Trusfluks 20 & 40 20 mg, 40 mg Gastro Resistant tablet

TRUSFLUKS 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 non-steroidal anti-inflammatory drug (NSAID) therapy in patients at risk
• In combination with appropriate antibacterial therapeutic regimens for the eradication of Helicobacter pylori:
  • healing of Helicobacter pylori associated duodenal ulcer
  • prevention of relapse of peptic ulcers in patients with Helicobacter pylori associated ulcer disease
• TRUSFLUKS 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:
  • healing of Helicobacter pylori associated duodenal ulcer.
  • prevention of relapse of peptic ulcers in patients with Helicobacter pylori associated ulcer disease. 20 mg TRUSFLUKS 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 TRUSFLUKS 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.

Special populations

• Elderly population: 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: 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 TRUSFLUKS should be used.
• Paediatric population: Adolescents 12-18 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. Children: The safety and efficacy of TRUSFLUKS in children younger than 12 years of age has not been established. No data is available.

Method of administration

For oral 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.

TRUSFLUKS is contraindicated in:

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

u2022 TRUSFLUKS is not indicated for mild gastrointestinal complaints such as nervous dyspepsia.

u2022 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 TRUSFLUKS may alleviate the symptoms of malignant ulcers and can thus delay diagnosis.

Tubulointerstitial nephritis

u2022 Increased risk of subclinical acute or chronic interstitial nephritis associated with protein pump inhibitors (PPIu2019s) leading to chronic renal inflammation and reduced renal function. The preferred term to describe the histological findings of tubular injury being u201ctubulointerstitial nephritisu201d. 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.

u2022 The risk of tubulointerstitial nephritis leading to chronic inflammation and reduced renal function associated with the use of protein pump inhibitors such as TRUSFLUKS, is a class effect.

Clopidogrel

u2022 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 TRUSFLUKS and clopidogrel should be avoided.

Interference with laboratory tests

u2022 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, TRUSFLUKS should be temporarily stopped days before CgA measurements.

Special Precautions:

Long term treatment

u2022 Patients on long-term treatment (particularly those treated for more than a year) should be kept under regular surveillance.

Gastrointestinal infections and Clostridium difficile

u2022 Decreased gastric acidity due to any means including proton pump inhibitors such as TRUSFLUKS tablets, increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with TRUSFLUKS may lead to increased risk of gastrointestinal infections such as Salmonella and Campylobacter and also Clostridium difficile in hospitalised patients.

u2022 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.

Absorption of vitamin B12 (Cyanocobalamin)

u2022 TRUSFLUKS, 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.

Hypomagnesaemia

u2022 Severe hypomagnesaemia has been reported in patients treated with proton pump inhibitors (PPIs) like TRUSFLUKS 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 TRUSFLUKS 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.

Risk of fracture

u2022 Proton pump inhibitors such as TRUSFLUKS, 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 should have an adequate intake of vitamin D and calcium.

Subacute cutaneous lupus erythematosus (SCLE).

u2022 Proton pump inhibitors like TRUSFLUKS, 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 TRUSFLUKS. SCLE after previous treatment with a proton pump inhibitor may increase the risk of SCLE with other proton pump inhibitors.

Paediatric population

The safety and efficacy of TRUSFLUKS in children younger than 12 years of age has not been established.

Effects of TRUSFLUKS on the pharmacokinetics of other medicines:

Medicines with pH dependent absorption

The decreased intragastric acidity during treatment with TRUSFLUKS 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 TRUSFLUKS. 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 TRUSFLUKS is given at high doses in elderly patients. Therapeutic monitoring of digoxin levels should be done.

Medicines metabolised by CYP2C19

Diazepam

u2022 TRUSFLUKS inhibits CYP2C19, the major TRUSFLUKS metabolising enzyme. Concomitant administration of 30 mg TRUSFLUKS resulted in a 45 % decrease in clearance of the CYP2C19 substrate diazepam. This interaction is unlikely to be of clinical relevance.

Phenytoin

u2022 Concomitant administration of 40 mg TRUSFLUKS 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.

Voriconazole

u2022 TRUSFLUKS (40 mg once daily) increases voriconazole (a CYP2C19 substrate) Cmax and AUC by 15% and 41%, respectively.

Warfarin

u2022 Concomitant administration of 40 mg TRUSFLUKS 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.

u2022 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 TRUSFLUKS at initiation of treatment, during the treatment and at ending treatment.

Clopidogrel

u2022 Concomitant use of TRUSFLUKS 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 %.

Cilostazol

u2022 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. TRUSFLUKS can be suspected to have a similar effect.

Cisapride

u2022 concomitant administration of 40 mg TRUSFLUKS 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.

Methotrexate

u2022 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 TRUSFLUKS may need to be considered.

Tacrolimus

u2022 Concomitant administration of TRUSFLUKS 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.

Antiretroviral medicines

u2022 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 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.

u2022 Concomitant administration of TRUSFLUKS and antiretroviral medicines such as atazanavir and nelfinavir is not recommended. TRUSFLUKS substantially decreases the concentration of atazanavir and nelfinavir (see section 4.3).

u2022 Co-administration of TRUSFLUKS (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 u2013 90 %.

u2022 Tipranavir may decrease the concentration of TRUSFLUKS. Co-administration is not recommended. However, if used concurrently, the dose of TRUSFLUKS should be increased.

Investigated medicines with no clinically relevant interaction

u2022 ULICIUM has been shown to have no clinically relevant effects on the pharmacokinetics of amoxicillin or quinidine.

u2022 Studies evaluating concomitant administration of TRUSFLUKS 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 TRUSFLUKS:

Medicines which inhibit CYP2C19 and/or CYP3A4

u2022 TRUSFLUKS is metabolised by CYP2C19 and CYP3A4. Concomitant administration of TRUSFLUKS and a CYP3A4 inhibitor, clarithromycin (500 mg twice daily), resulted in a doubling of the exposure (AUC) to TRUSFLUKS. Concomitant administration of TRUSFLUKS and a combined inhibitor of CYP2C19 and CYP3A4, such as voriconazole, may result in more than tripling of the TRUSFLUKS exposure. Dose adjustment of TRUSFLUKS is not required. However, dose adjustment should be considered in patients with severe hepatic impairment and if long-term treatment is indicated.

Medicines which induce CYP2C19 and/or CYP3A4

u2022 Medicines known to induce CYP2C19 or CYP3A4 or both (such rifampicin and St. Johnu2019s Wort) may lead to decreased TRUSFLUKS esomeprazole serum levels by increasing the metabolism of TRUSFLUKS.

The safety of TRUSFLUKS in pregnancy and lactation has not been established.

Pregnancy

Clinical data on exposed pregnancies with TRUSFLUKS 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.

Breastfeeding

It is not known whether TRUSFLUKS is excreted in human breast milk. There is insufficient information on the effects of esomeprazole in newborns/infants. TRUSFLUKS should not be used during breast-feeding.

Fertility

Animal studies with the racemic mixture omeprazole, given by oral administration do not indicate effects with respect to fertility.

TRUSFLUKS 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 TRUSFLUKS, patients should not drive, use machinery or perform any tasks that require concentration, until they are certain that TRUSFLUKS does not adversely affect their ability to do so (see section 4.4 and/or 4.8).

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) for TRUSFLUKS. 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 list of adverse reactions

The following adverse reactions have been identified or suspected in the clinical trials programme for TRUSFLUKS. 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

Post marketing experience:

The following adverse events have been reported during the post marketing use of TRUSFLUKS. 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

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 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 requested to report any suspected adverse drug reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website.

HOTLINE for reporting of side effects directly to Innovata Pharmaceuticals (Pty) Ltd: 086 999 0912

Symptoms

There is very limited experience to date with deliberate overdose. The symptoms described in connection with 280 mg were gastrointestinal symptoms and weakness. In overdose, side effects can be precipitated and/or be of increased severity (see section 4.8).

Treatment

No specific antidote is known. TRUSFLUKS is extensively plasma protein bound and is therefore not readily dialysable. Treatment should be symptomatic and general supportive measures should be utilised.