Source: Health Products Regulatory Authority (ZA) Publisher: Dezzo Trading 392 (Pty) Ltd, Jespan Centre, Corner Garrick and Flagtail Street, Extension 8, Lenasia, 1821, South Africa
Prior to treatment or in the presence of any alarm symptom (e.g. significant unintentional weight loss, recurrent vomiting, dysphagia, haematemesis, or melaena), the possibility of malignancy or gastric ulcer or a malignant disease of the oesophagus should be excluded as the treatment with TUMSIGON may alleviate the symptoms of malignant ulcers and can thus delay diagnosis.
Proton pump inhibitor (PPI) therapy like TUMSIGON may be associated with an increased risk of Clostridium difficile-associated diarrhoea (CDAD), especially in hospitalised patients.
This diagnosis should be considered for diarrhoea that does not improve (see section 4.8).
Patients should use the lowest dose and shortest duration of TUMSIGON therapy appropriate to the condition being treated.
TUMSIGON may increase the risk of subclinical acute interstitial nephritis (AIN) associated with proton pump inhibitors (PPIs) leading to chronic renal inflammation and reduced renal function (tubular injury being “tubulointerstitial nephritis” also called “Acute interstitial nephritis (AIN)”) (see section 4.8).
AIN has been observed in patients taking PPIs, such as TUMSIGON, and may occur at any point during PPI therapy. AIN is characterised by an inflammatory reaction within the tubulointerstitial space of the kidney. Acute interstitial inflammatory reactions are associated with damage to the tubulointerstitium and can progress to acute kidney injury (AKI) (acute renal failure).
AIN may be drug-related, infectious, systemic, autoimmune, genetic, and idiopathic with the most common cause being related to a medicine or drug exposure.
Patients may present with varying signs and symptoms from symptomatic hypersensitivity reactions to non-specific symptoms of decrease renal function (e.g., malaise, nausea, anorexia). A delay in diagnosis and continued use of the PPI can lead to chronic renal failure.
Patients on treatment with PPIs must be frequently monitored for renal function and the urine checked for haematuria and/or proteinuria. Patients should be advised to report any decrease in urine volumes or if they suspect that there is blood in their urine. Treatment with PPIs should be discontinued in patients with AIN.
The plasma levels of nelfinavir and atazanavir are decreased in case of co-administration with omeprazole. Concomitant administration of proton pump inhibitors such as omeprazole as in TUMSIGON with nelfinavir is contraindicated and with atazanavir is not recommended (see sections 4.3 and 4.5).
If the combination of atazanavir with TUMSIGON is judged unavoidable, close clinical monitoring (e.g. virus load) is recommended in combination with an increase in the dose of atazanavir to 400 mg with 100 mg of ritonavir; omeprazole 20 mg should not be exceeded.
The long-term safety of TUMSIGON in patients with renal and/or hepatic impairment has not been established.
Hepatic impairment may require a reduction in dose (see sections 4.2 and 5.2).
Clopidogrel is a prodrug. Inhibition of platelet aggregation by clopidogrel is entirely due to an active metabolite. The metabolism of clopidogrel to its active metabolite can be impaired by use with concomitant medicines, such as TUMSIGON, that interfere with CYP2C19 activity. Avoid concomitant use of clopidogrel and TUMSIGON. Concomitant use of clopidogrel with 80 mg omeprazole, reduced the pharmacological activity of clopidogrel even when administered 12 hours apart. When using TUMSIGON, consider alternative anti-platelet therapy (see section 4.5).
The clinical relevance of this interaction is uncertain. As a precaution, concomitant use of TUMSIGON and clopidogrel should be discouraged.
Proton pump inhibitors, such as TUMSIGON, 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 (see section 4.8).
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 proton pump inhibitors (PPIs) like omeprazole 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 such as TUMSIGON 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 inhibitor (PPI) therapy like TUMSIGON is associated with very infrequent cases of SCLE (see section 4.8). 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 TUMSIGON. SCLE after previous treatment with TUMSIGON may increase the risk of SCLE with other proton pump inhibitors.
TUMSIGON, 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.
Atrophic gastritis has been noted occasionally in gastric corpus biopsies from patients treated long-term with omeprazole.
Decreased gastric acidity increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with TUMSIGON may lead to slightly increased risk of gastrointestinal infections, such as Salmonella and Campylobacter (see section 4.8).
During long-term treatment gastric glandular cysts have been reported in somewhat increased frequency (see section 4.8). These changes are a physiological consequence of pronounced inhibition of acid secretion, are benign and appear to be reversible.
Serum chromogranin A (CgA) levels increase secondary to medicine-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumours.
To avoid this interference, TUMSIGON 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 TUMSIGON treatment.
Concomitant use of PPIs such as TUMSIGON with methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities. In high-dose methotrexate administration a temporary withdrawal of TUMSIGON may be considered in some patients (see section 4.5).
Medicines which induce CYP2C19 or CYP3A4 (such as St John’s Wort or rifampicin) can substantially decrease omeprazole concentrations. Avoid concomitant use of TUMSIGON with St John’s Wort or rifampicin.
As in all long-term treatments, especially when exceeding a treatment period of 1 year, patients should be kept under regular surveillance.
TUMSIGON contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
TUMSIGON contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
TUMSIGON contains mannitol which, on rare occasions, may cause hypersensitivity reactions and may have a laxative effect.
There is very limited experience with the use of TUMSIGON in children. Some children with chronic illnesses may require long-term treatment although it is not recommended.
The decreased intragastric acidity during treatment with omeprazole might increase or decrease the absorption of active substances with a gastric pH dependent absorption.
The plasma levels of nelfinavir and atazanavir are decreased in case of co-administration with omeprazole.
Concomitant administration of omeprazole with 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 to 90%. The interaction may also involve CYP2C19 inhibition. Concomitant administration of omeprazole with atazanavir is not recommended (see sections 4.3 and 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 TUMSIGON and digoxin in healthy subjects increased the bioavailability of digoxin by 10% as consequence of the increased intragastic pH. Digoxin toxicity has been rarely reported. However caution should be exercised when omeprazole is given at high doses in elderly patients. Therapeutic drug monitoring of digoxin should then be reinforced.
The absorption of 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 is a moderate inhibitor of CYP2C19, the major omeprazole metabolising enzyme. Thus, the metabolism of concomitant pro-drugs or active substances also metabolised by CYP2C19, may be decreased and the systemic exposure to these active substances decreased or increased, respectively. Examples of such an pro-drug is clopidogrel and of active substances are R-warfarin and other vitamin K antagonists, cilostazol, diazepam and phenytoin.
Clopidogrel is metabolised to its active metabolite in part by CYP2C19. Co-administration of clopidogrel with omeprazole, an inhibitor of CYP2C19, reduces the pharmacological activity of clopidogrel given concomitantly or 12 hours apart. Concomitant use of medicines that inhibit the activity of this enzyme may result in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in inhibition of platelet aggregation.
Results from studies in healthy subjects have shown a pharmacokinetic (PK)/pharmacodynamic (PD) interaction between clopidogrel (300 mg loading dose/75 mg daily maintenance dose) and omeprazole (80 mg p.o. daily) resulting in a decreased exposure to the active metabolite of clopidogrel by an average of 46% and a decreased maximum inhibition of (ADP induced) platelet aggregation by an average of 16%.
Inconsistent data on the clinical implications of a PK/PD interaction of omeprazole in terms of major cardiovascular events have been reported from both observational and clinical studies. As a precaution, concomitant use of omeprazole and clopidogrel should be discouraged (see section 4.4).
The elimination of R-warfarin and other vitamin K antagonists may be prolonged when TUMSIGON is given concomitantly. Monitoring of INR is recommended and dosage reductions may be necessary.
Omeprazole, given in doses of 40 mg to healthy subjects in a cross-over study, increased C and AUC for cilostazol by 18% and 26% respectively, and one of its active metabolites by 29% and 69% respectively.
The elimination of diazepam may be prolonged when TUMSIGON is given concomitantly.
The elimination of phenytoin may be prolonged when TUMSIGON is given concomitantly.
Monitoring phenytoin plasma concentration is recommended during the first two weeks after initiating omeprazole treatment and, if a phenytoin dose adjustment is made, monitoring and a further dose adjustment should occur upon ending omeprazole treatment.
Concomitant administration of omeprazole as in TUMSIGON has been reported to increase the serum levels of tacrolimus due to decreased CYP3A4 metabolism 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.
Concomitant administration of omeprazole as in TUMSIGON with saquinavir/ritonavir resulted in increased plasma levels up to approximately 70% for saquinavir associated with good tolerability in HIV-infected patients.
When given together with proton-pump inhibitors, such as TUMSIGON methotrexate levels have been reported to increase in some patients. In high-dose methotrexate administration a temporary withdrawal of omeprazole may need to be considered.
Since omeprazole is metabolised by CYP2C19 and CYP3A4, active substances 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. As high doses of omeprazole have been well-tolerated adjustment of the omeprazole dose is not generally required. However, dose adjustment should be considered in patients with severe hepatic impairment and if long-term treatment is indicated.
It has been reported that use of omeprazole with clarithromycin in healthy volunteers resulted in an approximate 30% increase in peak plasma concentrations of omeprazole, and an increase in its mean half-life from 1,2 to 1,6 hours. At the same time, plasma concentrations of clarithromycin were also modestly increased, as were local concentrations in gastric tissue and mucus. Clarithromycin inhibits the metabolism of omeprazole mediated by the cytochrome P450 isoenzyme CYP3A4.
The interaction may contribute to the benefits of combined therapy for Helicobacter pylori infection.
Active substances 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.
Proton pump inhibitors including, omeprazole as in TUMSIGON, can cause hypomagnesaemia when used for a prolonged period, and the risk may be further increased when combined with other medicines that also have this effect.
For patients expected to be on prolonged treatment or who take TUMSIGON with medicines that may cause hypomagnesaemia such as digoxin, tacrolimus or diuretics, measuring of magnesium levels before starting TUMSIGON treatment and periodically during treatment should be considered (see section 4.4).
The absorption of TUMSIGON is not affected by alcohol or food.
Safety in pregnancy has not been established (see section 4.3).
Safety lactation has not been established (see section 4.3).
Animal studies with the racemic mixture omeprazole, given by oral administration do not indicate effects with respect to fertility.
TUMSIGON may lead to drowsiness and impaired concentration that may be aggravated by the simultaneous intake of alcohol or other central nervous system depressants. Adverse drug reactions such as dizziness, visual disturbances and vertigo may occur (see section 4.8). Patients should be advised, particularly at the initiation of therapy, against taking charge of vehicles or machinery or performing potentially hazardous tasks where loss of concentration could lead to accidents.
It is reported that the most common side effects (1–10%) are headache, abdominal pain, constipation, diarrhoea, flatulence and nausea/vomiting.
The table below shows all adverse drug reactions (ADRs) observed during clinical trials and postmarket spontaneous reports with omeprazole.
| System Organ Class | Frequency | ||
|---|---|---|---|
| Frequent | Less Frequent | Not known | |
| Infections and infestations | Clostridium difficile-associated diarrhoea | ||
| Blood and 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, confusion, depression, aggression, hallucinations | |
| 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, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN) | subacute cutaneous lupus erythematosus (see section 4.4) |
| Musculoskeletal and connective tissue disorders | fracture of the hip, wrist or spine | arthralgia, myalgia, muscular weakness | |
| Renal and urinary disorders | interstitial nephritis (see section 4.4) | ||
| Reproductive system and breast disorders | gynaecomastia | ||
| General disorders and administration site conditions | malaise, peripheral oedema | increased sweating | |
The adverse event profile was generally the same in children as for adults in short- as well as in long-term treatment for acid-related disease. There are no long-term data regarding the effects of omeprazole treatment on puberty and growth. (see sections 4.2, 4.4 and 5.2).
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions to SAHPRA via the “6.04 Adverse Drug Reaction Reporting Form”, found online under SAHPRA’s publications: https://www.sahpra.org.za/Publications/Index/8
Not applicable.
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