New Zealand Datasheet
1 PRODUCT NAME
Omeprazole Infusion 40 mg
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Omeprazole 40 mg for intravenous infusion
3 PHARMACEUTICAL FORM
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
5% glucose (solution not supplied with the dosage form). No other infusion solution should
be used. The cap is aluminium with a white coloured plastic flip-off lid.
4.1 Therapeutic indications
Omeprazole Infusion 40 mg 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.
4.2 Dose and method of administration
In patients with duodenal ulcer, gastric ulcer or reflux oesophagitis where oral medication is
inappropriate, Omeprazole Infusion 40 mg once daily is recommended. In patients with
Zollinger-Ellison syndrome the recommended initial dose of omeprazole 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 omeprazole IV in children.
Method of Administration
Omeprazole Infusion 40 mg infusion 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 of
5% dextrose for infusion or 100 ml of 0.9% saline for infusion. Do not use the solution if
reconstitution is not complete. The solution should be used within 6 hours when dissolved in
5% dextrose and 12 hours when dissolved in saline. 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.
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 melena) and when gastric ulcer is suspected or
present, the possibility of malignancy should be excluded as treatment may alleviate
symptoms and delay diagnosis.
4.5 Interaction with other medicines and other forms of interaction
Effects of omeprazole on the pharmacokinetics of other medicines
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.
Citalopram / Escitalopram
Co-administration of omeprazole (20 mg) with citalopram (20 mg single dose) doubles the
AUC of the S-isomer of citalopram, but the R-isomer of citalopram is not affected. A
reduction in the dose of citalopram may be necessary based on clinical judgement. For
patients taking omeprazole, the citalopram dose should not exceed the maximum dose of 20
mg/day.
Co-administration of omeprazole (30 mg) with escitalopram (20 mg single dose) increased
the plasma levels (approximately 50%) and terminal half-life (31%) of escitalopram. A
reduction in the dose of escitalopram may be necessary based on clinical judgement.
Digoxin
Concomitant treatment with omeprazole (20 mg daily) and digoxin in healthy subjects
increased the bioavailability of digoxin by 10% (up to 30% in two out of ten subjects).
Clopidogrel
Results from studies in healthy subjects have shown a pharmacokinetic/pharmacodynamic
interaction between clopidogrel (300 mg loading dose/75 mg daily maintenance dose) and
omeprazole (80 mg p.o. daily, i.e. four times the recommended dose) resulting in decreased
exposure to the active metabolite of clopidogrel by an average of 46%, and resulting in
decreased maximum inhibition of (ADP induced) platelet aggregation by an average of 16%.
It is, however, uncertain to what extent this interaction is clinically important. One
prospective, randomised (but incomplete) study (in over 3760 patients comparing placebo
with omeprazole 20 mg in patients treated with clopidogrel and ASA) and non-randomised,
post-hoc analyses of data from large, prospective, randomised clinical outcome studies (in
over 47000 patients) did not show any evidence of an increased risk for adverse
cardiovascular outcome when clopidogrel and PPIs, including omeprazole, were given
concomitantly.
Results from a number of observational studies are inconsistent with regard to increased risk
or no increased risk for CV thromboembolic events when clopidogrel is given together with a
PPI.
When clopidogrel was given together with a fixed dose combination of esomeprazole 20 mg
+ ASA 81 mg compared to clopidogrel alone in a study in healthy subjects there was a
decreased exposure by almost 40% of the active metabolite of clopidogrel. However, the
maximum levels of inhibition of (ADP induced) platelet aggregation in these subjects were
the same in the clopidogrel and the clopidogrel + the combined (esomeprazole + ASA)
product groups, likely due to the concomitant administration of low dose ASA.
Other active substances
The absorption of erlotinib, ketoconazole and itraconazole is significantly reduced and thus
clinical efficacy may be impaired. For posaconazole and erlotinib concomitant use should be
avoided.
Active substances metabolised by CYP2C19
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 omeprazole capsules 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 omeprazole capsules 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, lidocaine, quinidine, oestradiol, erythromycin, and
budesonide. However, omeprazole has been shown to induce CYP1A2-mediated
metabolism of clozapine. Close monitoring of plasma clozapine levels is recommended.
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). However, omeprazole has been shown to induce CYP1A2-mediated
metabolism of clozapine. Close monitoring of plasma clozapine levels is recommended.
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 CYP3A4
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 CYP3A4
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.
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. Omeprazole 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
Omeprazole 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, <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
Very rare: Hypomagnesaemia, severe hypomagnesaemia may result in hypocalcaemia.
Hypomagnesaemia may also result in hypokalaemia
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, microscopic colitis
Frequency not known: Withdrawal of long-term PPI therapy can lead to aggravation of acid-
related symptoms and may result in rebound acid hypersecretion.
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.
Reporting of suspected adverse reactions
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
https://nzphvc.otago.ac.nz/reporting/.
4.9 Overdose
Omeprazole 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.
For advice on the management of overdose please contact the National Poisons Centre on
0800 POISON (0800 764766).
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Proton pump inhibitors, ATC code: A02BC01
Omeprazole is 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 Omeprazole capsules 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.
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 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 dosage of Omeprazole.
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 Omeprazole for intravenous use in children.
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 H2-
receptor antagonists, proton pump inhibitors and after partial fundectomy. Thus, these
changes are not from a direct effect of any individual drug.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Each vial contains disodium edetate 1.0 mg and sodium hydroxide q.s. for pH adjustment.
6.2 Incompatibilities
None known when instructions in section 4.2 are followed.
6.3 Shelf life
Unopened packages: 2 years at a temperature not exceeding 25ºC.
6.4 Special precautions for storage
Omeprazole infusion 40 mg must be dissolved in 100 ml 5% dextrose for infusion or 100 ml
0.9% saline for infusion. Chemical and physical in-use stability has been demonstrated for 6
hours after reconstitution with 5% dextrose and 12 hours after reconstitution with saline.
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.
6.5 Nature and contents of container
Omeprazole Infusion 40 mg for Infusion: 1 or 5 vials of lyophilised powder.
6.6 Special precautions for disposal
Any unused product or waste material should be disposed of in accordance with local
requirements.
7 MEDICINE SCHEDULE
Prescription Medicine.
8 SPONSOR
Dr Reddy’s New Zealand Ltd
82 Totara Crescent
Lower Hutt 5011
WELLINGTON
Tel: 0800 362 733
9 DATE OF FIRST APPROVAL
28 August 2008
10 DATE OF REVISION OF THE TEXT
14 February 2019
SUMMARY TABLE OF CHANGES
Section changed Summary of new information
4.8 Reporting of adverse events added
4.8 Additional adverse effect for rebound acid hypersecretion
4.9 Poison centre contact details added
