Omeprazole 40 mg powder for solution for infusion for intravenous use is
indicated as an alternative to oral therapy for the following indications i.e.
Adults
• Treatment of duodenal ulcers
• Prevention of relapse of duodenal ulcers
• Treatment of gastric ulcers
• Prevention of relapse of gastric ulcers
• In combination with appropriate antibiotics, Helicobacter pylori (H.
pylori) eradication in peptic ulcer disease
• Treatment of NSAID-associated gastric and duodenal ulcers
• Prevention of NSAID-associated gastric and duodenal ulcers in patients
at risk
• Treatment of reflux esophagitis
• Long-term management of patients with healed reflux esophagitis
• Treatment of symptomatic gastro-esophageal reflux disease
• Treatment of Zollinger-Ellison syndrome

Posology
Alternative to oral therapy
In patients where the use of oral medicinal products is inappropriate,
Omeprazole 40 mg powder for solution for infusion IV 40 mg once daily is
recommended. In patients with Zollinger-Ellison Syndrome the recommended
initial dose of Omeprazole 40 mg powder for solution for infusion 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.
Omeprazole 40 mg powder for solution for infusion is to be administered in an
intravenous infusion for 20-30 minutes.
For instructions on reconstitution of the product before administration, see
section 6.6.
Special populations
Impaired renal function
Dose adjustment is not needed in patients with impaired renal function. (see
section 5.2).
Impaired hepatic function
In patients with impaired hepatic function a daily dose of 10-20 mg may be
sufficient (see section 5.2).
Older people (> 65 years old)
Dose adjustment is not needed in the elderly (see section 5.2).
Paediatric population
There is limited experience with Omeprazole 40 mg powder for solution for
infusion for intravenous use in children.

Hypersensitivity to omeprazole, substituted benzimidazoles or to any of the excipients. Omeprazole like other proton pump inhibitors (PPIs) should not be used concomitantly with nelfinavir (see section 4.5).

In the presence of any alarm symptoms (eg, significant unintentional weight
loss, recurrent vomiting, dysphagia, haematemesis or melena) and when gastric
ulcer is suspected or present, malignancy should be excluded, as treatment may
alleviate symptoms and delay diagnosis.
Co-administration of atazanavir with proton pump inhibitors is not
recommended (see section 4.5). If the combination of atazanavir with a proton
pump inhibitor 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.
Omeprazole, 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.
Omeprazole is a CYP2C19 inhibitor. When starting or ending treatment with
omeprazole, the potential for interactions with drugs metabolised through
CYP2C19 should be considered. An interaction is observed between
clopidogrel and omeprazole (see section 4.5). The clinical relevance of this
interaction is uncertain. As a precaution, concomitant use of omeprazole and
clopidogrel should be avoided.
Treatment with proton pump inhibitors may lead to slightly increased risk of
gastrointestinal infections such as Salmonella and Campylobacter (see section
5.1).
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 arrhythmia 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 with
digoxin or drugs that may cause hypomagnesaemia (e.g. diuretics), healthcare
professionals should consider measuring magnesium levels before starting PPI
treatment and periodically during treatment.
Proton pump inhibitors, 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.
Observational studies suggest that proton pump inhibitors may increase the
overall risk of fracture by 10-40%. 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.

Interference with laboratory tests
Increased Chromogranin A (CgA) level may interfere with investigations for
neuroendocrine tumours. To avoid this interference, Omeprazole Azevedos
treatment should be stopped for at least 5 days before CgA measurements (see
section 5.1). If CgA and gastrin levels have not returned to reference range after
initial measurement, measurements should be repeated 14 days after cessation
of proton pump inhibitor treatment.

As in all long-term treatments, especially when exceeding a treatment period of
1 year, patients should be kept under regular surveillance.

Subacute cutaneous lupus erythematosus (SCLE)
Proton pump inhibitors are associated with very infrequent cases of SCLE. 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 Omeprazole. SCLE after previous
treatment with a proton pump inhibitor may increase the risk of SCLE with other
proton pump inhibitors.

Effects of omeprazole on the pharmacokinetics of other active substances
 

Active substances with pH dependent absorption
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
The plasma levels of nelfinavir and atazanavir are decreased in case of coadministration
with omeprazole.
Concomitant administration of omeprazole with nelfinavir is contraindicated
(see section 4.3). Co-administration of omeprazole (40 mg once daily) reduced
mean nelvinavir exposure by ca. 40% and the mean exposure of the
pharmacologically active metabolite M8 was reduced by ca. 75-90%. The
interaction may also involve CYP2C19 inhibition.
Concomitant administration of omeprazole with atazanavir is not recommended
(see section 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.

Digoxin
Concomitant treatment with omeprazole (20 mg daily) and digoxin in healthy
subjects increased the bioavailability of digoxin by 10%. 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 be then be reinforced.

 

Clopidogrel
Result from studies in healthy subjects have shown a pharmacokinetics
(PK/pharmacodynamic (PD) iteraction between clopidogrel (330 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 this PK/PD interaction of
omeprazole in terms of major cardiovascular events have been reported from
observational and clinical studies. As precaution, concomitant use of
omeprazole and clopidogrel should be discouraged (see section 4.4).
 

Other active substances
The absorption of posaconazole, erlotinib, ketoconazol and itraconazol is
significantly reduced and thus clinical efficacy may be impaired. For
posaconazol and erlotinib concomitant use should be avoided.

Active substances metabolised by CYP2C19
Omeprazole is a moderate inhibitor of CYP2C19, the major omeprazole
metabolising enzyme. Thus, the metabolism of concomitant active substances
also metabolised by CYP2C19, may be decreased and the systemic exposure to
these substances increased. Examples of such drugs are R-warfarin and other
vitamin K antagonists, cilostazol, diazepam and phenytoin.
 

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.
 

Phenytoin
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.

 

Unknown mechanism
 

Saquinavir
Concomitant administration of omeprazole with saquinavir/ritonavir resulted in
increased plasma levels up to approximately 70% for saquinavir associated with
good tolerability in HIV-infected patients.

Tacrolimus
Concomitant administration of omeprazole has been reported to increase the
serum levels 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.

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.
 

Effects of other active substances on the pharmacokinetics of omeprazole
 

Inhibitors of CYP2C19 and/or CYP3A4
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.
 

Inducers of CYP2C19 and/or CYP3A4
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.

Pregnancy
Results from three prospective epidemiological studies (more than 1000
exposed outcomes) indicate no adverse effects of omeprazole on pregnancy or
on the health of the foetus/newborn child. Omeprazole can be used during
pregnancy.
Breastfeeding
Omeprazole is excreted in breast milk but is not likely to influence the child
when therapeutic doses are used.
Fertility
Animal studies with the racemic mixture omeprazole, given by oral
administration do not indicate effects with respect to fertility.
 

Omeprazole 40 mg powder for solution for infusion is not likely to affect the
ability to drive or use machines. Adverse drug reactions such as dizziness and
visual disturbances may occur (see section 4.8). If affected, patients should not
drive or operate machinery.

Summary of safety profile
The most common side effects (1-10% of patients) are headache, abdominal
pain, constipation, diarrhoea, flatulence and nausea/vomiting.
Tabulated list of adverse reactions
The following adverse drug reactions have been identified or suspected in the
clinical trials programme for omeprazole and post-marketing. None was found
to be dose-related. Adverse reactions listed below are classified according to
frequency and System Organ Class (SOC). Frequency categories are defined
according to the following convention: Very common (≥ 1/10), Common (≥
1/100 to < 1/10), Uncommon (≥ 1/1,000 to < 1/100), Rare (≥ 1/10,000 to <
1/1,000), Very rare (< 1/10,000), Not known (cannot be estimated from the
available data).

SOC/frequency	Adverse reaction
Blood and lymphatic system disorders
Rare:	Leukopenia, thrombocytopenia
Veryrare:	Agranulocytosis, pancytopenia
Immunesystemdisorders
Rare:	Hypersensitivity reactions e.g. fever, angioedema and anaphylactic reaction/shock
Metabolismandnutritiondisorders
Rare:	Hyponatraemia
Notknown:	Hypomagnesaemia; severe hypomagnesaemia may result in hypocalcaemia. Hypomagnesaemia may also be associated with hypokalaemia.
Psychiatricdisorders
Uncommon:	Insomnia
Rare:	Agitation, confusion, depression
Veryrare:	Aggression, hallucinations
Nervoussystemdisorders
Common:	Headache
Uncommon:	Dizziness, paraesthesia, somnolence
Rare:	Tastedisturbance
Eyedisorders
Rare:	Blurredvision
Earandlabyrinthdisorders
Uncommon:	Vertigo
Respiratory, thoracic and mediastinal disorders
Rare:	Bronchospasm
Gastrointestinal disorders
Common:	Abdominal pain, constipation, diarrhoea, flatulence, nausea/vomiting, fundic gland polyps (benign)
Rare:	Dry mouth, stomatitis, gastrointestinal candidiasis
Notknown:	Microscopiccolitis
Hepatobiliarydisorders
Uncommon:	Increasedliverenzymes
Rare:	Hepatitis with or without jaundice
Veryrare:	Hepatic failure, encephalopathy in patients with pre-existing liver disease
Skin and subcutaneous tissue disorders
Uncommon:	Dermatitis, pruritus, rash, urticaria
Rare:	Alopecia, photosensitivity
Veryrare:	Erythema multiforme, Stevens-Johnson syndrome, toxicepidermalnecrolysis (TEN)
Notknown	Subacute cutaneous lupus erythematosus (see section 4.4)
Musculoskeletal and connective tissue disorders
Uncommon:	Fracture of the hip, wrist or spine
Rare:	Arthralgia, myalgia
Veryrare:	Muscular weakness
Renal andurinarydisorders
Rare:	Interstitialnephritis
Reproductive system and breast disorders
Veryrare:	Gynaecomastia
General disorders and administration site conditions
Uncommon:	Malaise, peripheraloedema
Rare:	Increasedsweating

 

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 causal relationship has been established.

Reporting of suspected adverse reactions

 

To report any side effect(s):

The National Pharmacovigilance and Drug Safety Centre (NPC) o Fax: +966-11-205-7662 o Call NPC at +966-11-2038222, Exts: 2317-2356-2340. o Toll free phone: 19999 o E-mail: npc.drug@sfda.gov.sa o Website: www.sfda.gov.sa/npc

There is limited information available on the effects of overdoses of omeprazole
in humans. 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. Also apathy, depression and confusion have been described in single
cases.
The symptoms described have been transient, and no serious outcome has been
reported. The rate of elimination was unchanged (first order kinetics) with
increased doses. Treatment, if needed, is symptomatic.
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 reactions.

Pharmacotherapeutic group: Proton pump inhibitors, ATC code: A02BC01
 

Mechanism of action
Omeprazole, a racemic mixture of two 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 rapidly acting and provides control
through reversible inhibition of gastric acid secretion with once-daily dosing.

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 stimulus.
 

Pharmacodynamic effects
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%
for both iv injection and iv infusion.
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 H. pylori
H. pylori is associated with peptic ulcer 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 is a major factor in the development of atrophic gastritis
which is associated with an increased risk of developing gastric cancer.
Eradication of H. pylori with omeprazole and antimicrobials is associated with
high rates of healing and long-term remission of peptic ulcers.

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.
During treatment with antisecretory medicinal products, serum gastrin increases
in response to the decreased acid secretion. Also CgA increases due to decreased
gastric acidity. The increased CgA level may interfere with investigations for
neuroendocrine tumors. Literature reports indicate that proton pump inhibitor
treatment should be stopped at least 5 days before CgA measurements should
be repeated 14 days after cessation of omeprazole treatment.
An increased number of ECL cells possibly related to the increased serum
gastrin levels, have been observed in some patients (both children and adults)
during long term treatment with omeprazole. The findings are considered to be
of no clinical significance.
During treatment with antisecretory medicinal products, serum gastrin increases
in response to the decreased acid secretion. Also CgA increases due to decreased
gastric acidity. The increased CgA level may interfere with investigations for
neuroendocrine tumours.
Available published evidence suggests that proton pump inhibitors should be
discontinued between 5 days and 2 weeks prior to CgA measurements. This is
to allow CgA levels that might be spuriously elevated following PPI treatment
to return to reference range.

Distribution
The apparent volume of distribution in healthy subjects is approximately 0.3
l/kg body weight. Omeprazole is 97% plasma protein bound.

Biotransformation
Omeprazole is completely metabolised by the cytochrome P450 system (CYP).
The major part of its metabolism is dependent on the polymorphically expressed
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. In
addition, omeprazole lacks an inhibitory effect on the main CYP enzymes.
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 omeprazole.

EliminationTotal 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 once-daily dosing. Omeprazole is completely
eliminated from plasma between doses with no tendency for accumulation
during once-daily administration. Almost 80% of a dose of omeprazole is
excreted as metabolites in the urine, the remainder in the faeces, primarily
originating from bile secretion.

Linearity/non-linearity
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 (e.g.
the sulphone).
No metabolite has been found to have any effect on gastric acid secretion.
 

Special 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.

Older people The metabolism rate of omeprazole is somewhat reduced in
elderly subjects (75-79 years of age).

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 active substance.

Disodium edetate,
Sodium hydroxide (for pH adjustment)

This medicinal product should not be mixed with other medicinal products than
those mentioned in section 6.6.

Unopened packs: 2 years. Reconstituted solution: Chemical and physical in-use stability has been demonstrated for 12 hours at 25°C after reconstitution with sodium chloride 9 mg/ml (0.9%) solution for infusion and for 6 hours at 25°C after reconstitution with glucose 50 mg/ml (5%) solution for infusion. From a microbiological point of view, the product should be used immediately unless it has been reconstituted under controlled and validated aseptic conditions.

Keep the vial in the outer carton in order to protect from light. Vials can however
be stored exposed to normal indoor light outside the box for up to 24 hours.
Do not store above 30°C
For storage conditions after reconstitution of the medicinal product, see section
6.3.

Vial made of colourless borosilicate glass, typeI. Stopper made of chlorobutyl
rubber, cap made of aluminium and a plastic polypropylene lid.
Pack sizes: 1 Vial and 10 Vials.
Not all pack sizes may be marketed.

The entire contents of each vial is to be dissolved in approximately 5 ml and
then immediately diluted to 100 ml. Sodium chloride 9 mg/ml (0.9%) solution
for infusion or glucose 50 mg/ml (5%) solution for infusion must be used. The
stability of omeprazole is influenced by the pH of the solution for infusion,
which is why no other solvent or quantities should be used for dilution.

Preparation
1. With a syringe draw 5 ml of infusion solution from the 100 ml infusion
bottle or bag.
2. Add this volume to the vial with the freeze-dried omeprazole, mix
thoroughly making sure all omeprazole is dissolved.
3. Draw the omeprazole solution back into the syringe.
4. Transfer the solution into the infusion bag or bottle.
5. Repeat steps 1-4 to make sure all omeprazole is transferred from the vial
into the infusion bag or bottle.
 

Alternative preparation for infusions in flexible containers
1. Use a double-ended transfer needle and attach to the injection membrane
of the infusion bag. Connect the other needle-end from the vial with
freeze-dried omeprazole.
2. Dissolve the omeprazole substance by pumping the infusion solution
back and forward between the infusion bag and the vial.
3. Make sure all omeprazole is dissolved.

The solution for infusion is to be administered in an intravenous infusion for 20-
30 minutes.
Any unused product or waste material should be disposed of in accordance with
local requirements.