1. Name Of The Medicinal Product
Losec® I.V. Injection 40 mg
2. Qualitative And Quantitative Composition
a) Each vial of powder for solution for injection contains omeprazole sodium 42.6 mg, equivalent to omeprazole 40 mg. After reconstitution, 1 ml contains omeprazole sodium 4.26 mg, equivalent to 4.00 mg omeprazole.
b) Each ampoule contains 10 ml of solvent for injection
For excipients, see 6.1.
3. Pharmaceutical Form
Powder and solvent for solution for injection.
4. Clinical Particulars
4.1 Therapeutic Indications
Prophylaxis of acid aspiration.
In patients who are unable to take oral therapy for the short
4.2 Posology And Method Of Administration
Dosage
Adults only
Prophylaxis of acid aspiration: Losec 40 mg to be given slowly (over a period of 5 minutes) as an intravenous injection, one hour before surgery.
Treatment in patients where oral therapy is inappropriate e.g. in severely ill patients with either reflux oesophagitis, duodenal ulcer or gastric ulcer: Losec 40 mg given as an intravenous injection once daily is recommended for up to 5 days.
Clinical experience in Zollinger-Ellison syndrome is limited (see section 5.1 Pharmacodynamic properties).
Administration
Losec powder and solvent for solution for injection is for intravenous administration only and must not be given by any other route.
Losec powder and solvent for solution for injection should only be dissolved in the solvent provided. No other solvents for I.V. injection should be used.
After reconstitution outside validated aseptic conditions, use within 4 hours of preparation and any unused portion should be discarded.
The duration of administration should be over 5 minutes.
Use in the elderly
Dosage adjustment is not necessary.
Use in children
There is limited experience of use in children.
Impaired renal function
Dose adjustment is not required in patients with impaired renal function.
Impaired hepatic function
As half-life is increased in patients with impaired hepatic function, the dose requires adjustment and a daily dose of 10 mg–20 mg may be sufficient.
4.3 Contraindications
Known hypersensitivity to any of the constituents of the formulation.
Omeprazole like other PPIs should not be administered with atazanavir (see section 4.5).
4.4 Special Warnings And Precautions For Use
When gastric ulcer is suspected, the possibility of malignancy should be excluded before treatment with Losec is instituted, as treatment may alleviate symptoms and delay diagnosis.
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 a slightly increased risk of gastrointestinal infections, such as Salmonella and Campylobacter.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Due to the decreased intragastric acidity, the absorption of ketoconazole or itraconazole may be reduced during omeprazole therapy as it is during treatment with other acid secretion inhibitors.
As omeprazole is metabolised in the liver through cytochrome P450 it can prolong the elimination of diazepam, phenytoin, warfarin and other vitamin K antagonists, which are in part substrates for this enzyme.
Monitoring of patients receiving phenytoin is recommended and a reduction of the phenytoin dose may be necessary when Losec is added to treatment. However, concomitant treatment with Losec 20 mg orally daily, did not change the blood concentration of phenytoin in patients on continuous treatment with phenytoin. 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 orally daily, did not change coagulation time in patients on continuous treatment with warfarin.
Plasma concentrations of omeprazole and clarithromycin are increased during concomitant oral administration. There is no interaction with metronidazole or amoxicillin. These antimicrobials are used together with omeprazole for eradication of Helicobacter pylori .
There is no evidence of an interaction with phenacetin, theophylline, caffeine, propranolol, metoprolol, ciclosporin, lidocaine, quinidine, estradiol, or antacids when Losec is given orally. The absorption of Losec given orally is not affected by alcohol or food.
There is no evidence of an interaction with piroxicam, diclofenac or naproxen, this is considered useful when patients are required to continue these treatments.
Simultaneous treatment with omeprazole and digoxin in healthy subjects led to a 10% increase in the bioavailability of digoxin as a consequence of the increased intragastric pH.
Interaction with other drugs also metabolised via the cytochrome P450 system cannot be excluded.
Co-administration of omeprazole (40mg once daily) with atazanavir 300 mg/ritonavir 100mg to healthy volunteers resulted in a substantial reduction in atazanavir exposure (approximately 75% decrease in AUC, Cmax, and Cmin). Increasing the atazanavir dose to 400mg did not compensate for the impact of omeprazole on atazanavir exposure. PPIs including omeprazole should not be co-administered with atazanavir (see section 4.3)
Concomitant administration of omeprazole and tacrolimus may increase the serum levels of tacrolimus.
Concomitant administration of omeprazole and a CYP2C19 and CYP3A4 inhibitor, voriconazole, resulted in more than doubling of the omeprazole exposure. Omeprazole (40 mg once daily) increased voriconazole (a CYP2C19 substrate) Cmax and AUC by 15% and 41%, respectively. A dose adjustment of omeprazole is not regularly required in either of these situations. However, dose adjustment should be considered in patients with severe hepatic impairment and if long-term treatment is indicated.
4.6 Pregnancy And Lactation
Use in pregnancy
The analysis of the results from three epidemiological studies has revealed no evidence of adverse events of omeprazole on pregnancy or on the health of the foetus/newborn child. Losec can be used during pregnancy.
Use in lactation
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
No effects are foreseen.
4.8 Undesirable Effects
Losec is well tolerated and adverse reactions have generally been mild and reversible. The following have been reported as adverse events in clinical trials or reported from routine use, but in many cases a relationship to treatment with omeprazole has not been established.
The following definitions of frequencies are used:
Common - > 1/100
Uncommon - > 1/1000 and < 1/100
Rare - < 1/1000
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Isolated cases of irreversible visual impairment have been reported in critically ill patients who have received Losec Intravenous Injection, particularly at high doses, however no causal relationship has been established.
4.9 Overdose
Intravenous 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 effects.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Omeprazole reduces gastric acid secretion through a unique mechanism of action. It is a specific inhibitor of the gastric proton pump in the parietal cell. It is rapidly acting and produces reversible control of gastric acid secretion with once daily dosing.
Intravenous administration of omeprazole results in an immediate reduction of intragastric acidity and a mean decrease over 24 hours of approximately 90% in patients with duodenal ulcer disease. A single 40 mg i.v. dose has similar effect on intragastric acidity over a 24 hour period as repeated oral dosing with 20 mg once daily. A higher dose of 60 mg i.v. twice daily has been used in a clinical study in patients with Zollinger-Ellison syndrome.
Site and mechanism of action
Omeprazole is a weak base and is concentrated and converted to the active form in the acid environment of the intracellular canaliculi within the parietal cell, where it inhibits the enzyme H+, K+,-ATPase–the proton pump. This effect on the final step of the gastric acid formation process is dose-dependent and provides for effective inhibition of both basal acid secretion and stimulated acid secretion irrespective of the stimulus.
All pharmacodynamic effects observed are explained by the effect of omeprazole on acid secretion. No tachyphylaxis has been observed during treatment with omeprazole.
5.2 Pharmacokinetic Properties
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 the elderly 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
The average half-life of the terminal phase of the plasma concentration-time curve following i.v. administration of omeprazole is approximately 40 minutes; the total plasma clearance is 0.3 to 0.6 L/min. There is no change in half-life during treatment.
Omeprazole is completely metabolised by the cytochrome P450 system, mainly in the liver. The major part of its metabolism is dependent on the polymorphically expressed, specific isoform CYP2C19 (S-mephenytoin hydroxylase), responsible for the formation of hydroxyomeprazole, the major metabolite in plasma.
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 biliary secretion.
Elimination of omeprazole is unchanged in patients with reduced renal function. The elimination half-life is increased in patients with impaired liver function, but omeprazole has not shown any accumulation with once daily oral dosing.
5.3 Preclinical Safety Data
Animal Toxicology
Gastric ECL-cell hyperplasia and carcinoids, have been observed in life-long studies in rats treated with omeprazole or subjected to partial fundectomy. These changes are the result of sustained hypergastrinaemia secondary to acid inhibition, and not from a direct effect of any individual drug.
6. Pharmaceutical Particulars
6.1 List Of Excipients
a) Vial: Sodium hydroxide.
b) Ampoule: Macrogol 400, Citric acid monohydrate and Water for Injections.
6.2 Incompatibilities
No other drugs should be mixed with reconstituted Losec I.V. Injection solution.
6.3 Shelf Life
Unopened packs: 2 years.
Reconstituted solution: 4 hours.
6.4 Special Precautions For Storage
Do not store above 25°C. Keep the containers in outer carton.
6.5 Nature And Contents Of Container
Combination pack consisting of a clear, Type I, glass vial containing omeprazole sodium 42.6 mg with grey bromobutyl rubber stopper, white polypropylene cap with aluminium frame and a clear, Type I, (OPC) glass ampoule containing solvent for intravenous administration, both packed together in a plastic tray in a hard cardboard box.
6.6 Special Precautions For Disposal And Other Handling
The entire contents of the vial should be completely dissolved with the 10 ml of solvent provided in the ampoule. No other solvents for I.V. injection should be used.
Use on one patient during one treatment only.
Do not use if any particles are present in the reconstituted solution.
Chemical and physical in-use stability of the reconstituted product has been shown for 4 hours when stored at 25°C.
From a microbiological point of view, once opened and reconstituted the product may be stored for a maximum of 4 hours at 25°C. Other in-use storage times and conditions are the responsibility of the user.
Any unused portion should be discarded.
Preparation:
NOTE: Stages 1 to 5 should be done in immediate sequence.
With a syringe draw 10 ml of solvent from the ampoule.
Add approximately 5 ml of the solvent to the vial with freeze-dried omeprazole.
Withdraw as much air as possible from the vial back into the syringe in order to reduce positive pressure. This will make it easier to add the remaining solvent.
Add the remaining solvent into the vial, make sure that the syringe is empty.
Rotate and shake the vial to ensure all the freeze-dried omeprazole has dissolved.
7. Marketing Authorisation Holder
AstraZeneca UK Ltd.,
600 Capability Green,
Luton, LU1 3LU, UK.
8. Marketing Authorisation Number(S)
PL 17901/0135
9. Date Of First Authorisation/Renewal Of The Authorisation
18th June 2002
10. Date Of Revision Of The Text
28th January 2008
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