Data Sheet
Losec
Omeprazole 40 mg/10 mL for intravenous injection
Omeprazole 40 mg for intravenous infusion
Presentation
LOSEC IV injection combination pack consisting of a vial and a separate ampoule of reconstituting solution. Each 10 mL clear glass vial contains a white to off-white lyophilised powder consisting of omeprazole sodium 42.6 mg equivalent to 40 mg of omeprazole. The reconstituted solution is clear. The cap is a colourless aluminium frame with a white coloured plastic lid.
LOSEC IV infusion 40 mg. Each vial contains a white to off-white lyophilised powder consisting of omeprazole sodium 42.6 mg, equivalent to omeprazole 40 mg, which is intended to be reconstituted with 100 mL normal saline or 5% glucose (neither solution supplied with the dosage form). No other infusion solution should be used. The cap is a golden coloured aluminium frame with a blue coloured plastic lid.
Uses
Actions
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
Intravenous omeprazole produces a dose dependent inhibition of gastric acid secretion in humans. In order to immediately achieve a similar reduction of intragastric acidity as after repeated dosing with 20 mg orally, a first dose of 40 mg intravenously is recommended. This results in an immediate decrease in intragastric acidity and a mean decrease over 24 hours of approximately 90%.
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
See LOSEC Capsules/Tablets datasheet for information.
Other effects related to acid inhibition
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 drugs may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter and possibly also Clostridium difficile in hospitalised patients.
Pharmacokinetics
Distribution
The apparent volume of distribution in healthy subjects is approximately 0.3 L/kg and a similar value is also seen in patients with renal insufficiency. In elderly patients, and in patients with hepatic insufficiency, the volume of distribution is slightly decreased. The plasma protein binding of omeprazole is about 95%.
Metabolism and excretion
Omeprazole is completely metabolised by the cytochrome P450 system (CYP). The major part of its metabolism is dependent on the polymorphically expressed, specific isoform CYP2C19, responsible for the formation of hydroxyomeprazole, the major metabolite in plasma. The remaining part is dependent on another specific isoform, CYP3A4, responsible for the formation of omeprazole sulphone. As a consequence of high affinity of omeprazole to CYP2C19 , there is a potential for competitive inhibition and metabolic drug-drug interactions with other substrates for CYP2C19. However, due to low affinity to CYP3A4, omeprazole has no potential to inhibit the metabolism of other CYP3A4 substrates.
The parameters below reflect mainly the pharmacokinetics in individuals with a functional CYP2C19 enzyme, extensive metabolisers.
Total plasma clearance is about 30-40 L/h after a single dose. The plasma elimination half-life of omeprazole is usually shorter than one hour both after single and repeated oral once daily dosing. The AUC of omeprazole increases with repeated administration. This increase is dose-dependent and results in a non-linear dose-AUC relationship after repeated administration. This time- and dose-dependency is due to a decrease of first pass metabolism and systemic clearance probably caused by an inhibition of the CYP2C19 enzyme by omeprazole and/or its metabolites (eg, the sulphone). Omeprazole is completely eliminated from plasma between doses with no tendency for accumulation during once daily administration.
No metabolite has been found to have any effect on gastric acid secretion. Almost 80% of an intravenously given dose is excreted as metabolites in the urine, and the remainder is found in the faeces, primarily originating from bile secretion.
Poor metabolisers: Approximately 3% of the Caucasian population and 15-20% of Asian populations lack a functional CYP2C19 enzyme and are called poor metabolisers. In such individuals the metabolism of omeprazole is probably mainly catalysed by CYP3A4. After repeated once-daily administration of 20 mg omeprazole, the mean AUC was 5 to 10 times higher in poor metabolisers than in subjects having a functional CYP2C19 enzyme (extensive metabolisers). Mean peak plasma concentrations were also higher, by 3 to 5 times. These findings have no implications for the posology of LOSEC.
Special patient populations
Impaired hepatic function: The metabolism of omeprazole in patients with liver dysfunction is impaired, resulting in an increased AUC. Omeprazole has not shown any tendency to accumulate with once daily dosing.
Impaired renal function: The pharmacokinetics of omeprazole, including systemic bioavailability and elimination rate, are unchanged in patients with reduced renal function.
Elderly: The metabolism rate of omeprazole is somewhat reduced in elderly subjects (75-79 years of age).
Children: There is limited experience with LOSEC for intravenous use in children.
Indications
LOSEC IV is indicated primarily for the treatment of Zollinger-Ellison syndrome, and may also be used for the treatment of gastric ulcer, duodenal ulcer and reflux oesophagitis.
Dosage and Administration
In patients with duodenal ulcer, gastric ulcer or reflux oesophagitis where oral medication is inappropriate, LOSEC IV 40 mg once daily is recommended. In patients with Zollinger-Ellison syndrome the recommended initial dose of LOSEC given intravenously is 60 mg daily. Higher daily doses may be required and the dose should be adjusted individually. When doses exceed 60 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 plasma half-life of omeprazole is 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.
Children
There is limited experience with LOSEC IV in children.
Method of Administration
Injection
LOSEC IV injection 40 mg should be given as a slow intravenous injection. The solution for IV injection is obtained by adding to the vial 10 mL of the solvent provided. (No other solvent should be used). Discoloration may occur if incorrect reconstitution technique is used. For practical information about the reconstitution see the package insert. After reconstitution the injection should be given slowly over a period of at least 2.5 minutes at a maximum rate of
4 mL per minute. The solution should be used within 4 hours of reconstitution.
Infusion
LOSEC IV infusion 40 mg should be given as an intravenous infusion (over a period of 20-30 minutes or more). The contents of one vial must be dissolved in 100 mL saline for infusion or 100 mL 5% dextrose for infusion. The solution should be used within 12 hours when omeprazole is dissolved in saline and within 6 hours when dissolved in 5% dextrose. After reconstitution, start the infusion immediately. The constituted solution should not be mixed or co-administered in the same infusion set with any other drug.
Contraindications
Known hypersensitivity to omeprazole substituted benzimidazoles or any other constituent
of the formulation.
Warnings and Precautions
In the presence of any alarm symptom (e.g. significant unintentional weight loss, recurrent vomiting, dysphagia, haematemesis or melena) and when gastric ulcer is suspected or present, the possibility of malignancy should be excluded as treatment may alleviate symptoms and delay diagnosis.
Use in Pregnancy and Lactation
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.
Omeprazole is excreted in breast milk but is not likely to influence the child when therapeutic doses are used.
Effects on ability to drive and use machines
LOSEC is not likely to affect the ability to drive or use machines.
Adverse 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, <1/10; uncommon >1/1000, <1/100; rare >1/10000, <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
Psychiatric disorders
Uncommon: Insomnia
Rare: Agitation, aggression, confusion, depression, hallucinations
Nervous system disorders
Common: Headache
Uncommon: Dizziness, paraesthesia, somnolence
Rare: Taste disturbance
Eye disorders
Rare: Blurred vision
Ear and labyrinth disorders
Uncommon: Vertigo
Respiratory, thoracic and mediastinal disorders
Rare: Bronchospasm
Gastrointestinal disorders
Common: Abdominal pain, constipation, diarrhoea, flatulence, nausea/vomiting
Rare: Dry mouth, stomatitis, gastrointestinal candidiasis
Hepatobiliary disorders
Uncommon: Increased liver enzymes
Rare: Hepatitis with or without jaundice, hepatic failure, encephalopathy in patients with
pre-existing liver disease
Skin and subcutaneous tissue disorders
Uncommon: Dermatitis, pruritus, rash, urticaria
Rare: Alopecia, photosensitivity, erythema multiforme, Stevens-Johnson syndrome, toxic
epidermal necrolysis (TEN)
Musculoskeletal, connective tissue and bone disorders
Rare: Arthralgia, myalgia, muscular weakness
Renal and urinary disorders
Rare: Interstitial nephritis
Reproductive system and breast disorders
Rare: Gynaecomastia
General disorders and administration site conditions
Uncommon: Malaise
Rare: Increased sweating, peripheral oedema
Irreversible visual impairment has been reported in isolated cases of critically ill patients who have received omeprazole intravenous injection, especially at high doses, but no casual relationship has been established.
Interactions
Effects of omeprazole on the pharmacokinetics of other medicines
Absorption: The decreased intragastric acidity during treatment with omeprazole might increase or decrease the absorption of medicines with a gastric pH dependent absorption. Like with other gastric acid suppressive medicines, the absorption of medicines, such as ketoconazole and itraconazole, can decrease during treatment with omeprazole. .
Metabolism: Omeprazole inhibits CYP2C19, the major omeprazole metabolising enzyme. Thus, the metabolism of concomitant medicines also metabolised by CYP2C19, such as diazepam, phenytoin, warfarin (R-warfarin) or other vitamin K antagonists and cilostazol, may be delayed. Monitoring of patients receiving phenytoin is recommended and a reduction of the phenytoin dose may be necessary. However, concomitant treatment with LOSEC 20 mg daily did not change the blood concentration of phenytoin in patients on continuous treatment with this medicine. 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 LOSEC 20 mg daily did, however, not change coagulation time in patients on continuous treatment with warfarin. 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.
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, lidocaine, quinidine, estradiol, erythromycin, and budesonide.
Omeprazole is partly metabolised also by CYP3A4, but omeprazole does not inhibit this enzyme. Thus, omeprazole does not affect the metabolism of drugs metabolised by CYP3A4, such as cyclosporin, lidocaine, quinidine, estradiol, 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: Concomitant administration of omeprazole has been reported to increase the serum levels of tacrolimus.
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. 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
Metabolism: 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. Medicines known to induce CYP 2C19 or CYP 3A4 or both (such as rifampicin) may lead to decreased omeprazole serum levels by increasing omeprazole's rate of metabolism.
Overdosage
LOSEC IV doses of up to 270 mg on a single day and up to 650 mg over a three-day period have been given in clinical trials without any dose-related adverse reactions.
Pharmaceutical Precautions
Shelf-life and Storage conditions
Intravenous Injection
Unopened packages (the hard paper box): 2 years at a temperature not exceeding 25°C.
Vials (outside the hard paper box): Should be protected from light and stored at normal indoor light for not more than 24 hours.
Chemical and physical in-use stability has been demonstrated for 4 hours at 25°C after reconstitution.
The solution can be handled at normal indoor light without special precaution.
Substance for Infusion
Unopened packages (the hard paper box): 2 years at a temperature not exceeding 25°C.
Vials (outside the hard paper box): Should be protected from light and stored at normal in-door light for not more than 24 hours.
Substance for infusion must be dissolved in 100 mL saline for infusion or 100 mL 5% dextrose for infusion.
Chemical and physical in-use stability has been demonstrated for 12 hours after reconstitution with saline or for 6 hours after reconstitution with 5% dextrose.
From a microbiological point of view, the product should be used immediately, unless reconstitution has taken place in controlled and validated aseptic conditions. The solution can be handled at normal indoor light without special precaution.
Incompatibilities
None known when instructions in DOSAGE AND ADMINISTRATION are followed.
Medicine Classification
Prescription Medicine.
Package Quantities
LOSEC IV for Injection: Individual injection packs.
LOSEC IV for Infusion: 5 x vials of lyophilised powder.
Further Information
Excipients
LOSEC IV Injection
LOSEC IV injection 40 mg combination pack consisting of a vial and an ampoule. Each vial contains sodium hydroxide q.s. for pH adjustment. Each reconstituting solution ampoule contains citric acid monohydrate 5 mg (for pH adjustment), macrogol 400 (polyethylene glycol 400) 4 g, and water for injection up to 10 mL.
LOSEC IV Infusion
LOSEC IV infusion 40 mg. Each vial contains disodium edetate 1.5 mg and sodium hydroxide q.s. for pH adjustment.
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 H2-receptor antagonists, proton pump inhibitors and after partial fundectomy. Thus, these changes are not from a direct effect of any individual drug.
Name and Address
AstraZeneca Limited
303 Manukau Road, Epsom
PO Box 1301
Auckland
Telephone: (09) 623-6300
Date of Preparation
10 September 2009
CDS June 2009
Copyright - No part may be reproduced by any process without the prior written permission of AstraZeneca Limited