Esomeprazole

Registered South African indications:

• Gastro-oesophageal reflux disease as an alternative where oral therapy is not appropriate and for the shortest possible time
  - Treatment of erosive reflux oesophagitis
  - Long-term management of patients with healed oesophagitis to prevent relapse
  - Treatment of severe symptoms of reflux disease
• Short-term maintenance of haemostasis and prevention of rebleeding in patients following therapeutic endoscopy for acute bleeding gastric or duodenal ulcers

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Hypersensitivity to substituted benzimidazoles
• Coadministration with atazanavir and nelfinavir

South African recommendations

Caution in the following patient groups

• Pregnancy
• Breastfeeding
• Severe renal impairment
• Severe hepatic impairment
• Elderly

Malignancy

• 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, malignancy should be excluded, as treatment with esomeprazole IV may alleviate symptoms and delay diagnosis

Concomitant use with other medicines

• Coadministration 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 esomeprazole and clopidogrel should be avoided
• Codministration with esomeprazole IV and medicines such as atazanavir and nelfinavir is not recommended
• Therapeutic medicine monitoring is recommended during concomitant treatment with warfarin

Hypomagnesaemia

• Severe hypomagnesaemia has been reported in patients treated with proton pump inhibitors (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 digoxin or other medicines that may cause hypomagnesaemia (e.g. diuretics), the medical practitioner should consider measuring magnesium serum levels before starting PPI treatment and periodically during treatment

Gastrointestinal infections

• 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

Other effects related to acid inhibition

• During treatment with esomeprazole IV serum gastrin increases, in response to decreased acid secretion. During long-term oral treatment with esomeprazole IV gastric glandular cysts occur
• These changes are a physiological consequence of pronounced inhibition of acid secretion, are benign, and appear to be reversible. Decreased gastric acidity due to any means including proton pump inhibitors such as esomeprazole IV, increases gastric 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 also Clostridium difficile in hospitalised patients

Risk of fractures

• 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 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

Serious cutaneous adverse reactions (SCARs)

• 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
• Esomeprazole IV 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

Absorption of vitamin B₁₂

• Esomeprazole, 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

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
• 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

Effects on ability to drive and use machines

• Esomeprazole IV may cause dizziness and blurred vision, thereby affecting the ability to drive or use machinery

Forms avail. in SA and covered in this monograph: inj

South African registered indications and dosages

Gastro-oesophageal reflux disease (GORD)

• IV: 40mg, once daily; Treatment duration: Up to 7 days, as part of a full treatment period for the specified indications

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When oral therapy is possible or appropriate, intravenous therapy with esomeprazole should be discontinued and the therapy should be continued orally

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- Treatment of erosive reflux oesophagitis

• IV: 40mg, once daily; Treatment duration: 4 weeks; An additional 4 weeks treatment is recommended for patients in whom the oesophagitis has not healed or who have persistent symptoms

- Long-term management of patients with healed oesophagitis to prevent relapse
- Treatment of severe symptoms of reflux disease

• IV: 20mg, once daily

- Maintenance of haemostasis and prevention of rebleeding of gastric or duodenal ulcers

• IV: 80mg, admin. as bolus infusion over 30mins; Followed by: 8mg/hr, as a continuous infusion given over 3 days; The parenteral treatment period should be followed by acid-suppression therapy with oral esomeprazole 40mg, once daily for 4 weeks

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See additional prescribing points for method of administration

Not established for use in children

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Esomeprazole IV should not be used in children since no data are available

Pregnancy

South African recommendations

• Caution
• For esomeprazole limited clinical data on exposed pregnancies are available

Breastfeeding

South African recommendations

• Caution
• It is not known whether esomeprazole is excreted in human breast milk. No studies in lactating women have been performed
• Therefore, esomeprazole IV should not be used during breastfeeding

Fertility

South African recommendations

• No information available

South African recommendations

• Mild to moderate: No dose adjustment recommended
• Severe: Caution; no dose adjustment recommended
  Use with caution in patients with severe renal insufficiency due to limited experience in these patients

South African recommendations

Gastro-oesophageal reflux disease (GORD)

• Mild to moderate (Child-Pugh class A and B): No dose adjustment recommended
• Severe (Child-Pugh class C): Caution; dose adjustment recommended
  Max. daily dose: 20mg

Bleeding ulcers

• Mild to moderate (Child-Pugh class A and B): No dose adjustment recommended
• Severe (Child-Pugh class C): Caution; dose adjustment recommended
  Initial bolus dose: 80mg; Then: 4mg/hr, as a continuous infusion may be sufficient to maintain adequate acid control

South African recommendations

• Caution; no dose adjustment recommended
  Caution should be exercised when esomeprazole IV is given at high doses in elderly patients

Blood and Lymphatic System Disorders

Rare

• Leukopenia
• Thrombocytopenia

Very rare

• Agranulocytosis
• Pancytopenia

Immune System Disorders

Rare

• Hypersensitivity reactions e.g. angioedema 
• Anaphylactic reaction/shock

Metabolism and Nutrition Disorders

Uncommon

• Peripheral oedema

Rare

• Hyponatraemia

Very rare

• Hypomagnesaemia
  - Severe hypomagnesaemia may result in hypocalcaemia, hypomagnesaemia may also result in hypokalaemia

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

Hepato-Biliary Disorders

Uncommon

• Increased liver enzymes

Rare

• Hepatitis with or without jaundice
• Hepatic encephalopathy
• Hepatic failure

Skin and Subcutaneous Tissue Disorders

Common

• Administration site reactions

Uncommon

• Dermatitis
• Pruritus
• Urticaria
• Rash

Rare

• Alopecia
• Photosensitivity

Very rare

• Erythema multiforme
• Stevens-Johnson syndrome
• Toxic epidermal necrolysis (TEN)
• Acute generalised exanthematous pustulosis (AGEP)
• Drug rash with eosinophilia and systemic symptoms (DRESS)

Musculoskeletal, Connective Tissue and Bone Disorders

Uncommon

• Fracture of the hip, wrist or spine

Rare

• Arthralgia
• Myalgia

Very rare

• Musclar 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

• Atazanavir
• Nelfinavir
• Clopidogrel
• Saquinavir
• Tipranavir
• Medicines with a gastric pH dependent absorption
• Ketoconazole
• Itraconazole
• Erlotinib
• Digoxin
• Diazepam
• Phenytoin
• Warfarin
• Cilostazol
• High dose methotrexate
• Tacrolimus
• CYP3A4 inhibitors
• Clarithromycin
• CYP2C19 inhibitors
• Voriconazole
• CYP2C19 inducers
• CYP3A4 inducers
• Rifampicin

Other interactions

• St. John's Wort
• Vitamin B₁₂ (absorption affected)
• Interference with laboratory tests
  - Investigations for neuroendocrine tumours, see Warnings and Precautions

None routine. Specific cases may require

• Serum magnesium levels
• Digoxin levels (when coadministered)
• International normalised ratio (when coadministered with warfarin)
• Plasma concentrations of phenytoin (when coadministered)

Additional observations

• Symptoms and signs of fracture
  - Assess osteoporosis risk especially with long-term therapy
• Signs and symptoms of severe skin reactions

Method of administration

• Intravenous esomeprazole should be reconstituted with sodium chloride 0.9% solution for injection/infusion before use. No other solvent should be used
• To reduce contamination the product should be used immediately after reconstitution. If the entire reconstituted content of the vial is not required for a single dose, any unused reconstituted solution should be discarded. Esomeprazole IV is for single use in one patient only

Injection (40 mg vial):

• A solution for injection is prepared by adding 5ml of 0.9% sodium chloride for intravenous use to the vial
• 40mg dose: The reconstituted solution should be given as an intravenous injection over a period of at least 3 minutes
• 20mg dose: Half of the reconstituted solution should be given as an intravenous injection over a period of approximately 3 minutes

Infusion (40 mg vial):

• A solution for infusion is prepared by dissolving the contents of 1 vial in up to 100ml 0.9% sodium chloride for intravenous use
• 40mg dose: The reconstituted solution should be given as an intravenous infusion over a period of 10-30 minutes
• 20mg dose: Half of the reconstituted solution should be given as an intravenous infusion over a period of 10-30 minutes

Continuous infusion (40mg vial):

• A solution for infusion is prepared by dissolving the content of 2 vials of esomeprazole 40 mg in up to 100 mL of 0.9% sodium chloride for intravenous use
• 80mg bolus dose: The reconstituted solution containing 80mg esomeprazole should be given as an intravenous infusion over a period of 30 minutes
• 8mg/hour dose: The reconstituted solution should be given as a continuous intravenous infusion over a period of 71.5 hours (calculated rate of infusion of 8mg/hr)

Esomeprazole, the S-isomer of omeprazole, reduces gastric acid secretion through inhibition of the enzyme H⁺K⁺-ATPase, the acid pump in the parietal cell, where it is concentrated and converted to the active form in the highly acidic environment of the secretory canaliculi. This effect on the final step of the gastric acid secretion is dose-dependent and inhibitory for both basal and stimulated acid secretion.

Tablet 20mg

• Esotab 20mg (Forrester Pharma)
• Nectizole (Abex)
• Nesopram (Ranbaxy)
• Nexiflux (Abex)
• Nexipraz (Ranbaxy)
• Nexiam (AstraZeneca) originator
• Nexmezol (Sandoz)
• Nexomep (Sandoz)
• Trustan (Pharmacare Limited)

Tablet 40mg

• Esotab 40mg (Forrester Pharma)
• Mitogut 40 (Dr Reddy's)
• Nectizole (Abex)
• Nesopram (Ranbaxy Pharmaceuticals)
• Nexiflux (Abex)
• Nexipraz (Ranbaxy Pharmaceuticals)
• Nexiam (AstraZeneca) originator
• Nexmezol (Sandoz)
• Nexomep (Sandoz)
• Trustan (Pharmacare Limited)

Sachet 2.5mg

• Nexiam (AstraZeneca) originator

Sachet 5mg

• Nexiam (AstraZeneca) originator

Sachet 10mg

• Nexiam (AstraZeneca) originator

Injection (per vial) 40mg

• Aspepraz (Pharmacare)
• Nexiam (AstraZeneca) originator
• Nexipraz (Ranbaxy Pharmaceuticals)
• Truloc IV 40mg (Pharma Dynamics)

COMBINATION PREPARATIONS

Naproxen/ Esomeprazole

Tablet 500mg/20mg

• Vimovo (AstraZeneca) originator