Source: Health Products Regulatory Authority (ZA) Revision Year: 2021 Publisher: PHARMACARE LIMITED, Healthcare Park, Woodlands Drive, Woodmead, 2191
TRUSTAN is contraindicated in:
TRUSTAN 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 TRUSTAN may alleviate the symptoms of malignant ulcers and can thus delay diagnosis.
Increased risk of subclinical acute or chronic interstitial nephritis associated with protein pump inhibitors (PPI’s) leading to chronic renal inflammation and reduced renal function. The preferred term to describe the histological findings of tubular injury being “tubulointerstitial nephritis”.
Acute tubulointerstitial nephritis is characterised by an inflammatory reaction within the tubulointerstitial space of the kidney. Acute interstitial inflammatory reactions are associated with damage to the tubulointerstitium, leading to acute kidney injury. Tubulointerstitial nephritis may be medicine-related, infectious, systemic, autoimmune, genetic, and idiopathic with the most common cause being related to a medication or medicine exposure.
The risk of tubulointerstitial nephritis leading to chronic inflammation and reduced renal function associated with the use of protein pump inhibitors such as TRUSTAN, is a class effect.
Co-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 TRUSTAN and clopidogrel should be avoided.
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, TRUSTAN should be temporarily stopped 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 TRUSTAN tablets, increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with TRUSTAN 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.
TRUSTAN, 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.
Severe hypomagnesaemia has been reported in patients treated with proton pump inhibitors (PPIs) like TRUSTAN 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 arrhythmia 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 on TRUSTAN or who take PPIs with digoxin or medicines that may cause hypomagnesaemia (e.g. diuretics), healthcare professionals should consider measuring magnesium levels before starting PPI treatment and periodically during treatment.
Proton pump inhibitors such as TRUSTAN, especially if used in high doses and over long durations (>1 year), 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 to 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 22 should have an adequate intake of vitamin D and calcium.
Proton pump inhibitors like TRUSTAN, are associated with very infrequent cases of 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 TRUSTAN. SCLE after previous treatment with a proton pump inhibitor may increase the risk of SCLE with other proton pump inhibitors.
The safety and efficacy of TRUSTAN in children younger than 12 years of age has not been established.
TRUSTAN contains sucrose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.
The decreased intragastric acidity during treatment with TRUSTAN might increase or decrease the absorption of medicines if the mechanism of absorption is influenced by gastric acidity.
In common with the use of other inhibitors of acid secretion or antacids, the absorption of ketoconazole, itraconazole and erlotinib can decrease while the absorption of medicines such as digoxin can increase during treatment with TRUSTAN.
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 TRUSTAN is given at high doses in elderly patients. Therapeutic monitoring of digoxin levels should be done.
TRUSTAN inhibits CYP2C19, the major TRUSTAN metabolising enzyme. Concomitant administration of 30 mg TRUSTAN 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 TRUSTAN resulted in a 13% increase in trough plasma levels of phenytoin in epileptic patients; dose adjustment was not required in this study. It is recommended to monitor the plasma concentrations of phenytoin when treatment with esomeprazole is introduced or withdrawn.
TRUSTAN (40 mg once daily) increases voriconazole (a CYP2C19 substrate) Cmax and AUC by 15% and 41%, respectively.
Concomitant administration of 40 mg TRUSTAN to warfarin-treated patients showed that, despite elevation in the trough plasma concentration of the less potent Risomer of warfarin, the coagulation times were within the accepted range.
From post marketed use cases of elevated International Normalised Ratio (INR) of clinical significance have been reported during concomitant treatment with warfarin. Close monitoring is recommended when warfarin is co-administered with TRUSTAN at initiation of treatment, during the treatment and at ending treatment.
Concomitant use of TRUSTAN and clopidogrel should be avoided in healthy subjects due to 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%.
Omeprazole as well as esomeprazole act as inhibitors of CYP2C19. Omeprazole given in doses of 40 mg to healthy subjects in a cross-over study, increased Cmax and AUC for cilostazol by 18% and 26% respectively, and one of its metabolites by 29% and 69% respectively.
TRUSTAN can be suspected to have a similar effect.
In healthy volunteers, concomitant administration of 40 mg TRUSTAN resulted in a 32% increase in area under the plasma concentration-time curve (AUC) and a 31% prolongation of elimination half-life (t1/2) 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 by up to three-fold. In high-dose methotrexate administration a temporary withdrawal of TRUSTAN may need to be considered.
Concomitant administration of TRUSTAN 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.
Omeprazole has been reported to interact with some antiretroviral medicines. Increased gastric pH during omeprazole treatment may change the absorption of the antiretroviralmedicines. 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 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.
Concomitant administration of TRUSTAN and antiretroviral medicines such as atazanavir and nelfinavir is not recommended. TRUSTAN substantially decreases the concentration of atazanavir and nelfinavir (see section 4.3).
Co-administration of TRUSTAN (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%.
Tipranavir may decrease the concentration of TRUSTAN. Co-administration is not recommended. However, if used concurrently, the dose of TRUSTAN should be increased.
TRUSTAN has been shown to have no clinically relevant effects on the pharmacokinetics of amoxicillin or quinidine.
Studies evaluating concomitant administration of TRUSTAN and either naproxen (non-selective NSAID) or rofecoxib (COX-2-selective NSAID) did not identify any clinically relevant interaction.
TRUSTAN is metabolised by CYP2C19 and CYP3A4. Concomitant administration of TRUSTAN and a CYP3A4 inhibitor, clarithromycin (500 mg twice daily), resulted in a doubling of the exposure (AUC) to TRUSTAN. Concomitant administration of TRUSTAN and a combined inhibitor of CYP2C19 and CYP3A4, such as voriconazole, may result in more than tripling of the TRUSTAN exposure. Dose adjustment of TRUSTAN is not required. However, dose adjustment should be considered in patients with severe hepatic impairment and if long-term treatment is indicated.
Medicines known to induce CYP2C19 or CYP3A4 or both (such rifampicin and St. John’s Wort) may lead to decreased TRUSTAN esomeprazole serum levels by increasing the metabolism of TRUSTAN.
The safety of TRUSTAN in pregnancy and lactation has not been established.
Clinical data on exposed pregnancies with TRUSTAN are insufficient. With the racemic mixture omeprazole data on a larger number of exposed pregnancies from epidemiological studies indicate no malformative nor foetotoxic effect. Animal studies with esomeprazole do not indicate direct or indirect harmful effects with respect to embryonal/foetal development. Animal studies with the racemic mixture do not indicate direct or indirect harmful effects with respect to pregnancy, parturition or postnatal development. Caution should be exercised when prescribing to pregnant women. A moderate amount of data on pregnant women (between 300-1000 pregnancy outcomes) indicates no malformative or foeto/neonatal toxicity of esomeprazole. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity
It is not known whether TRUSTAN is excreted in human breast milk. There is insufficient information on the effects of esomeprazole in newborns/infants. TRUSTAN should not be used during breast-feeding.
Animal studies with the racemic mixture omeprazole, given by oral administration do not indicate effects with respect to fertility.
TRUSTAN has moderate influence on the ability to drive and use machines. Since adverse reactions such as dizziness and blurred vision have been reported in patients receiving TRUSTAN, patients should not drive, use machinery or perform any tasks that require concentration, until they are certain that TRUSTAN does not adversely affect their ability to do so (see section 4.4 and/or 4.8).
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) for TRUSTAN. 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.
The following adverse reactions have been identified or suspected in the clinical trials programme for TRUSTAN. None, however, were found to be dose-related.
| System organ class | Frequent | Less frequent |
|---|---|---|
| Blood and the lymphatic system disorders | Leukopenia, thrombocytopenia | |
| 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, gastrointestinal infections, microscopic colitis. |
| Hepato-biliary disorders | Increased liver enzymes, hepatitis with or without jaundice, hepatic encephalopathy. | |
| Skin and subcutaneous tissue disorders | Dermatitis, pruritus, urticaria, rash, alopecia, photosensitivity. | |
| Musculoskeletal and connective tissue disorders | Arthralgia, myalgia, fracture of the hip, wrist or spine. | |
| Reproductive system and breast disorders | Gynaecomastia. | |
| General disorders and administrative site conditions | Malaise, hyperhydrosis |
The following adverse events have been reported during the post marketing use of TRUSTAN. Because these are spontaneous reports from a population of uncertain size, it is not possible to reliably estimate their frequency.
| System organ class | Frequency unknown (cannot be estimated from the available data) |
|---|---|
| Blood and the 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, microscopic colitis. |
| Hepato-biliary 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 and connective tissue disorders | Arthralgia, myalgia, muscular weakness. |
| Renal and urinary disorders | Interstitial nephritis. |
| Reproductive system and breast disorders | Gynaecomastia. |
| General disorders and administrative site conditions | Malaise, hyperhidrosis. |
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare providers are asked to report any suspected adverse reactions to:
SAHPRA: https://www.sahpra.org.za/health-products-vigilance/
Aspen Pharmacare:
E-mail: Drugsafety@aspenpharma.com
Tel: 0800 118 088
Not applicable.
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