Source: Health Products Regulatory Authority (ZA) Revision Year: 2023 Publisher: Acino Pharma (Pty) Ltd, 106 16th Road, Midrand, 1686
ALTOSEC 20 is contraindicated in:
ALTOSEC 20 is not indicated for mild gastrointestinal complaints such as nervous dyspepsia.
Prior to treatment the possibility of malignancy or gastric ulcer or a malignant disease of the oesophagus should be excluded as the treatment with ALTOSEC 20 may alleviate the symptoms of malignant ulcers and can thus delay diagnosis.
There is an increased risk of subclinical acute or chronic interstitial nephritis associated with proton 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 medicine exposure. The risk of tubulointerstitial nephritis leading to chronic inflammation and reduced renal function associated with the use of proton pump inhibitors such as omeprazole, is a class effect.
Omeprazole, as in ALTOSEC 20, is a CYP2C19 inhibitor. When starting or ending treatment with ALTOSEC 20, the potential for interactions with medicines metabolised through CYP2C19 should be considered. An interaction is observed between clopidogrel and ALTOSEC 20. The clinical relevance of this interaction is uncertain. As a precaution, concomitant use of ALTOSEC 20 and clopidogrel should be avoided (see section 4.5).
Concomitant administration of ALTOSEC 20 and atazanavir and nelfinavir is not recommended (see sections 4.3 and 4.5).
ALTOSEC 20 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.
Use caution when administering high-dose methotrexate to patients receiving proton pump inhibitor therapy. Case reports and published population pharmacokinetic studies suggest that concomitant use of PPIs, such as omeprazole as in ALTOSEC 20, with methotrexate (primarily at high dose), may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities (see section 4.5).
The use of proton pump inhibitors, as in ALTOSEC 20, may be associated with an increased risk of CDAD. A diagnosis of CDAD should be considered for patients taking ALTOSEC 20 who develop diarrhoea that does not improve.
Clostridium difficile (C. difficile) is a bacterium that can cause diarrhoea that does not improve. Symptoms include watery stool, abdominal pain and fever, and patients may develop more serious intestinal conditions. The disease can also be spread in hospitals. Factors that may predispose an individual to developing CDAD include advanced age, certain chronic medical conditions and taking broad spectrum antibiotics. Treatment for CDAD includes the replacement of fluids and electrolytes and the use of indicated antibiotics.
In the presence of any alarm symptoms (e.g., significant unintentional weight loss, recurrent vomiting, dysphagia, haematemesis or melena) and when a gastric ulcer is suspected or present, malignancy should be excluded, as treatment with ALTOSEC 20 may alleviate symptoms and delay diagnosis.
Proton pump inhibitors, such as ALTOSEC 20, 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.
Severe hypomagnesaemia has been reported in patients treated with PPIs like omeprazole, as in ALTOSEC 20, 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 omeprazole, as in ALTOSEC 20. For patients expected to be on prolonged treatment or who take ALTOSEC 20 with digoxin or medicines that may cause hypomagnesaemia (e.g., diuretics), healthcare professionals should consider measuring magnesium levels before starting ALTOSEC 20 treatment and periodically during treatment.
Proton pump inhibitors, such as ALTOSEC 20, 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 healthcare provider should consider stopping ALTOSEC 20. SCLE after previous treatment with a proton pump inhibitor may increase the risk of SCLE with other proton pump inhibitors.
Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalized exanthematous pustulosis (AGEP), which can be life-threatening or fatal, have been reported very rarely and rarely, respectively in association with omeprazole, as in ALTOSEC 20, treatment.
Increased Chromogranin A (CgA) level may interfere with investigations for neuroendocrine tumours. To avoid this interference, ALTOSEC 20 treatment should be temporarily stopped five 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.
Hepatic impairment may require a reduction in dose The long-term safety of ALTOSEC 20 in patients with renal and/or hepatic impairment has not been established.
Treatment with proton pump inhibitors such as ALTOSEC 20 may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter and, in hospitalised patients, possibly also Clostridium difficile. Decreased gastric acidity increases gastric counts of bacteria normally present in the gastrointestinal tract.
When exceeding a treatment period of 1 year, patients should be kept under regular surveillance.
During long-term treatment gastric glandular cysts have been reported in somewhat increased frequency. These changes are a physiological consequence of pronounced inhibition of acid secretion, are benign and appear to be reversible.
There is very limited experience with the use of ALTOSEC 20 in children.
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose galactose malabsorption should not take ALTOSEC 20.
ALTOSEC 20 also contains mannitol and may have a laxative effect.
The decreased intragastric acidity during treatment with ALTOSEC 20 might increase or decrease the absorption of active medicines with a gastric pH dependent absorption.
The plasma levels of nelfinavir and atazanavir are decreased in case of co-administration with ALTOSEC 20. Concomitant administration of ALTOSEC 20 with atazanavir and nelfinavir is contraindicated (see sections 4.3 and 4.4). Co-administration of omeprazole (40 mg once daily) reduced mean nelfinavir exposure by ca. 40% and the mean exposure of the pharmacologically active metabolite M8 was reduced by ca. 75–90%. The interaction may also involve CYP2C19 inhibition.
Concomitant administration of omeprazole with atazanavir is not recommended (see section 4.4). Concomitant administration of omeprazole (40 mg once daily) and atazanavir 300 mg/ritonavir 100 mg to healthy volunteers resulted in a 75% decrease of the atazanavir exposure. Increasing the atazanavir dose to 400 mg did not compensate for the impact of omeprazole on atazanavir exposure. The co-administration of omeprazole (20 mg once daily) with atazanavir 400 mg/ritonavir 100 mg to healthy volunteers resulted in a decrease of approximately 30% in the atazanavir exposure as compared to atazanavir 300 mg/ritonavir 100 mg once daily.
Concomitant treatment with omeprazole (20 mg daily), as in ALTOSEC 20, and digoxin increases the bioavailability of digoxin by 10%. Digoxin toxicity has been reported. Caution should be exercised when ALTOSEC 20 is given at high doses in elderly patients. Therapeutic medicine monitoring of digoxin should be reinforced.
Pharmacokinetic/pharmacodynamic interaction between omeprazole and clopidogrel results in a decreased exposure to the active metabolite of clopidogrel by an average of 46% for omeprazole. This leads to a decreased maximum inhibition of (ADP induced) platelet aggregation by an average of 16% for omeprazole. The consequence of this would be a reduction in the antiplatelet activity of clopidogrel, which may predispose to an increase in cardiovascular events. Concomitant use of omeprazole, as in ALTOSEC 20, and clopidogrel should be avoided.
The absorption of erlotinib, posaconazole, erlotinib, ketoconazole and itraconazole is significantly reduced and thus clinical efficacy may be impaired. For posaconazole and erlotinib concomitant use should be avoided.
Omeprazole, as in ALTOSEC 20 is a moderate inhibitor of CYP2C19, the major omeprazole metabolising enzyme. Thus, the metabolism of concomitant active medicines also metabolised by CYP2C19 may be decreased and the systemic exposure to these medicines increased. Examples of such medicines are warfarin and other vitamin K antagonists, cilostazol, diazepam and phenytoin.
Omeprazole, as in ALTOSEC 20 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 active metabolites by 29% and 69% respectively.
Monitoring phenytoin plasma concentration is recommended during the first two weeks after initiating ALTOSEC 20 treatment and, if a phenytoin dose adjustment is made, monitoring and a further dose adjustment should occur upon ending ALTOSEC 20 treatment.
Concomitant administration of ALTOSEC 20 with saquinavir/ritonavir resulted in increased plasma levels up to approximately 70% for saquinavir associated with good tolerability in HIV-infected patients.
Concomitant administration of ALTOSEC 20 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.
When given together with proton-pump inhibitors, like ALTOSEC 20, methotrexate levels have been reported to increase in some patients. In high-dose methotrexate administration a temporary withdrawal of ALTOSEC 20 should be considered (see section 4.4.).
Since omeprazole, as in ALTOSEC 20, is metabolised by CYP2C19 and CYP3A4, medicines known to inhibit CYP2C19 or CYP3A4 (such as clarithromycin and voriconazole) may lead to increased omeprazole serum levels by decreasing omeprazole’s rate of metabolism. Concomitant voriconazole treatment resulted in more than doubling of the omeprazole exposure. 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 as rifampicin and St John’s wort) may lead to decreased omeprazole serum levels by increasing omeprazole’s rate of metabolism. Omeprazole is also partly metabolised by CYP3A4, but omeprazole does not inhibit this enzyme. Thus, ALTOSEC 20 does not affect the metabolism of medicines metabolised by CYP3A4, such as ciclosporin, lidocaine/lignocaine, quinidine, oestradiol, erythromycin, and budesonide. There is no evidence of interactions with theophylline, propranolol, metoprolol, amoxicillin piroxicam, diclofenac, naproxen, or antacids, but there may be interactions with other medicine also metabolised via the cytochrome P450 enzyme system.
The absorption of ALTOSEC 20 is not affected by alcohol or food.
Safety in pregnancy and lactation has not been established (see section 4.3.)
Results from three prospective epidemiological studies (more than 1000 exposed outcomes) indicate no adverse effects of omeprazole on pregnancy or on the health of the foetus/newborn child.
Omeprazole is excreted in breast milk.
Animal studies with the racemic mixture omeprazole, given by oral administration do not indicate effects with respect to fertility.
ALTOSEC 20 has minor influence on ability to drive and use machines. Since adverse reactions such as dizziness and blurred vision have been reported in patients receiving ALTOSEC 20, patients should not drive, use machinery or perform any tasks that require concentration, until they are certain that ALTOSEC 20 does not adversely affect their ability to do so (see section 4.8).
The most frequent side effects (1 to 10% of patients) are headache, abdominal pain, constipation, diarrhoea, flatulence, and nausea/vomiting. Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalized exanthematous pustulosis (AGEP) have been reported in association with omeprazole, as in ALTOSEC 20, treatment.
| System organ class | Frequent | Less frequent | Frequency unknown (Cannot be estimated from the available data) |
|---|---|---|---|
| Infections and infestations | Clostridium difficile associated diarrhoea (CDAD) | ||
| Blood and the lymphatic system disorders | Leukopenia, thrombocytopenia, agranulocytosis, pancytopenia | ||
| Immune system disorders | Hypersensitivity reactions e.g., fever, angioedema and anaphylactic reaction/shock | ||
| Metabolism and nutrition disorders | Hyponatraemia, hypomagnesaemia, severe hypomagnesaemia may result in hypocalcaemia, hypomagnesaemia may also be associated with hypokalaemia | ||
| Psychiatric disorders | Insomnia, agitation, reversible mental confusion, depression, aggression, hallucinations (predominantly in severely ill patients) | ||
| 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, constipation, diarrhoea*, flatulence, nausea/vomiting, fundic gland polyps (benign) | Dry mouth, stomatitis, gastrointestinal candidiasis, microscopic colitis | |
| Hepatobiliary disorders | Increased liver enzymes, hepatitis with or without jaundice, hepatic failure, encephalopathy in patients with pre- existing liver disease | ||
| Skin and subcutaneous tissue disorders | Dermatitis, pruritus*, rash*, urticaria*, alopecia, photosensitivity, erythema multiforme, bullous eruption, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), acute generalised exanthematous pustulosis (AGEP), drug rash with eosinophilia and systemic symptoms (DRESS) | Subacute cutaneous lupus erythematosus | |
| Musculoskeletal and connective tissue disorders | Arthralgia, arthritic and myalgic symptoms*, muscular weakness, fracture of the hip, wrist or spine | ||
| Renal and urinary disorders | Interstitial nephritis (may lead to renal failure) | ||
| Reproductive system and breast disorders | Gynaecomastia | ||
| General disorders and administrative site conditions | Malaise, increased sweating, peripheral oedema |
* Symptoms resolved after discontinuation of therapy
The safety of omeprazole has been assessed in a total of 310 children aged 0 to 16 years with acid-related disease. There are limited long-term safety data from 46 children who received maintenance therapy of omeprazole during a clinical study for severe erosive oesophagitis for up to 749 days. The adverse event profile was generally the same as for adults in short as well as in long-term treatment. There are no long-term data regarding the effects of omeprazole treatment on puberty and growth.
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/
Acino Pharma (Pty) Ltd:
E-mail: drugsafety_ZA@acino.swiss
Tel: 060 998 7896
Not applicable.
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