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ZANPROL 10 MG TABLETS

Active substance(s): OMEPRAZOLE / OMEPRAZOLE / OMEPRAZOLE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Zanprol 10 mg Tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Omeprazole 10 mg
For excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Gastro-resistant coated tablets.
Brownish-pink, capsule-shaped film-coated tablets.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Zanprol 10 mg Tablets are indicated for the treatment of reflux symptoms (e.g.
heartburn, acid regurgitation) in adults.

4.2

Posology and method of administration
Posology in adults
The recommended dose is 20 mg once daily for 14 days.
It might be necessary to take the tablets for 2-3 consecutive days to achieve
improvement of symptoms.
The majority of patients achieve complete relief of heartburn within 7 days.
Once complete relief of symptoms has occurred, treatment should be
discontinued.
Special populations
Impaired renal function

Dose adjustment is not needed in patients with impaired renal function (see
section 5.2).
Impaired hepatic function
Patients with impaired hepatic function should be advised by a doctor before
taking Zanprol 10 mg Tablets (see section 5.2).
Elderly (> 65 years old)
Dose adjustment is not needed in the elderly (see section 5.2).
Method of administration
It is recommended to take Zanprol 10mg Tablets in the morning, swallowed
whole with half a glass of water. The tablets must not be chewed or crushed.
For patients with swallowing difficulties
Break the tablet and disperse it in a spoonful of non-carbonated water - if so
wished, mix with some fruit juices or applesauce. The dispersion should be
taken immediately (or within 30 minutes). The dispersion should always be
stirred just before drinking and rinsed down with half a glass of water. DO
NOT USE milk or carbonated water. Do not chew.

4.3

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

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, 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 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 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 discouraged.
Zanprol Tablets contain lactose. Patients with rare hereditary problems of
galactose intolerance, the Lapp lactase deficiency or glucose-galactose
malabsorption should not take this medicine.
Treatment with proton pump inhibitors may lead to slightly increased risk of
gastrointestinal infections such as Salmonella or Campylobacter (see section
5.1).
Patients with long-term recurrent symptoms of indigestion or heartburn should
see their doctor at regular intervals. Especially, patients over 55 years taking
any “over the counter” (OTC, non-prescription) indigestion or heartburn
remedy on a daily basis should inform their pharmacist or doctor.
Patients should be instructed to consult a doctor if:
• They have had previous gastric ulcer or gastrointestinal surgery.
• They are on continuous symptomatic treatment of indigestion or heartburn
for 4 or more weeks.
• They have jaundice or severe liver disease.
• They are aged over 55 years with new or recently changed symptoms.
Patients should not take omeprazole as a preventative medication.

4.5

Interaction with other medicinal products and other forms of interaction
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 then be reinforced.
Clopidogrel
In a crossover clinical study, clopidogrel (300 mg loading dose followed by 75
mg/day) alone and with omeprazole (80 mg at the same time as clopidogrel)
were administered for 5 days. The exposure to the active metabolite of
clopidogrel was decreased by 46% (day 1) and 42% (Day 5) when clopidogrel
and omeprazole were administered together. Mean inhibition of platelet
aggregation (IPA) was diminished by 47% (24 hours) and 30% (Day 5) when
clopidogrel and omeprazole were administered together. In another study it
was shown that administering clopidogrel and omeprazole at different times
did not prevent their interaction that is likely to be driven by the inhibitory
effect of omeprazole on CYP2C19. Inconsistent data on the clinical
implications of this PK/PD interaction in terms of major cardiovascular events
have been reported from observational and clinical studies.
Other active substances
The absorption of posaconazole, 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 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
concentration as well as renal function (creatinine clearance) should be
performed, and dosage of tacrolimus adjusted if needed.
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.

4.6

Fertility, Pregnancy and lactation
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.
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
Zanprol 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.

4.8

Undesirable effects
The most common side effects (1-10% of patients) are headache, abdominal
pain, constipation, diarrhoea, flatulence and nausea/vomiting.
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
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
Very rare:
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
Psychiatric disorders
Uncommon:
Insomnia
Rare:
Agitation, confusion, depression
Very rare:
Aggression, 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
Very rare:
Hepatic failure, encephalopathy in patients with preexisting liver disease

Skin and subcutaneous tissue disorders
Uncommon:
Dermatitis, pruritus, rash, urticaria
Rare:
Alopecia, photosensitivity
Very rare:
Erythema multiforme, Steven-Johnson syndrome,
toxic epidermal necrolysis (TEN)
Musculoskeletal and connective tissue disorders
Rare:
Arthralgia, myalgia
Very rare:
Muscular weakness
Renal and urinary disorders
Rare:
Interstitial nephritis
Reproductive system and breast disorders
Very rare:
Gynaecomastia
General disorders and administration site conditions
Uncommon:
Malaise, peripheral oedema
Rare:
Increased sweating

4.9

Overdose
There is limited information available on the effects of overdose of
omeprazole in humans. In the literature, doses up to 560 mg have been
described, and occasional reports have been received when single 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 in connection to omeprazole overdose 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.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
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
Oral dosing with omeprazole once daily provides for rapid and sustained
inhibition of daytime and night-time gastric acid secretion with maximum
effect being achieved within 4 days of treatment. With omeprazole 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 about 70% 24 hours after dosing.
Oral dosing with omeprazole 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
omeprazole dose-dependently reduces/normalizes acid exposure
esophagus in patients with gastro-esophageal reflux disease.
The inhibition of acid secretion is related to the area under the
concentration-time curve (AUC) of omeprazole and not to the actual
concentration at a given time.

acidity,
of the
plasma
plasma

No tachyphylaxis has been observed during treatment with omeprazole.
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.
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.

5.2

Pharmacokinetic properties
Absorption
Omeprazole and omeprazole magnesium are acid labile and are therefore
administered orally as enteric-coated granules in capsules or tablets.
Absorption of omeprazole is rapid, with peak plasma levels occurring
approximately 1-2 hours after dose. Absorption of omeprazole takes place in
the small intestine and is usually completed within 3-6 hours. Concomitant
intake of food has no influence on the bioavailability. The systemic availability
(bioavailability) from a single oral dose of omeprazole is approximately 40%.
After repeated once-daily administration, the bioavailability increases to about
60%.
Distribution
The apparent volume of distribution in healthy subjects is approximately 0.3
l/kg body weight. Omeprazole is 97% plasma protein bound.
Metabolism
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.
Excretion
The plasma elimination half-life of omeprazole is usually shorter than one hour
both after single and repeated oral once-daily dosing. Omeprazole is
completely eliminated from plasma between doses with no tendency for
accumulation during once-daily administration. Almost 80% of an oral dose of
omeprazole is excreted as metabolites in the urine, the remainder in the faeces,
primarily originating from bile secretion.
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.
Elderly
The metabolism rate of omeprazole is somewhat reduced in elderly subjects
(75-79 years of age).

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 active substance.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Core
lactose monohydrate
sodium starch glycollate
sodium stearate
sodium stearyl fumarate
Enteric Coating
hydroxypropyl methylcellulose (HPMC) acetate succinate
talc
triethyl citrate
monoethanolamine
sodium lauryl sulphate

Sepisperse AP-3527 [containing: propylene glycol, titanium dioxide (E-171),
red iron oxide (E-172), yellow iron oxide (E-172) and hydroxypropyl
methylcellulose]
Polish
carnauba wax

6.2

Incompatibilities
Not applicable

6.3

Shelf life
2 years

6.4

Special precautions for storage
Store in the original package. Do not store above 30°C.

6.5

Nature and contents of container
Aluminium/aluminium blisters strips containing 7, 14 or 28 tablets, in a
cardboard carton.

6.6

Special precautions for disposal
Not applicable.

7

MARKETING AUTHORISATION HOLDER
Omega Pharma Ltd.
1st Floor
32 Vauxhall Bridge Road
LONDON, SW1V 2SA
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 02855/0083

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
26/06/2009

10

DATE OF REVISION OF THE TEXT
31/01/2013

Expand Transcript

Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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