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NEW ZEALAND DATA SHEET
1. PRODUCT NAME
LOSEC®^ 10 mg Capsules LOSEC®^ 20 mg Capsules LOSEC®^ 40 mg Capsules LOSEC®^ 40 mg MUPS Enteric Coated Tablets.
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule contains omeprazole 10 mg, 20 mg or 40 mg. Each tablet contains omeprazole magnesium 41.3 mg (corresponding to omeprazole 40 mg).
For the full list of excipients see section 6.1.
3. PHARMACEUTICAL FORM
LOSEC capsules 10 mg: hard gelatine size 3 capsules with an opaque pink body, marked 10 , and an opaque pink cap marked A/OS. Each capsule contains omeprazole 10 mg as enteric coated pellets.
LOSEC capsules 20 mg: hard gelatine size 2 capsules with an opaque pink body, marked 20 and an opaque reddish-brown cap marked A/OM. Each capsule contains omeprazole 20 mg as enteric coated pellets.
LOSEC capsules 40 mg: hard gelatine size 1 capsules with an opaque, reddish-brown body, marked 40 and an opaque reddish-brown cap marked A/OL. Each capsule contains omeprazole 40 mg as enteric coated pellets.
LOSEC MUPS (Multiple Unit Pellet System) tablets 40 mg: Dark red-brown, oblong, biconvex,
film-coated tablets engraved with or on one side and 40 mg and a score on the other side. Each tablet contains omeprazole magnesium 41.3 mg (corresponding to omeprazole 40 mg) as enteric coated pellets. [LOSEC MUPS 40 mg are not available in New Zealand]
4. CLINICAL PARTICULARS
4.1 THERAPEUTIC INDICATIONS
LOSEC capsules and LOSEC MUPS tablets are indicated for the treatment of: reflux oesophagitis duodenal ulcer gastric ulcer NSAID-associated gastric and duodenal ulcers or erosions Symptoms of acid related dyspepsia Zollinger-Ellison syndrome.
In the treatment of peptic ulceration, the eradication of H.pylori , as the causative organism, must be a high priority.
Accordingly, LOSEC should be used as part of combination therapy for the eradication of H.pylori.
Maintenance
LOSEC capsules and LOSEC MUPS tablets are indicated for maintenance treatment of: reflux oesophagitis duodenal ulcer gastric ulcer Zollinger-Ellison syndrome.
4.2 DOSE AND METHOD OF ADMINISTRATION
LOSEC capsules and LOSEC MUPS tablets are recommended to be given in the morning and swallowed whole with half a glass of water. The contents of the capsule or MUPS tablet should not be chewed or crushed.
For patients with swallowing difficulties and for children who can drink or swallow semi-solid food
LOSEC MUPS Tablets: The tablets should be taken with half a glass of liquid. The tablets must not be chewed or crushed. The tablets can also be dispersed in half a glass of non- carbonated water or fruit juices. 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 fluid and drink. The pellets must not be chewed or crushed. Do not use milk or carbonated water.
LOSEC Capsules: For patients with swallowing difficulties the capsule can be opened and the contents swallowed directly with half a glass of liquid or after mixing the contents in a slightly acidic fluid e.g. fruit juice, yoghurt or in non carbonated water. The dispersion should be taken immediately or within 30 minutes. Alternatively patients can suck the capsule and swallow the pellets with liquid. The pellets must not be chewed or crushed.
Reflux oesophagitis
The recommended dosage is LOSEC 20 mg once daily. Symptom resolution is rapid and in most patients healing occurs within 4 weeks. For those patients who may not be fully healed after the initial course, healing usually occurs during a further 4 week treatment period.
In patients with severe reflux oesophagitis LOSEC 40 mg once daily is recommended and healing is usually achieved within 8 weeks.
For the long-term management of patients with healed reflux oesophagitis the recommended dose is LOSEC 10 mg once daily. If needed the dose can be increased to LOSEC 20-40 mg once daily.
Severe reflux oesophagitis in children from one year and older
The management of severe reflux oesophagitis should be diagnosed or recommended by a specialist paediatrician or gastroenterologist.
The recommended dosage regime for healing is: Weight Dosage 10-20 kg LOSEC 10 mg daily
20 kg LOSEC 20 mg daily
NSAID-associated gastroduodenal lesions
For NSAID-associated gastric ulcers, duodenal ulcers or gastroduodenal erosions in patients with or without continued NSAID treatment, the recommended dosage of LOSEC is 20 mg once daily. Symptom resolution is rapid and in most patients healing occurs within 4 weeks. For those patients who may not be fully healed after the initial course, healing usually occurs during a further 4 weeks treatment period.
For the prevention of NSAID-associated gastric ulcers, duodenal ulcers, gastroduodenal erosions and dyspeptic symptoms the recommended dosage of LOSEC is 20 mg once daily.
Symptoms of acid-related dyspepsia
For the 24-hour relief, and prevention of symptoms in patients with epigastric pain/discomfort with or without heartburn and indigestion, 20 mg LOSEC once daily in the morning for 14 – 28 days*. If symptom control has not been achieved after 4 weeks treatment with LOSEC 20 mg daily, further investigation is recommended.
*Patients may respond adequately to 10 mg daily and this dose could be considered as a starting dose.
Zollinger-Ellison syndrome
In patients with Zollinger-Ellison syndrome the dosage should be individually adjusted and treatment continued as long as is clinically indicated. The recommended initial dosage is LOSEC 60 mg daily. All patients with severe disease and inadequate response to other therapies have been effectively controlled and more than 90% of the patients maintained on doses of LOSEC 20-120 mg daily. When doses exceed LOSEC 80 mg daily, the dose should be divided and given twice daily.
Impaired Renal Function
Dose adjustment is not needed in patients with impaired renal function.
Impaired Hepatic Function
As bioavailability and plasma half-life of omeprazole are increased in patients with impaired hepatic function a daily dose of 10 - 20 mg may be sufficient.
Elderly
Dose adjustment is not needed in the elderly.
4.3 CONTRAINDICATIONS
Known hypersensitivity to omeprazole, substituted benzimidazoles or any other constituent of the formulation.
4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE
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 should be excluded as treatment may alleviate symptoms and delay diagnosis.
Concomitant administration of omeprazole and medicines such as atazanavir and nelfinavir is not recommended (see section 4.5 Interactions).
Concomitant use of omeprazole and clopidogrel should be avoided see section 4. Interactions).
Some published studies have shown that withdrawal of long-term proton pump inhibitor (PPI) therapy can lead to aggravation of acid-related symptoms and may result in rebound acid hypersecretion. The causal relationship with omeprazole has not been fully established.
Risk of osteoporosis related fractures
Some published observational studies suggest that proton pump inhibitor (PPI) therapy may be associated with a small increased risk for osteoporosis related fractures. However, in other similar observational studies no such increased risk was found.
In randomized, double-blind and controlled clinical studies on omeprazole and esomeprazole (including two open long-term studies of up to more than 12 years) there are no indications that PPIs are associated with osteoporotic fractures.
Although a causal relationship between omeprazole/esomeprazole and osteoporotic fractures has not been established, patients at risk for developing osteoporosis or osteoporotic fractures are advised to have appropriate clinical monitoring in accordance with current clinical guidelines for these conditions.
Hypomagnesaemia
Symptomatic hypomagnesaemia has been reported rarely in patients treated with long-term PPI medication. In some severe cases hypocalcaemia was also reported. Severe hypomagnesaemia may result in serious adverse events such as tetany, seizures and potentially also arrhythmias. In some patients, treatment of hypomagnesaemia with magnesium replacement was not sufficient to correct the magnesium imbalance and discontinuation of the PPI was required. In patients later retreated with the same or different PPI, hypomagnesaemia returned within a shorter time period. For patients expected to be on prolonged treatment or who take PPIs with other medicines such as digoxin or medicines that may cause hypomagnesaemia, consideration should be given to monitoring magnesium levels prior to initiation and periodically thereafter.
4.5 INTERACTION WITH OTHER MEDICINES AND OTHER FORMS OF
INTERACTION
EFFECTS OF OMEPRAZOLE ON THE PHARMACOKINETICS OF OTHER MEDICINES
The decreased intragastric acidity during treatment with omeprazole might increase or decrease the absorption of active substances with a gastric pH dependent absorption.
Nelfinavir, atazanavir
Omeprazole has been reported to interact with some antiretroviral medicines. The clinical importance and the mechanisms behind these interactions are not always known. Increased gastric pH during omeprazole treatment may change the absorption of the antiretroviral medicine. Other possible interaction mechanisms are via CYP 2C19. For some antiretroviral medicines, such as atazanavir and nelfinavir, decreased serum levels have been reported when given together with omeprazole. Concomitant administration with omeprazole and medicines such as atazanavir and nelfinavir is therefore not recommended.
Phenytoin
Monitoring of patients receiving phenytoin is recommended and a reduction of the phenytoin dose may be necessary. However, concomitant treatment with omeprazole 20 mg daily did not change the blood concentration of phenytoin in patients on continuous treatment with this medicine.
Warfarin or other Vitamin K antagonists
In patients receiving warfarin or other vitamin K antagonists, monitoring of INR is recommended and a reduction of the warfarin (or other vitamin K antagonist) dose may be necessary. Concomitant treatment with omeprazole 20 mg daily did, however, not change coagulation time in patients on continuous treatment with warfarin.
Cilostazol
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 active metabolites by 29% and 69% respectively.
Other
Omeprazole is partly metabolised also by CYP3A4, but omeprazole does not inhibit this enzyme. Thus, omeprazole does not affect the metabolism of medicines metabolised by CYP3A4, such as cyclosporin, lignocaine, quinidine, oestradiol, erythromycin and budesonide.
Results from a range of interaction studies with omeprazole versus other medicines demonstrate that omeprazole, 20-40 mg daily, has no significant influence on any other CYP enzymes relevant for medicine metabolism, as shown by the lack of metabolic interaction with substrates for CYP1A2 (such as caffeine , theophylline ), CYP2C9 (such as S- warfarin , piroxicam, diclofenac, naproxen ), CYP2D6 (such as metoprolol, propranolol ), CYP2E1 (such as ethanol ).
UNKNOWN MECHANISM
Tacrolimus
Concomitant administration of omeprazole has been reported to increase the serum levels of tacrolimus.
Methotrexate
When given together with proton pump inhibitors, 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.
Saquinavir
For other antiretroviral medicines, such as saquinavir, elevated serum levels have been reported. There are also some antiretroviral medicines of which unchanged serum levels have been reported when given with omeprazole.
EFFECTS OF OTHER MEDICINES ON THE PHARMACOKINETICS OF OMEPRAZOLE
Inhibitors CYP2C19 and/or CYP3A
Since omeprazole is metabolised by CYP2C19 and CYP3A4, medicines known to inhibit CYP 2C19 or CYP 3A4 or both (such as clarithromycin and voriconazole ) may lead to increased omeprazole serum levels by decreasing the rate of omeprazole’s metabolism. Concomitant voriconazole treatment resulted in more than doubling of the omeprazole exposure. Since high doses of omeprazole have been well-tolerated, adjustment of the omeprazole dose is not required during temporary concomitant use.
Inducers of CYP2C19 and/or CYP3A
Medicines known to induce CYP 2C19 or CYP 3A4 or both (such as rifampicin and St John’s wort ) may lead to decreased omeprazole serum levels by increasing omeprazole’s rate of metabolism.
4.6 FERTILITY, PREGNANCY AND LACTATION
Pregnancy
Results from three prospective epidemiological studies indicate no adverse effects of omeprazole on pregnancy or on the health of the foetus/newborn child. LOSEC can be used during pregnancy.
Breast-feeding
Omeprazole is excreted in breast milk but is not likely to influence the child when therapeutic doses are used.
4.7 EFFECTS ON ABILITY TO DRIVE AND USE MACHINES
LOSEC is not likely to affect the ability to drive or use machines.
4.8 UNDESIRABLE EFFECTS
The following adverse reactions have been identified or suspected in the clinical trials programme for omeprazole and post-marketing. None was found to be dose-related. The reactions are classified according to frequency (common ≥1/100 to <1/10; uncommon ≥1/1000 to <1/100; rare ≥1/10000 to <1/1000; very rare <1/10000).
Blood and lymphatic system disorders
Rare: Leukopenia, thrombocytopenia, agranulocytosis, pancytopenia
Immune system disorders
Rare: Hypersensitivity reactions e.g. fever, angioedema and anaphylactic reaction/shock
Metabolism and nutrition disorders
Rare: Hyponatraemia Very Rare: Hypomagnesaemia, severe hypomagnesaemia may result in hypocalcaemia. Hypomagnesaemia may also result in hypokalaemia.
4.9 OVERDOSE
Rare reports have been received of overdosage with omeprazole. In the literature doses of up to 560 mg have been described and occasional reports have been received when single oral doses have reached up to 2,400 mg omeprazole (120 times the usual recommended clinical dose). Nausea, vomiting, dizziness, abdominal pain, diarrhoea and headache have been reported from overdosage with omeprazole. Also apathy, depression and confusion have been described in single cases.
The symptoms described in connection to omeprazole overdosage have been transient, and no serious outcome due to omeprazole has been reported. The rate of elimination was unchanged (first order kinetics) with increased doses and no specific treatment has been needed.
For advice on the management of overdose please contact the National Poisons Centre on 0800 POISON (0800 764 766).
5. PHARMACOLOGICAL PROPERTIES
5.1 PHARMACODYNAMIC PROPERTIES
LOSEC (omeprazole), a racemic mixture of two active enantiomers, reduces gastric acid secretion through a highly targeted mechanism of action. It is a specific inhibitor of the acid pump in the parietal cell. It is rapid acting and provides control through reversible inhibition of gastric acid secretion with once daily dosing.
Site and mechanism of action
Omeprazole is a weak base and is concentrated and converted to the active form in the highly acidic environment of the intracellular canaliculi within the parietal cell, where it inhibits
the enzyme H+,K+-ATPase, the acid pump. This effect on the final step of the gastric acid formation process is dose-dependent and provides for highly effective inhibition of both basal acid secretion and stimulated acid secretion, irrespective of the stimulus.
All pharmacodynamic effects observed can be explained by the effect of omeprazole on acid secretion.
Effect on gastric acid secretion
Oral dosing with LOSEC once daily provides for rapid and effective inhibition of daytime and night-time gastric acid secretion with maximum effect being achieved within 4 days of treatment. With LOSEC 20 mg, a mean decrease of at least 80% in 24-hour intragastric acidity is then maintained in duodenal ulcer patients, with the mean decrease in peak acid output after pentagastrin stimulation being about 70% twenty-four hours after dosing.
Oral dosing with LOSEC 20 mg maintains an intragastric pH of 3 for a mean time of 17 hours of the 24 hour period in duodenal ulcer patients.
As a consequence of reduced acid secretion and intragastric acidity, omeprazole dose- dependently reduces/normalises acid exposure of the oesophagus in patients with gastro- oesophageal reflux disease.
The inhibition of acid secretion is related to the area under the plasma concentration-time curve (AUC) of omeprazole and not to the actual plasma concentration at a given time.
No tachyphylaxis has been observed during treatment with omeprazole.
Effect on Helicobacter pylori
Helicobacter pylori is associated with acid peptic disease, including duodenal and gastric ulcer disease. H.pylori is a major factor in the development of gastritis. H.pylori together with gastric acid are major factors in the development of peptic ulcer disease. H.pylori has been found to play a causal role in the development of gastric carcinoma.
Omeprazole has a bactericidal effect on H.pylori in vitro.
Eradication of H.pylori with omeprazole and antimicrobials is associated with rapid symptom relief, high rates of healing of any mucosal lesions, and long-term remission of peptic ulcer disease thus reducing complications such as gastrointestinal bleeding as well as the need for prolonged anti-secretory treatment.
Other effects related to acid inhibition
During treatment with antisecretory medicines, serum gastrin increases in response to the decreased acid secretion. Also chromogranin A (CgA) increases due to decreased gastric acidity. The increased CgA level may interfere with investigations for neuroendocrine tumours. Literature reports indicate that proton pump inhibitor treatment should be stopped 5 to 14 days before CgA measurements. Measurements should be repeated if levels have not normalised by this time.
An increased number of ECL cells possibly related to the increased serum gastrin levels, have been observed in both children and adults during long term treatment with omeprazole. The findings are considered to be of no clinical significance.
During long-term treatment gastric glandular cysts have been reported in a somewhat increased frequency. 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, increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with acid- reducing medicines may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter and, in hospitalised patients, possibly also Clostridium difficile.
5.2 PHARMACOKINETIC PROPERTIES
Absorption and distribution
Omeprazole and omeprazole magnesium are acid labile and is therefore administered orally as enteric-coated pellets in capsules or tablets.
Bioequivalence between LOSEC capsules and LOSEC MUPS tablets based on both area under the omeprazole plasma concentration-time curve and maximum plasma concentration of omeprazole, has been demonstrated for all doses, 10 mg; 20 mg and 40 mg.
Absorption of omeprazole takes place in the small intestine and is usually completed within 3-6 hours. The systemic bioavailability of omeprazole from a single oral dose of LOSEC is
Children: Available data from children (1 year and older) suggests that the pharmacokinetics, within the recommended dosages (see section 4.2 Dose and Method of Administration), is similar to those reported in adults.
5.3 PRECLINICAL SAFETY DATA
Gastric ECL-cell hyperplasia and carcinoids, have been observed in life-long studies in rats treated with omeprazole. These changes are the result of sustained hypergastrinaemia secondary to acid inhibition. Similar findings have been made after treatment with H 2 - receptor antagonists, proton pump inhibitors and after partial fundectomy. Thus, these changes are not from a direct effect of any individual drug.
6. PHARMACEUTICAL PRECAUTIONS
6.1 LIST OF EXCIPIENTS
Capsules: Disodium hydrogen phosphate dihydrate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose anhydrous, magnesium stearate, mannitol, methacrylic acid co- polymer, microcrystalline cellulose, macrogol (polyethylene glycol), sodium lauryl sulphate, iron oxide (E 172), titanium dioxide (E 171) and gelatine.
Tablets: Microcrystalline cellulose, glyceryl monostearate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium stearate, methacrylic acid co-polymer, sugar spheres, paraffin, macrogol (polyethylene glycol), polysorbate, polyvinylpyrrolidone crosslinked, sodium stearyl fumarate, talc, triethyl citrate, iron oxide (E 172), titanium dioxide (E 171).
6.2 INCOMPATIBILITIES
None known when instructions in section 4.2 Dosage and Method of Administration are followed.
6.3 SHELF-LIFE
HDPE bottles – Capsules and tablets
3 years when stored tightly closed in the original container. Shelf-life of three months when stored in non-original container.
Aluminium Blisters - Tablets
3 years
6.4 SPECIAL PRECAUTIONS FOR STORAGE
Store below 25°C
6.5 NATURE AND CONTENTS OF CONTAINER
HDPE bottles of 30 capsules HDPE bottles of 30 tablets (Not marketed in New Zealand) Aluminium blisters containing 30 tablets (Not marketed in New Zealand)
6.6 SPECIAL PRECAUTIONS FOR DISPOSAL
Return unused and expired medicines to your local pharmacy for disposal.
7. MEDICINE SCHEDULE
Prescription Medicine.
8. SPONSOR
Pharmaco (N.Z.) Ltd 4 Fisher Crescent Mt Wellington Auckland 1060 Telephone: 0800 804 079
9. DATE OF FIRST APPROVAL
Losec 10 mg Capsules: 7 January 1997 Losec 20 mg Capsules: 27 April 1990 Losec 40 mg Capsules: 21 October 1997 Losec MUPS 40 mg Tablets: 15 February 2001
10. DATE OF REVISION OF THE TEXT
23 August 2021
CDS 220121
SUMMARY TABLE OF CHANGES
Section changed Summary of new information
4.2 Removal of Dual therapy treatment regimen
4.8 Addition of AGEP and DRESS adverse events
