concomitant administration with esomeprazole and antiretroviral medicines such as atazanavir and nelfinavir is not recommended.

NEXIAM has been shown to have no clinically relevant effects on the pharmacokinetics of amoxicillin or quinidine. 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.

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 twice daily), 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 doubling of the NEXIAM exposure. Dose adjustment of NEXIAM is not required. Medicines known to induce CYP2C19 or CYP3A4 or both (such as rifampicin and St. Johnu2019s Wort) may lead to decreased esomeprazole serum levels by increasing the esomeprazole metabolism.

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

Common: u2265 1/100

Uncommon: u2265 1/1 000 and < 1/100

Rare: u2265 1/10 000 and < 1/1 000

Very rare: < 1/10 000

Nervous system disorders:

• Common: Headache
• Uncommon: Dizziness, paraesthesia, somnolence
• Rare: Taste disturbance

Gastrointestinal disorders:

• Common: Abdominal pain, diarrhoea, flatulence, nausea/vomiting, constipation
• Uncommon: Dry mouth
• Rare: Stomatitis, gastrointestinal candidiasis

Skin and subcutaneous tissue disorders:

• Uncommon: Dermatitis, pruritus, urticaria, rash
• Rare: Alopecia, photosensitivity
• Very rare: Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN)

Blood and lymphatic system disorders:

• Rare: Leukopenia, thrombocytopenia
• Very rare: Agranulocytosis, pancytopenia

Immune system disorders:

• Rare: Hypersensitivity reactions e.g. angioedema and anaphylactic reaction/shock

Metabolism and nutrition disorders:

• Uncommon: Peripheral oedema
• Rare: Hyponatraemia

Psychiatric disorders:

• Uncommon: Insomnia
• Rare: Agitation, confusion, depression
• Very rare: Aggression, hallucination

Eye disorders:

• Rare: Blurred vision

Ear and labyrinth disorders:

• Uncommon: Vertigo

Respiratory, thoracic and mediastinal disorders:

• Rare: Bronchospasm

Hepatobiliary disorders:

• Uncommon: Increased liver enzymes
• Rare: Hepatitis with or without jaundice
• Very rare: Hepatic failure, hepatic encephalopathy

Musculoskeletal, connective tissue and bone disorders:

• Rare: Arthralgia, myalgia
• Very rare: Muscular weakness

Renal and urinary disorders:

• Very rare: Interstitial nephritis

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.

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

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

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

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

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

Eye disorders: Blurred vision

Ear and labyrinth disorders: Vertigo

Respiratory, thoracic and mediastinal disorders: Bronchospasm

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

Reproductive system and breast disorders: Gynaecomastia

General disorders and administration site conditions: Malaise, hyperhidrosis

The symptoms described in connection with deliberate NEXIAM overdose (limited experience of doses in excess of 240 mg/day) are transient. Single doses of 80 mg NEXIAM were uneventful. 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.