Hetenex 40 mg Solution

HETENEX is indicated for:

Gastro-oesophageal reflux disease (GORD) as an alternative to oral therapy in patients when 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.

HETENEX is indicated for short-term maintenance of haemostasis and prevention of rebleeding in patients following therapeutic endoscopy for acute bleeding gastric or duodenal ulcers.

Posology

When oral therapy is possible or appropriate, intravenous therapy with HETENEX should be discontinued and the therapy should be continued orally. For single use only.

Adults:

Gastro-oesophageal reflux disease (GORD): Treatment with HETENEX can be given for up to 7 days as part of a full treatment period for the specified indications. When oral therapy is possible or appropriate, intravenous therapy with HETENEX should be discontinued and therapy should be continued orally.

Erosive reflux oesophagitis: 40 mg once daily. The duration of treatment should be 4 weeks. An additional 4 week 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 and treatment of severe symptoms of reflux disease: 20 mg once daily.

Maintenance of haemostasis and prevention of rebleeding of gastric or duodenal ulcers: 80 mg administered as bolus infusion over 30 minutes followed by a continuous IV infusion of 8 mg/hour given over 3 days.

The parenteral treatment period should be followed by acid-suppression therapy with 40 mg esomeprazole orally once daily for 4 weeks.

Special populations

Elderly: Dose adjustment is not required in the elderly.

Renal impairment: 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.

Hepatic impairment: Gastro-oesophageal reflux disease (GORD): Dose adjustment is not required in patients with mild to moderate liver impairment (Child-Pugh class A, B). For patients with severe liver impairment (Child-Pugh class C), a maximum daily dose of 20 mg of HETENEX should not be exceeded see section 5.2). Bleeding ulcers: Dose adjustment is not required in patients with mild to moderate liver impairment. For patients with severe liver impairment, following an initial bolus dose of 80 mg of HETENEX, a continuous IV dose of 4 mg/hour may be sufficient to maintain adequate acid control.

Method of administration

For instructions on dilution of the product before administration, see section 6.6 Special precautions for disposal and other handling).

Injection:

40 mg dose 5 ml of the reconstituted solution (8 mg/ml) should be given as an intravenous injection over a period of at least 3 minutes.

20 mg dose 2.5 ml or half of the reconstituted solution (8 mg/ml) should be given as an intravenous injection over a period of at least 3 minutes. Any unused solution should be discarded.

Infusion:

40 mg dose The reconstituted solution should be given as an intravenous infusion over a period of 10 to 30 minutes.

20 mg dose Half of the reconstituted solution should be given as an intravenous infusion over a period of 10 to 30 minutes. Any unused solution should be discarded.

80 mg bolus dose: The reconstituted solution containing 2 HETENEX vials (2 x 40 mg) should be given as a continuous IV infusion over 30 minutes.

8 mg/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 8 mg/h. See section 6.3 Shelf-life for shelf-life of the reconstituted solution).

• Hypersensitivity to the esomeprazole, to substituted benzimidazoles or to any of the excipients listed in section 6.1. List of excipients.
• Concomitant use with nelfinavir and atazanavir (see section 4.5).

In the presence of any alarming 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 HETENEX may alleviate symptoms and thereby delay diagnosis.

Concomitant use with nelfinavir and atazanavir (see sections 4.3 and 4.5) is not recommended.

Therapeutic medicine monitoring is recommended during concomitant treatment with warfarin.

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

Gastrointestinal infections: Decreased gastric acidity due to any means including proton pump inhibitors such as HETENEX increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with HETENEX may lead to increased risk of gastrointestinal infections such as Salmonella and Campylobacter and possibly also Clostridium difficile in hospitalised patients (see section 5.1).

Absorption of vitamin B12: HETENEX 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.

Hypomagnesaemia: There have been reports of severe hypomagnesaemia in patients treated with proton pump inhibitors (PPIs) like HETENEX 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 HETENEX.

If patients are expected to be on prolonged HETENEX treatment or given HETENEX with digoxin or medicines that may cause hypomagnesaemia (e.g., diuretics), healthcare professionals should consider measuring magnesium levels before starting HETENEX treatment and periodically during treatment.

Subacute cutaneous lupus erythematosus (SCLE): Proton pump inhibitors, such as HETENEX, are associated with rare cases of subacute 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 discontinuation of HETENEX treatment should be considered. SCLE after previous treatment with a proton pump inhibitor may increase the risk of SCLE with other proton pump inhibitors.

Risk of fracture: HETENEX, especially if used in high doses and over long durations (> 1 year), increases the risk of hip, wrist and spine fracture, predominantly in the elderly or in the presence of other recognised risk factors. Observational studies suggest that proton pump inhibitors increase the overall risk of fracture by 10 u2013 40 %. Patients at risk of developing osteoporosis should be appropriately managed and they should have an adequate intake of vitamin D and calcium.

Co-administration of esomeprazole with atazanavir is not recommended (see sections 4.3 and 4.5). If the combination of atazanavir with a proton pump inhibitor is judged unavoidable, close clinical monitoring is recommended in combination with an increase in the dose of atazanavir to 400 mg with 100 mg of ritonavir; esomeprazole 20 mg should not be exceeded.

Esomeprazole is a CYP2C19 inhibitor. When starting or ending treatment with esomeprazole, the potential for interactions with medicinal products metabolised through CYP2C19 should be considered. An interaction is observed between clopidogrel and esomeprazole (see section 4.5). The clinical relevance of this interaction is uncertain. As a precaution, concomitant use of esomeprazole and clopidogrel should be discouraged.

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.

Paediatric population: HETENEX 40 mg IV should not be used in children, since no data are available.

Renal Failure: Interstitial nephritis may progress to renal failure as it is not necessarily reversed when treatment is discontinued. HETENEX contains less than 1 mmol sodium (23 mg) per dosage unit, that is to say essentially u2018sodium - freeu2019.

Pregnancy: Limited clinical data on exposed pregnancies are available. A moderate amount of data on pregnant women (between 300 u2013 1 000 pregnancy outcomes) indicated no malformative or foetal/neonatal toxicity of HETENEX. However, caution should be exercised when prescribing HETENEX to pregnant women.

Breastfeeding: It is not known whether HETENEX is excreted in human breast milk. No studies in lactating women have been performed. Therefore, HETENEX should not be used during breastfeeding.

HETENEX has minor influence on the ability to drive and use machines. Adverse reactions such as dizziness (less frequent) and blurred vision (less frequent) have been reported (see section 4.8). If affected patients should not drive or use machines.

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. No dose-related adverse reactions have been identified.

b. Tabulated summary of adverse reactions:

Blood and the lymphatic system disorders: Less frequent Leucopenia, agranulocytosis, pancytopenia, thrombocytopenia.

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

Metabolism and nutrition disorders: Less frequent Peripheral oedema, hyponatraemia. Frequency not known Hypomagnesaemia (see section 4.4), severe hypomagnesaemia can correlate with hypocalcaemia. Hypomagnesaemia may also be associated with hypokalaemia.)

Psychiatric disorders: Less frequent Insomnia, agitation, confusion, depression, aggression, hallucinations.

Nervous system disorders: Frequent Headache. Less frequent Dizziness, paraesthesia, somnolence, taste disturbance.

Eye disorders: Less frequent Blurred vision, eye disorders.

Ear and labyrinth disorders: Less frequent Vertigo, tinnitus.

Cardiac disorders: Frequency not known: Angina, tachycardia, bradycardia.

Respiratory, thoracic and mediastinal disorders: Less frequent Bronchospasm, coughing.

Gastrointestinal disorders: Frequent Abdominal pain, diarrhoea, flatulence, nausea, vomiting, constipation. Less frequent Dry mouth, stomatitis, gastrointestinal candidiasis, pancreatitis. Frequency not known: Microscopic colitis.

Hepato-biliary disorders: Less frequent Increased liver enzymes, hepatitis with or without jaundice, hepatic failure, hepatic encephalopathy.

Skin and subcutaneous tissue disorders: Frequent Administration site reactions * Less frequent Dermatitis, pruritus, urticaria, rash, alopecia, photosensitivity, erythema multiforme, Stevens Johnson syndrome, toxic epidermal necrolysis, bullous eruption. Frequency not known Subacute cutaneous lupus erythematosus.

Musculoskeletal, connective tissue and bone disorders: Less frequent Arthralgia, myalgia, muscular weakness, fractures of the hip, wrist or spine (see section 4.4), back pain.

Renal and urinary disorders: Less frequent Interstitial nephritis, urinary disorders.

Reproductive system and breast disorders: Less frequent Gynaecomastia.

General disorders and administrative site conditions: Less frequent Malaise, hyperhidrosis.

*Administration site reactions have mainly been observed in a study with high-dose exposure over 3 days (72 hours). In the non-clinical programme for esomeprazole intravenous formulation there was no evidence of vaso-irritation but a slight tissue inflammatory reaction at the injection site after subcutaneous (paravenous) injection was noted. The non-clinical findings somewhat indicated that the clinical tissue irritation was concentration related.

c. Description of selected adverse reactions: Other effects related to acid inhibition: During treatment with HETENEX serum gastrin increases, in response to decreased acid secretion. During long-term oral treatment with HETENEX 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 HETENEX, increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with HETENEX may lead to increased risk of gastrointestinal infections such as Salmonella and Campylobacter and possibly also Clostridium difficile in hospitalised patients. Irreversible visual impairment has been reported in isolated cases of critically ill patients who have received omeprazole (the racemate) intravenous injection, especially at high doses, but no causal relationship has been established.

Paediatric population Malabsorption HETENEX may reduce cyanocobalamin (vitamin B 12) absorption probably related to the increase in gastric pH and indicating a potential risk of vitamin deficiency with long-term therapy. It is recommended that vitamin B 12 concentrations be monitored in severely ill children, who may have borderline body stores and require long-term therapy (see section 4.4).

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 or to the Holder of certificate of registration through the mail: [email protected].

The symptoms described in connection with deliberate HETENEX overdose (limited experience of oral doses in excess of 240 mg/day) are transient. Single oral dose of 80 mg and intravenous doses of 308 mg HETENEX over 24 hours were uneventful. No specific antidote is known. HETENEX is extensively plasma protein bound and is therefore not readily dialysable. As is any case of overdose, treatment should be symptomatic and general supportive measures should be utilised.