Pantoprazole 40mg gastro-resistant tablets

United Kingdom - English - MHRA (Medicines & Healthcare Products Regulatory Agency)

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Active ingredient:
Pantoprazole sodium sesquihydrate
Available from:
Accord Healthcare Ltd
ATC code:
A02BC02
INN (International Name):
Pantoprazole sodium sesquihydrate
Dosage:
40mg
Pharmaceutical form:
Gastro-resistant tablet
Administration route:
Oral
Class:
No Controlled Drug Status
Prescription type:
Valid as a prescribable product
Product summary:
BNF: 01030500; GTIN: 5012617017697
Authorization number:
PL 20075/0700

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G. Worth

11/02/2020

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G. Worth

190x600

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Teva Bulgaria

Dupnitsa

11/02/2020

12/02/2020

Pantoprazole 40 mg Gastro-resistant tablet PIL - UK

Black

BBBA7553

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* Please note that only Artwork Studio is permitted to make changes to the above artwork.

No changes are permitted by any 3rd party other than added notes and mark ups for required changes.

GTIN 13

(Belgium & Slovenia):

Version 6

12.12.2019

German GTIN 14

(incorporating PZN):

Cartons and label leaflets only

(labels only when specified)

Read all of this leaflet carefully before

you start taking this medicine because it

contains important information for you.

Keep this leaflet. You may need to read it

again.

If you have any further questions, ask your

doctor or pharmacist.

This medicine has been prescribed for you

only. Do not pass it on to others. It may

harm them, even if their signs of illness are

the same as yours.

If you get any side effects, talk to your

doctor or pharmacist. This includes any

possible side effects not listed in this leaflet.

See section 4.

The full name of this medicine is

Pantoprazole 40mg Gastro-resistant Tablets

but within the leaflet it will be referred to as

Pantoprazole tablets.

What is in this leaflet:

1

What Pantoprazole tablets are and what

they are used for

2

What you need to know before you take

Pantoprazole tablets

3

How to take Pantoprazole tablets

4

Possible side effects

5

How to store Pantoprazole tablets

6

Contents of the pack and other

information

1

What Pantoprazole tablets are and what

they are used for

Pantoprazole is a selective “proton pump inhibitor”,

a medicine which reduces the amount of acid

produced in your stomach. It is used for treating

acid-related diseases of the stomach and intestine.

Pantoprazole tablets are used for treating:

Adults and adolescents 12 years of age and above:

Reflux oesophagitis. An inflammation of your

oesophagus (the tube which connects your

throat to your stomach) accompanied by the

regurgitation of stomach acid.

Adults:

An infection with a bacterium called Heliobacter

pylori in patients with duodenal ulcers and

stomach ulcers in combination with two

antibiotics (eradication therapy). The aim is to get

rid of the bacteria and reduce the likelihood of

these ulcers returning.

Stomach and duodenal ulcers.

Zollinger-Ellison Syndrome and other conditions

producing too much acid in the stomach.

2

What you need to know before you take

Pantoprazole tablets

Do not take Pantoprazole tablets if you

are allergic to pantoprazole or any of the other

ingredients of this medicine (listed in section 6).

are allergic to medicines containing other proton

pump inhibitors.

Warnings and precautions

Talk to your doctor or pharmacist before taking

Pantoprazole tablets if you

have severe liver problems. Please tell your

doctor if you ever had problems with your liver

in the past. They will check your liver enzymes

more frequently, especially when you are taking

Pantoprazole tablets as a long-term treatment. In

the case of a rise of liver enzymes the treatment

should be stopped.

have an increased secretory condition (e.g.

Zollinger–Ellison syndrome), or you have

reduced body stores or risk factors for reduced

vitamin B12 and receive pantoprazole long-

term treatment. As with all acid reducing agents,

pantoprazole may lead to a reduced absorption of

vitamin B12.

are taking a medicine containing atazanavir (for

the treatment of HIV-infection) at the same time as

pantoprazole, ask your doctor for specific advice.

are due to have a specific blood test

(Chromogranin A).

have ever had a skin reaction after treatment with

a medicine similar to Pantoprazole that reduces

stomach acid.

If you get a rash on your skin, especially in areas

exposed to the sun, tell your doctor as soon as you

can, as you may need to stop your treatment with

Pantoprazole. Remember to also mention any other

ill-effects like pain in your joints.

If you are on Pantoprazole for more than three

months it is possible that the levels of magnesium

in your blood may fall. Low levels of magnesium can

be seen as fatigue, involuntary muscle contractions,

disorientation, convulsions, dizziness, increased

heart rate. If you get any of these symptoms, please

tell your doctor promptly. Low levels of magnesium

can also lead to a reduction in potassium or calcium

levels in the blood. Your doctor may decide to

perform regular blood tests to monitor your levels

of magnesium.

Taking a proton pump inhibitor like Pantoprazole,

especially over a period of more than one year, may

slightly increase your risk of fracture in the hip, wrist

or spine. Tell your doctor if you have osteoporosis or

if you are taking corticosteroids (which can increase

the risk of osteoporosis).

Tell your doctor immediately if you notice any of

the following symptoms:

an unintentional loss of weight

repeated vomiting

difficulty swallowing

vomiting blood

you look pale and feel weak (anaemia)

chest pain

stomach pain

you notice blood in your stools

severe and/or persistent diarrhoea, as

pantoprazole has been associated with a small

increase in infectious diarrhoea.

Your doctor may decide that you need some tests

to rule out malignant disease because pantoprazole

also alleviates the symptoms of cancer and could

cause delay in diagnosing it. If your symptoms

continue in spite of your treatment, further

investigations will be considered.

If you take Pantoprazole tablets on a long-term

basis (longer than 1 year) your doctor will probably

keep you under regular surveillance. You should

report any new and exceptional symptoms and

circumstances whenever you see your doctor.

Children and adolescents

Pantoprazole is not recommended for use in

children below 12 years of age.

Other medicines and Pantoprazole tablets

Tell your doctor or pharmacist if you are taking,

have recently taken or might take any other

medicine. Pantoprazole tablets may influence the

effectiveness of other medicines.

Medicines such as ketoconazole, itraconazole

and posaconazole (used to treat fungal

infections) or erlotinib (used for certain types of

cancer) because Pantoprazole tablets may stop

these and other medicines from working properly.

Warfarin and phenprocoumon, which affect

the thickening, or thinning of the blood. You may

need further checks.

Methotrexate (used in treatment of cancer and

autoimmune diseases).

Atazanavir (used to treat HIV-infection).

Fluvoxamine (used to treat depression and other

psychiatric diseases)- if you are taking fluvoxamine

your doctor may reduce the dose.

Rifampicin (used to treat infections).

St. John’s wort (Hypericum perforatum) (used to

treat mild depression).

Pregnancy and breast-feeding

There are no adequate data from the use of

pantoprazole in pregnant women. Excretion into

human milk has been reported. If you are pregnant,

or think you may be pregnant, or if you are breast-

feeding, you should use this medicine only if your

doctor considers the benefit for you greater than

the potential risk for your unborn child or baby.

Ask your doctor or pharmacist for advice before

taking any medicine.

Driving and using machines

Pantoprazole has no or negligible influence on the

ability to drive and use machines.

If you experience side effects like dizziness or

disturbed vision, you should not drive or operate

machines.

Pantoprazole tablets contain sodium

This medicine contains less than 1 mmol sodium

(23 mg) per tablet, that is to say essentially ‘sodium-

free’.

3

How to take Pantoprazole tablets

Always take this medicine exactly as your doctor or

pharmacist has told you. Check with your doctor or

pharmacist if you are not sure.

When and how should you take Pantoprazole

tablets

Take the tablets 1 hour before a meal without

chewing or breaking them and swallow them

whole with some water.

Unless told otherwise by your doctor, the

recommended dose is:

Adults and adolescents 12 years of age and above:

To treat reflux oesophagitis.

The usual dose is one tablet a day. Your doctor may

tell you to increase to 2 tablets daily. The treatment

period for reflux oesophagitis is usually between 4

and 8 weeks. Your doctor will tell you how long to

take your medicine.

Adults:

For the treatment of an infection with a

bacterium called Heliobacter pylor in patients

with duodenal ulcers and stomach ulcers in

combination with two antibiotics (Eradication

therapy).

One tablet, two times a day plus two antibiotic

tablets of either amoxicillin, clarithromycin and

metronidazole (or tinidazole), each to be taken two

times a day with your pantoprazole tablet. Take the

first pantoprazole tablet 1 hour before breakfast

and the second pantoprazole tablet 1 hour

before your evening meal. Follow your doctor’s

instructions and make sure you read the package

leaflets for these antibiotics. The usual treatment

period is one to two weeks.

For the treatment of stomach and duodenal

ulcers.

The usual dose is one tablet a day. After

consultation with your doctor, the dose may be

doubled.

Your doctor will tell you how long to take your

medicine. The treatment period for stomach ulcers

is usually between 4 and 8 weeks. The treatment

period for duodenal ulcers is usually between 2 and

4 weeks.

For the long-term treatment of Zollinger-Ellison

Syndrome and of other conditions in which too

much stomach acid is produced.

The recommended starting dose is usually two

tablets a day.

Take the two tablets 1 hour before a meal. Your

doctor may later adjust the dose, depending on the

amount of stomach acid you produce. If prescribed

more than two tablets a day, the tablets should be

taken twice daily.

If your doctor prescribes a daily dose of more than

four tablets a day, you will be told exactly when to

stop taking the medicine.

Special patient groups:

If you have kidney problems, moderate or severe

liver problems, you should not take Pantoprazole

tablets for eradication of Helicobacter pylori.

If you suffer from severe liver problems, you

should not take more than one tablet 20mg

pantoprazole a day (for this purpose tablets

containing 20mg pantoprazole are available).

Children below 12 years. These tablets are not

recommended for use in children below 12 years.

If you take more Pantoprazole tablets than you

should

Contact your doctor or pharmacist. There are no

known symptoms of overdose.

If you forget to take Pantoprazole tablets

Do not take a double dose to make up for the

forgotten dose. Take your next, normal dose at the

usual time.

If you stop taking Pantoprazole tablets

Do not stop taking these tablets without first

talking to your doctor or pharmacist.

If you have further questions on the use of this

medicine, ask your doctor or pharmacist.

Package leaflet: Information for the patient

Pantoprazole 40mg Gastro-resistant Tablets

BBBA7553

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Dimensions:

Min Body Text Size:

Supplier:

Non Printing Colours

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EU-Artwork-Support@accord-healthcare.com

G. Worth

11/02/2020

05/03/2020

G. Worth

190x600

10pt

Teva Bulgaria

Dupnitsa

11/02/2020

12/02/2020

Pantoprazole 40 mg Gastro-resistant tablet PIL - UK

Black

BBBA7553

4

* Please note that only Artwork Studio is permitted to make changes to the above artwork.

No changes are permitted by any 3rd party other than added notes and mark ups for required changes.

GTIN 13

(Belgium & Slovenia):

Version 6

12.12.2019

German GTIN 14

(incorporating PZN):

Cartons and label leaflets only

(labels only when specified)

4

Possible side effects

Like all medicines, this medicine can cause side

effects, although not everybody gets them.

If you get any of the following side effects, stop

taking these tablets and tell your doctor

immediately, or contact the casualty department

at your nearest hospital:

Serious allergic reactions (frequency rare):

swelling of the tongue and/or throat, difficulty

in swallowing, hives (nettle rash), difficulties

in breathing, allergic facial swelling (Quincke’s

oedema/ angioedema), severe dizziness with very

fast heartbeat and heavy sweating.

Serious skin conditions (frequency not known):

blistering of the skin and rapid deterioration of

your general condition, erosion (including slight

bleeding) of eyes, nose, mouth/lips or genitals

(Stevens-Johnson Syndrome, Lyell Syndrome,

Erythema multiforme) and sensitivity to light.

Other serious conditions (frequency not

known):

yellowing of the skin or whites of the eyes

(severe damage to liver cells, jaundice) or fever,

rash, and enlarged kidneys sometimes with

painful urination and lower back pain (serious

inflammation of the kidneys).

Other side effects are:

Common (may affect up to 1 in 10 people):

Benign polyps in the stomach.

Uncommon (may affect up to 1 in 100 people):

headache; dizziness; diarrhoea; feeling sick,

vomiting; bloating and flatulence (wind);

constipation; dry mouth; abdominal pain and

discomfort; skin rash, exanthema, eruption; itching;

feeling weak, exhausted or generally unwell; sleep

disorders; fracture of the hip, wrist or spine.

Rare (may affect up to 1 in 1,000 people):

disturbances in vision such as blurred vision;

hives; pain in the joints; muscle pains; weight

changes; raised body temperature; swelling of

the extremities (peripheral oedema); allergic

reactions; depression; breast enlargement in males;

agranulocytosis (severe reduction in number of

white blood cells, which makes infections more

likely), taste disorders.

Very Rare (may affect up to 1 in 10,000 people):

disorientation, thrombocytopenia (reduction in

blood platelets, which increases risk of bleeding

or bruising), leukopenia (decrease in the number

of white blood cells (leukocytes)), pancytopenia

(severe reduction in blood cells which can cause

weakness, bruising or make infections more likely).

Not known (frequency cannot be estimated from

the available data):

Rash, possibly with pain in the joints; pins

and needles / tingling, inflammation in the large

bowel that causes persistent watery diarrhoea,

hallucination, confusion (especially in patients

with a history of these symptoms), muscle spasm;

decreased sodium level, decreased calcium level,

decreased potassium level in blood, decreased

magnesium level in blood (see section 2).

Side effects identified through blood tests:

Uncommon (may affect up to 1 in 100 people):

an increase in liver enzymes.

Rare (may affect up to 1 in 1,000 people):

an increase in bilirubin; increased fats in the blood;

sharp drop in circulating granular white blood cells,

associated with high fever.

Very Rare (may affect up to 1 in 10,000 people):

a reduction in the number of blood platelets,

which may cause you to bleed or bruise more than

normal; a reduction in the number of white blood

cells, which may lead to more frequent infections;

coexisting abnormal reduction in the number of red

and white blood cells, as well as platelets.

Reporting of side effects

If you get any side effects, talk to your doctor,

pharmacist or nurse. This includes any possible side

effects not listed in this leaflet. You can also report

side effects directly via the Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for

MHRA Yellow Card in the Google Play or Apple App

Store.

By reporting side effects you can help provide more

information on the safety of this medicine.

5

How to store Pantoprazole tablets

Keep this medicine out of the sight and reach of

children.

Do not use Pantoprazole tablets after the expiry

date, which is stated on the carton and the

container after EXP.

The expiry date refers to the last day of that month.

This medicine does not require any special storage

conditions.

Do not throw away any medicines via wastewater

or household waste. Ask your pharmacist how to

throw away medicines you no longer use. These

measures will help protect the environment.

6

Contents of the pack and other

information

What Pantoprazole tablets contain

The active substance is pantoprazole. Each gastro-

resistant tablet contains 40mg of pantoprazole (as

sodium sesquihydrate).

The other ingredients are:

Mannitol, Sodium carbonate, Sodium starch

glycolate, Methacrylic acid copolymer,

Calcium stearate, Opadry white OY-D-7233

(hypromellose, titanium dioxide, talc, macrogol,

sodium lauryl sulfate), Kollicoat MAE 30 DP yellow

(methacrylic acid-ethyl acrylate copolymer

dispersion 30%, propylene glycol, yellow iron

oxide, titanium dioxide, talc).

What Pantoprazole tablets look like and

contents of the pack

Pantoprazole 40mg Gastro-resistant Tablets are

elliptical, biconvex, dark yellow gastro-resistant

tablets.

Pack sizes: 28

Marketing Authorisation Holder:

Accord Healthcare Limited

Sage House

319 Pinner Road

North Harrow

Middlesex

HA1 4HF

United Kingdom

Manufacturer:

Balkanpharma – Dupnitsa AD,

3 Samokovsko Schosse Str.,

Dupnitsa 2600,

Bulgaria

This leaflet was last revised in February 2020

If you would like a

leaflet with larger

text, please contact

01271 385257.

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Accord Healthcare Ltd, North Harrow, HA1 4HF, UK

Object 1

Pantoprazole 40mg gastro-resistant

tablets

Summary of Product Characteristics Updated 10-Mar-2020 | Accord-UK Ltd

1. Name of the medicinal product

2. Qualitative and quantitative composition

3. Pharmaceutical form

4. Clinical particulars

4.1 Therapeutic indications

4.2 Posology and method of administration

4.3 Contraindications

4.4 Special warnings and precautions for use

4.5 Interaction with other medicinal products and other forms of interaction

4.6 Pregnancy and lactation

4.7 Effects on ability to drive and use machines

4.8 Undesirable effects

4.9 Overdose

5. Pharmacological properties

5.1 Pharmacodynamic properties

5.2 Pharmacokinetic properties

5.3 Preclinical safety data

6. Pharmaceutical particulars

6.1 List of excipients

6.2 Incompatibilities

6.3 Shelf life

6.4 Special precautions for storage

6.5 Nature and contents of container

6.6 Special precautions for disposal and other handling

7. Marketing authorisation holder

8. Marketing authorisation number(s)

9. Date of first authorisation/renewal of the authorisation

10. Date of revision of the text

1. Name of the medicinal product

Pantoprazole 40 mg gastro-resistant tablets

2. Qualitative and quantitative composition

Each gastro-resistant tablet contains 40 mg pantoprazole

(as pantoprazole sodium sesquihydrate 45.16 mg)

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Gastro-resistant tablet

Elliptical, biconvex, dark yellow gastro-resistant tablet

4. Clinical particulars

4.1 Therapeutic indications

Adults and adolescents 12 years of age and above

Reflux oesophagitis.

Adults

Eradication of Helicobacter pylori (H. pylori) in combination with appropriate antibiotic therapy in

patients with H. pylori associated ulcers.

Gastric and duodenal ulcer.

Zollinger-Ellison-Syndrome and other pathological hypersecretory conditions.

4.2 Posology and method of administration

Posology

Adults and adolescents 12 years of age and above

Reflux oesophagitis

One tablet of Pantoprazole per day. In individual cases the dose may be doubled (increase to 2 tablets

Pantoprazole daily) especially when there has been no response to other treatment. A 4-week period is

usually required for the treatment of reflux oesophagitis. If this is not sufficient, healing will usually be

achieved within a further 4 weeks.

Adults

Eradication of H. pylori in combination with two appropriate antibiotics

In H. pylori positive patients with gastric and duodenal ulcers, eradication of the germ by a combination

therapy should be achieved. Considerations should be given to official local guidance (e.g. national

recommendations) regarding bacterial resistance and the appropriate use and prescription of antibacterial

agents. Depending upon the resistance pattern, the following combinations can be recommended for the

eradication of H. pylori:

a) twice daily one tablet Pantoprazole

+ twice daily 1000 mg amoxicillin

+ twice daily 500 mg clarithromycin

b) twice daily one tablet Pantoprazole

+ twice daily 400 - 500 mg metronidazole (or 500 mg tinidazole)

+ twice daily 250 - 500 mg clarithromycin

c) twice daily one tablet Pantoprazole

+ twice daily 1000 mg amoxicillin

+ twice daily 400 - 500 mg metronidazole (or 500 mg tinidazole)

In combination therapy for eradication of H. pylori infection, the second Pantoprazole tablet should be

taken 1 hour before the evening meal. The combination therapy is implemented for 7 days in general and

can be prolonged for a further 7 days to a total duration of up to two weeks. If, to ensure healing of the

ulcers, further treatment with pantoprazole is indicated, the dose recommendations for duodenal and

gastric ulcers should be considered.

If combination therapy is not an option, e.g. if the patient has tested negative for H. pylori, the following

dose guidelines apply for Pantoprazole tablets monotherapy:

Treatment of gastric ulcer

One tablet of Pantoprazole per day. In individual cases the dose may be doubled (increase to 2 tablets of

Pantoprazole daily) especially when there has been no response to other treatment. A 4-week period is

usually required for the treatment of gastric ulcers. If this is not sufficient, healing will usually be

achieved within a further 4 weeks.

Treatment of duodenal ulcer

One tablet of Pantoprazole tablets per day. In individual cases the dose may be doubled (increase to 2

tablets of Pantoprazole daily) especially when there has been no response to other treatment. A duodenal

ulcer generally heals within 2 weeks. If a 2-week period of treatment is not sufficient, healing will be

achieved in almost all cases within a further 2 weeks.

Zollinger-Ellison-Syndrome and other pathological hypersecretory conditions

For the long-term management of Zollinger-Ellison-Syndrome and other pathological hypersecretory

conditions patients should start their treatment with a daily dose of 80 mg (2 tablets of Pantoprazole 40

mg). Thereafter, the dose can be titrated up or down as needed using measurements of gastric acid

secretion to guide. With doses above 80 mg daily, the dose should be divided and given twice daily. A

temporary increase of the dose above 160 mg pantoprazole is possible but should not be applied longer

than required for adequate acid control.

Treatment duration in Zollinger-Ellison syndrome and other pathological hypersecretory conditions is not

limited and should be adapted according to clinical needs.

Patients with Hepatic Impairment

A daily dose of 20 mg pantoprazole (1 tablet of 20 mg pantoprazole) should not be exceeded in patients

with severe liver impairment. Pantoprazole must not be used in combination treatment for eradication of

H. pylori in patients with moderate to severe hepatic dysfunction since currently no data are available on

the efficacy and safety of Pantoprazole in combination treatment of these patients (see section 4.4).

Patients with Renal Impairment

No dose adjustment is necessary in patients with impaired renal function. Pantoprazole must not be used

in combination treatment for eradication of H. pylori in patients with impaired renal function since

currently no data are available on the efficacy and safety of Pantoprazole tablets in combination treatment

for these patients (see section 5.2).

Older people

No dose adjustment is necessary in older people (see section 5.2).

Paediatric population

Pantoprazole is not recommended for use in children below 12 years of age because of limited data on

safety and efficacy in the age group (see section 5.2).

Method of administration

Oral use

The tablets should not be chewed or crushed, and should be swallowed whole 1 hour before a meal with

some water.

4.3 Contraindications

Hypersensitivity to the active substance, substituted benzimidazoles or to any of the excipients listed in

section 6.1.

4.4 Special warnings and precautions for use

Hepatic Impairment

In patients with severe liver impairment, the liver enzymes should be monitored regularly during

treatment with pantoprazole, particularly on long-term use. In the case of a rise of the liver enzymes, the

treatment should be discontinued (see section 4.2).

Combination therapy

In the case of combination therapy, the summaries of product characteristics of the respective medicinal

products should be observed.

Gastric malignancy

Symptomatic response to pantoprazole may mask the symptoms of gastric malignancy and may delay

diagnosis. In the presence of any alarm symptom (e. g. significant unintentional weight loss, recurrent

vomiting, dysphagia, haematemesis, anaemia or melaena) and when gastric ulcer is suspected or present,

malignancy should be excluded.

Further investigation is to be considered if symptoms persist despite adequate treatment.

Co-administration with HIV protease inhibitors

Co-administration of pantoprazole is not recommended with HIV protease inhibitors for which absorption

is dependent on acidic intragastric pH such as atazanavir, due to significant reduction in their

bioavailability (see section 4.5).

Influence on vitamin B12 absorption

In patients with Zollinger-Ellison syndrome and other pathological hypersecretory conditions requiring

long-term treatment, pantoprazole, 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 or if respective

clinical symptoms are observed.

Long term treatment

In long-term treatment, especially when exceeding a treatment period of 1 year, patients should be kept

under regular surveillance.

Gastrointestinal infections caused by bacteria

Treatment with Pantoprazole may lead to a slightly increased risk of gastrointestinal infections caused by

bacteria such as Salmonella and Campylobacter or C. difficile.

Hypomagnesaemia

Severe hypomagnesaemia has been reported in patients treated with PPIs like pantoprazole 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 medicinal products

that may cause hypomagnesaemia (e.g., diuretics), health care professionals should consider measuring

magnesium levels before starting PPI treatment and periodically during treatment.

Bone fractures

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 older people or in the 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.

Pantoprazole tablets contain sodium

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-

free'.

Sub-acute 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 Pantoprazole. SCLE after previous

treatment with a proton pump inhibitor may increase the risk of SCLE with other proton pump inhibitors.

Interference with laboratory tests

Increased Chromogranin A (CgA) level may interfere with investigations for neuroendocrine tumours. To

avoid this interference, Pantoprazole 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.

4.5 Interaction with other medicinal products and other forms of interaction

Medicinal products with pH-dependent absorption pharmacokinetics

Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with

the absorption of other medicinal products where gastric pH is an important determinant of oral

availability, e.g some azole antifungals as ketoconazole, itraconazole, posaconazole and other medicine

such as erlotinib.

HIV protease inhibitors

Co-administration of pantoprazole is not recommended with HIV protease inhibitors for which absortion

is dependent on acidic intragastric pH such as atazanavir due to significant reduction in their

bioavailability (see section 4.4). If the combination of HIV protease inhibitors with a proton pump

inhibitor is judged unavoidable, close clinical monitoring (e.g. virus load) is recommended. A

pantoprazole dose of 20 mg per day should not be exceeded. Dosage of the HIV protease inhibitors may

need to be adjusted.

Coumarin anticoagulants (phenprocoumon or warfarin)

Co-administration of pantoprazole with warfarin or phenprocoumon did not affect the pharmacokinetics

of warfarin, phenprocoumon or INR. However, there have been reports of increased INR and prothrombin

time in patients receiving PPIs and warfarin or phenprocoumon concomitantly. Increases in INR and

prothrombin time may lead to abnormal bleeding, and even death. Patients treated with pantoprazole and

warfarin or phenprocoumon may need to be monitored for increase in INR and prothrombin time.

Methotrexate

Concomitant use of high dose methotrexate (e.g. 300 mg) and proton-pump inhibitors has been reported

to increase methotrexate levels in some patients. Therefore in settings where high-dose methotrexate is

used, for example cancer and psoriasis, a temporary withdrawal of pantoprazole may need to be

considered.

Other interactions studies

Pantoprazole is extensively metabolized in the liver via the cytochrome P450 enzyme system. The main

metabolic pathway is demethylation by CYP2C19 and other metabolic pathways include oxidation by

CYP3A4. Interaction studies with medicinal products also metabolised with these pathways, like

carbamazepine, diazepam, glibenclamide, nifedipine, and an oral contraceptive containing levonorgestrel

and ethinyl oestradiol did not reveal clinically significant interactions.

An interaction of pantoprazole with other medicinal products or compounds, which are metabolised using

the same enzyme, cannot be excluded.

Results from a range of interaction studies demonstrate that pantoprazole does not effect the metabolism

of active substances metabolised by CYP1A2 (such as caffeine, theophylline), CYP2C9 (such as

piroxicam, diclofenac, naproxen), CYP2D6 (such as metoprolol), CYP2E1 (such as ethanol) or does not

interfere with p-glycoprotein related absorption of digoxin.

There were no interactions with concomitantly administered antacids.

Interaction studies have also been performed by concomitantly administering pantoprazole concomitantly

with the respective antibiotics (clarithromycin, metronidazole, amoxicillin) No clinically relevant

interactions were found.

Medicinal products that inhibit or induce CYP2C19:

Inhibitors of CYP2C19 such as fluvoxamine could increase the systemic exposure of pantoprazole. A

dose reduction may be considered for patients treated long-term with high doses of pantoprazole, or those

with hepatic impairment.

Enzyme inducers affecting CYP2C19 and CYP3A4 such as rifampicin and St John´s wort (Hypericum

perforatum) may reduce the plasma concentrations of PPIs that are metabolised through these enzyme

systems.

4.6 Pregnancy and lactation

Pregnancy

A moderate amount of data on pregnant women (between 300-1000 pregnancy outcomes) indicate no

malformative or feto/ neonatal toxicity of Pantoprazole. Animal studies have shown reproductive toxicity

(see section 5.3). As a precautionary measure, it is preferable to avoid the use of Pantoprazole during

pregnancy.

Breast-feeding

Animal studies have shown excretion of pantoprazole in breast milk. There is insufficient information on

the excretion of pantoprazole in human milk but excretion into human milk has been reported. A risk to

the newborns/ infants cannot be excluded. Therefore, a decision on whether to discontinue breast-feeding

or to discontinue/ abstain from Pantoprazole therapy taking into account the benefit of breast-feeding for

the child, and the benefit of Pantoprazole therapy for the woman.

Fertility

There was no evidence of impaired fertility following the administration of pantoprazole in animal studies

(see section 5.3).

4.7 Effects on ability to drive and use machines

Pantoprazole has no or negligible influence on the ability to drive and 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 machines.

4.8 Undesirable effects

Approximately 5 % of patients can be expected to experience adverse drug reactions (ADRs). The most

commonly reported ADRs are diarrhoea and headache, both occurring in approximately 1 % of patients.

The table below lists adverse reactions reported with pantoprazole, ranked under the following frequency

classification:

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).

For all adverse reactions reported from post-marketing experience, it is not possible to apply any Adverse

Reaction frequency and therefore they are mentioned with a “not known” frequency.

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1. Adverse reactions with pantoprazole in clinical trials and post-marketing experience

Frequency

System Organ

class

Common

Uncommon

Rare

Very rare

Not known

Blood and

lymphatic system

disorders

Agranulocytosis

Thrombocytopenia

Leukopenia;

Pancytopenia

Immune system

disorders

Hypersensitivity

(including

anaphylactic

reactions and

anaphylactic

shock)

Metabolism and

nutrition

disorders

Hyperlipidaemias

and lipid

increases

(triglycerides,

cholesterol);

Weight changes

Hyponatraemia

Hypomagnesaemia

(see section 4.4)

Hypocalcaemia

Hypokalaemia

Psychiatric

disorders

Sleep disorders

Depression (and

all aggravations)

Disorientation

(and all

aggravations)

Hallucination;

Confusion

(especially in pre-

disposed patients,

as well as the

aggravation of

these symptoms in

case of pre-

existence)

Nervous system

disorders

Headache;

Dizziness

Taste disorders

Paraesthesia

Eye disorders

Disturbances in

vision/ blurred

vision

Gastrointestinal

disorders

Fundic gland

polyps

(benign)

Diarrhoea;

Nausea

/vomiting;

Abdominal

distension and

bloating;

Constipation;

Dry mouth;

Abdominal pain

and discomfort

Microscopic colitis

Hepatobiliary

disorders

Liver enzymes

increased

(transaminases,

γ-GT)

Bilirubin

increased

Hepatocellular

injury; Jaundice;

Hepatocellular

failure

Skin and sub-

cutaneous tissue

disorders

Rash /

exanthema /

eruption;

Pruritus

Urticaria;

Angioedema

Stevens-Johnson

syndrome; Lyell

syndrome;

Erythema

multiforme;

Photosensitivity

Sub-acute

cutaneous lupus

erythematosus (see

section 4.4).

Musculoskeletal

and connective

tissue disorders

Fracture of the

hip, wrist or

spine (see

section 4.4)

Arthralgia;

Myalgia

Muscle spasm

Renal and

urinary disorders

Interstitial

nephritis (with

possible

progression to

renal failure)

Reproductive

system and

breast disorders

Gynaecomastia

General

disorders and

administration

site conditions

Asthenia,

fatigue and

malaise

Body temperature

increased;

Oedema

peripheral

Hypocalcaemia in association with hypomagnesemia

Muscle spasm as a consequence of electrolyte disturbance.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows

continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are

asked to report any suspected adverse reactions via the Yellow Card Scheme Website: www.mhra.gov.uk/

yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

There are no known symptoms of overdose in man.

Systemic exposure with up to 240mg administered intravenously over 2 minutes were well tolerated.

As pantoprazole is extensively protein bound, it is not readily dialysable.

In the case of overdose with clinical signs of intoxication, apart from symptomatic and supportive

treatment, no specific therapeutic recommendations can be made.

5. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Proton pump inhibitors, ATC code: A02BC02

Mechanism of action

Pantoprazole is a substituted benzimidazole which inhibits the secretion of hydrochloric acid in the

stomach by specific blockade of the proton pumps of the parietal cells.

Pantoprazole is converted to its active form in the acidic environment in the parietal cells where it inhibits

the H+, K+-ATPase enzyme, i.e. the final stage in the production of hydrochloric acid in the stomach.

The inhibition is dose-dependent and affects both basal and stimulated acid secretion. In most patients,

freedom from symptoms is achieved within 2 weeks. As with other proton pump inhibitors and H2

receptor inhibitors, treatment with pantoprazole reduces acidity in the stomach and thereby increases

gastrin in proportion to the reduction in acidity. The increase in gastrin is reversible. Since pantoprazole

binds to the enzyme distal to the cell receptor level, it can inhibit hydrochloric acid secretion

independently of stimulation by other substances (acetylcholine, histamine, gastrin). The effect is the

same whether the product is given orally or intravenously.

Pharmacodynamic effects

The fasting gastrin values increase under pantoprazole. On short-term use, in most cases they do not

exceed the upper limit of normal. During long-term treatment, gastrin levels double in most cases. An

excessive increase, however, occurs only in isolated cases. As a result, a mild to moderate increase in the

number of specific endocrine (ECL) cells in the stomach is observed in a minority of cases during long-

term treatment (simple to adenomatoid hyperplasia). However, according to the studies conducted so far,

the formation of carcinoid precursors (atypical hyperplasia) or gastric carcinoids as were found in animal

experiments (see section 5.3) have not been observed in humans.

An influence of a long term treatment with pantoprazole exceeding one year cannot be completely ruled

out on endocrine parameters of the thyroid according to results in animal studies.

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.

5.2 Pharmacokinetic properties

Absorption

Pantoprazole is rapidly absorbed and the maximal plasma concentration is achieved even after one single

40mg oral dose. On average at about 2.5 h p.a. the maximum serum concentrations of about 2 - 3 μg/ml

are achieved, and these values remain constant after multiple administration.

Pharmacokinetics does not vary after single or repeated administration. In the dose range of 10 to 80mg,

the plasma kinetics of pantoprazole are linear after both oral and intravenous administration.

The absolute bioavailability from the tablet was found to be about 77 %. Concomitant intake of food had

PAR Pantoprazole 20mg and 40mg Gastro-Resistant Tablets

UK/H/0946/001-2/DC

1

Public Assessment Report

Decentralised Procedure

Pantoprazole 20mg Gastro-Resistant Tablets

Pantoprazole 40mg Gastro-Resistant Tablets

UK/H/0946/001-2/DC

UK licence no: PL 01656/0022-23

KRKA D.D.

PAR Pantoprazole 20mg and 40mg Gastro-Resistant Tablets

UK/H/0946/001-2/DC

LAY SUMMARY

The MHRA today granted KRKA d.d Marketing Authorisations (licences) for the medicinal

products Pantoprazole 20mg Gastro-Resistant Tablets (PL 01656/0022) and Pantoprazole

40mg Gastro-Resistant Tablets (PL 01656/0023). These are prescription only medicines

(POM) that are prescribed to patients with conditions caused by stomach acid.

Pantoprazole 20mg Gastro-Resistant Tablets are used:

in the treatment of mild gastrooesophageal reflux disease (a condition in which gastric

content may rise up to the oesophagus and which can be associated with oesophagitis)

caused by acid secretion, and the associated symptoms, such as heartburn, acidic

belches and pains on swallowing

in the long-term treatment and in the prevention of relapse in reflux oesophagitis (a

condition in which backwash of gastric content in oesophagus lead to inflammation

and pain)

in the prevention of gastric and duodenal ulcers caused by anti-inflammatory drugs in

high-risk patients needing continuous treatment with anti-inflammatory drugs.

Pantoprazole 40mg Gastro-Resistant Tablets are used in the short-term treatment and to

relieve the symptoms of:

duodenal ulcer

gastric ulcer

oesophagitis (inflammation of oesophagus) caused by acid secretion.

Additionally, the 40mg preparation is used:

in combination with antibiotics in patients whose ulceration is related to

Helicobacter

pylori

bacteria

in the long-term treatment of conditions where gastric acid is constantly being

secreted too much (e.g. Zollinger-Ellison syndrome).

Pantoprazole belongs to a group of medicines called proton pump inhibitors. Proton pump

inhibitors reduce the amount of acid that your stomach makes.

No new or unexpected safety concerns arose from these applications and it was therefore

judged that the benefits of taking Pantoprazole 20mg and 40mg Gastro-Resistant Tablets

outweigh the risks; hence Marketing Authorisations have been granted.

2

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TABLE OF CONTENTS

Module 1: Information about initial procedure

Page 3

Module 2: Summary of Product Characteristics

Page 4

Module 3: Product Information Leaflets

Page 22

Module 4: Labelling

Page 24

Module 5: Scientific Discussion

Page 28

1 Introduction

2 Quality aspects

3 Non-clinical aspects

4 Clinical aspects

5 Overall conclusions

Module 6

Steps taken after initial procedure

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Module 1

Product Name

Pantoprazole 20mg and 40mg Gastro-Resistant Tablets

Type of Application

Generic, Article 10.1

Active Substance

Pantoprazole

Form

Gastro-Resistant Tablets

Strength

20mg and 40mg

MA Holder

Krka, d.d., Novo mesto, Smarjeska cesta 6, 8501 Novo mesto,

Slovenia

United Kingdom

Austria, Belgium, Denmark, Finland, France, Germany, Greece,

Ireland, Italy, Malta, The Netherlands, Norway, Sweden, Spain,

Portugal

Procedure Number

UK/H/0946/001-2/DC

Timetable

Day 210 – 25

May 2007

4

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Module 2

Summary of Product Characteristics

1

NAME OF THE MEDICINAL PRODUCT

Pantoprazole 20 mg gastro-resistant tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each gastro-resistant tablet contains 20 mg pantoprazole (as pantoprazole sodium sesquihydrate).

Excipient:

Each Pantoprazole 20 mg gastro-resistant tablet contains 18 mg sorbitol.

For a full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM

Gastro-resistant tablet.

A light brownish yellow, oval, slightly biconvex tablet.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications

For the treatment of mild reflux disease and associated symptoms (e.g. heartburn, acid regurgitation,

pain on swallowing).

For long-term management and prevention of relapse in reflux oesophagitis.

Prevention of gastroduodenal ulcers induced by non-selective non-steroidal anti-inflammatory drugs

(NSAIDs) in patients at risk with a need for continuous NSAID treatment (see section 4.4).

4.2

Posology and method of administration

Method of administration

Pantoprazole 20 mg tablets should not be chewed or crushed, and should be swallowed whole with

water before a meal.

Treatment of mild reflux disease and associated symptoms (e.g. heartburn, acid regurgitation, pain on

swallowing)

The recommended dosage is 20 mg pantoprazole daily (1 Pantoprazole 20 mg gastro-resistant tablet).

Symptom relief is generally accomplished within 2

4 weeks, and a 4-week treatment period is usually

required for healing of associated oesophagitis. If this is not sufficient, healing will normally be

achieved within a further 4 weeks. When symptom relief has been achieved, reoccurring symptoms can

be controlled using an on-demand regimen of 20 mg once daily, when required. A switch to continuous

therapy may be considered in case satisfactory symptom control cannot be maintained with on-demand

treatment.

Long-term management and prevention of relapse in reflux oesophagitis

For long-term management, a maintenance dose of 20 mg pantoprazole daily (1 Pantoprazole 20 mg

gastro-resistant tablet) is recommended. If a relapse occurs, the dosage is increased to 40 mg

pantoprazole per day. Pantoprazole 40 mg gastro-resistant tablets are available for this case. After

healing of the relapse the dosage can be reduced again to 20 mg pantoprazole.

Prevention of gastroduodenal ulcers induced by non-selective non-steroidal anti-inflammatory drugs

(NSAIDs) in patients at risk with a need for continuous NSAID treatment

The recommended dosage is 20 mg pantoprazole daily (1 Pantoprazole 20 mg gastro-resistant tablet).

Elderly and patients with renal impairment

A daily dose of 40 mg pantoprazole should not be exceeded in these patient groups.

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Patients with hepatic impairment

A daily dose of 20 mg pantoprazole should not be exceeded in patients with severe liver impairment

(see section 4.4). In these patients, hepatic enzyme levels should be monitored during the treatment. If

hepatic enzyme levels become elevated, treatment with pantoprazole should be discontinued.

Children

There is no information on the use of pantoprazole in children. Therefore pantoprazole tablets should

not be used in children.

4.3

Contraindications

Hypersensitivity to pantoprazole or to any of the excipients.

Pantoprazole like other proton pump inhibitors should not be administered with atazanavir (see section

4.5).

4.4

Special warnings and precautions for use

In patients with severe liver impairment the liver enzymes should be monitored regularly during

treatment with pantoprazole, particularly on long-term use. In the case of a rise of the liver enzymes,

the treatment should be discontinued (see section 4.2).

The use of Pantoprazole 20 mg gastro-resistant as a preventive of gastroduodenal ulcers induced by

non-selective non-steroidal anti-inflammatory drugs (NSAIDs) should be restricted to patients who

require continued NSAID treatment and have an increased risk to develop gastrointestinal

complications. The increased risk should be assessed according to individual risk factors, e.g. high age

(>65 years), history of gastric or duodenal ulcer or upper gastrointestinal bleeding.

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.

Pantoprazole, as all acid-blocking medicinal products, 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 in long-term treatment.

In long term treatment, especially when exceeding a treatment period of 1 year, patients should be kept

under regular surveillance.

Prior to treatment a malignant disease of the oesophagus or stomach should be excluded as the

treatment with pantoprazole may alleviate the symptoms of malignant diseases and can thus delay

diagnosis.

Patients who do not respond after 4 weeks should be investigated.

There is no experience with the use of pantoprazole in children.

Pantoprazole contains sorbitol. Patients with rare hereditary problems of fructose intolerance should

not take this medicine.

4.5

Interaction with other medicinal products and other forms of interaction

Pantoprazole may reduce the absorption of drugs whose bioavailability is pH-dependent (e.g.

ketoconazole, itraconazole, atazanavir).

Studies with other proton pump inhibitors have shown a marked reduction in atazanavir exposure

during concomitant proton pump inhibitor treatment. Use of proton pump inhibitors is contraindicated

during atazanavir treatment.

Pantoprazole is metabolized in the liver via the cytochrome P450 enzyme system. interactions of

pantoprazole with other drugs or compounds which are metabolized using the same enzyme system

cannot be excluded. However, no clinically significant interactions were observed with a number of

such medicinal products or compounds, such as carbamazepine, caffeine, diazepam, diclofenac,

digoxin, ethanol, glibenclamide, metoprolol, naproxen, nifedipine, phenytoin, piroxicam, theophylline

and oral contraceptives.

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Even though no interactions with pantoprazole and phenprocoumon or warfarin have been observed in

clinical pharmacokinetics studies, a few isolated post-marketing cases of INR value changes in

concomitant treatment with these substances have been reported. If the patient is using coumarin-type

anticoagulants, measurements of prothrombin time / INR values are recommended after the initiation

and discontinuation of pantoprazole and in irregular use of pantoprazole.

There were also no interactions with concomitantly administered antacids.

4.6

Pregnancy and lactation

Clinical experience in pregnant women is limited. In animal reproduction studies, signs of slight

fetotoxicity were observed at doses above 5 mg/kg. There is no information on the excretion of

pantoprazole into human breast milk. During pregnancy and breast feeding, pantoprazole tablets should

only be used when the benefit to the mother is considered greater than the potential risk to the foetus or

child.

4.7

Effects on ability to drive and use machines

There are no known effects on the ability to drive and use machines. Adverse drug reactions such as

dizziness and visual disturbances may occur (see section 4.8). Under these conditions the ability to

react may be decreased.

4.8

Undesirable effects

Common ≥ 1/100 to < 1/10

Uncommon ≥ 1/1000 to < 1/100

Rare ≥ 1/10 000 to < 1/1000

Very rare < 1/10 000, including isolated reports

Frequency

Common

Uncommon

Rare

Very rare

Organ system

Blood and the lymphatic

system

Leucopenia, thrombocytopenia

Immune system

disorders

Anaphylactic reactions including

anaphylactic shock

Psychiatric disorders

Depression

Nervous system

disorders

Headache

Dizziness,

disturbances in

vision (blurred

vision)

Gastrointestinal

disorders

Upper abdominal

pain, diarrhoea,

constipation,

flatulence

Nausea,

vomiting,

Dry mouth

Hepatobiliary disorders

Severe hepatocellular damage

leading to jaundice with or without

hepatic failure

Skin and sub-cutaneous

tissue disorders

Allergic

reactions such as

pruritus and skin

rash

Urticaria, angioedema, severe skin

reactions such as Stevens Johnson

syndrome, erythema multi-forme,

Lyell's syndrome, photosensitivity

Musculoskeletal,

connective tissue

disorders

Arthralgia

Myalgia

Renal and urinary

disorders

Interstitial nephritis

General disorders and

administration site

conditions

Peripheral edema subsiding after

termination of therapy

Investigations

Increased liver enzymes

(transaminases,

glutamyltransferase),

elevated triglycerides,

increased body temperature

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4.9

Overdose

There are no known symptoms of over dosage in man.

Doses up to 240 mg i.v. were administered over 2 minutes and were well tolerated. As pantoprazole is

extensively protein bound, it is not readily dialyzable.

Cases of overdosage or poisoning should be treated according to the standard treatment practice of

toxic conditions.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Proton pump inhibitors

ATC code: A02BC02

Pantoprazole is a substituted benzimidazole which inhibits the secretion of hydrochloric acid in the

stomach by specific action on the proton pumps of the parietal cells.

Pantoprazole is converted to its active form in the acidic channel of the parietal cells where it inhibits

the H+, K+-ATPase enzyme, i.e. the final stage in the production of hydrochloric acid in the stomach.

The inhibition is dose-dependent and affects both basal and stimulated acid secretion. In most patients,

freedom from symptoms is achieved in 2 weeks. As with other proton pump inhibitors and H2 receptor

inhibitors, treatment with pantoprazole causes a reduced acidity in the stomach and thereby an increase

in gastrin in proportion to the reduction in acidity. The increase in gastrin is reversible. Since

pantoprazole binds to the enzyme distal to the cell receptor level, the substance can affect hydrochloric

acid secretion independently of stimulation by other substances (acetylcholine, histamine, gastrin). The

effect is the same whether the product is administered orally or intravenously.

The fasting gastrin values increase under pantoprazole. On short-term use, in most cases they do not

exceed the normal upper limit. During long-term treatment, gastrin levels double in most cases. An

excessive increase, however, occurs only in isolated cases. As a result, a mild to moderate increase in

the number of specific endocrine (ECL) cells in the stomach is observed in a minority of cases during

long-term treatment (simple to adenomatoid hyperplasia). However, according to the studies conducted

so far (see section 5.3), the formation of carcinoid precursors (atypical hyperplasia) or gastric

carcinoids can be ruled out for humans.

An influence of a long term treatment with pantoprazole exceeding one year cannot be completely

ruled out on endocrine parameters of the thyroid and liver enzymes according to results in animal

studies.

5.2

Pharmacokinetic properties

General pharmacokinetics

Pantoprazole is rapidly absorbed and the maximal plasma concentration is achieved even after one

single oral dose. On average, the maximum serum concentrations are 1

1.5 µg/ml at about

2.5 hours post-administration, and these values remain constant after multiple administration.

Volume of distribution is about 0.15 l/kg and clearance is about 0.1 l/h/kg.

Terminal half-life is about 1 h. There were a few cases of subjects with delayed elimination. Because

of the specific binding of pantoprazole to the proton pumps of the parietal cell the elimination half

life does not correlate with the much longer duration of action (inhibition of acid secretion).

Pharmacokinetics do not vary after single or repeated administration. In the dose range of 10 to 80 mg,

the plasma kinetics of pantoprazole are linear after both oral and intravenous administration.

Pantoprazole's serum protein binding is about 98%. The substance is almost exclusively metabolized in

the liver. Renal elimination represents the major route of excretion (about 80%) for the metabolites of

pantoprazole, the rest is excreted with the faeces. The main metabolite in both the serum and urine is

desmethylpantoprazole which is conjugated with sulphate. The half-life of the main metabolite (about

1.5 h) is not much longer than that of pantoprazole.

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Bioavailability

Pantoprazole is completely absorbed after oral administration. The absolute bioavailability from the

tablet was found to be about 77%. Concomitant intake of food had no influence on AUC, maximum

serum concentration and thus bioavailability. Only the variability of the lag-time will be increased by

concomitant food intake.

Characteristics in patients/special groups of subjects

No dose reduction is requested when pantoprazole is administered to patients with restricted kidney

function (incl. dialysis patients). As with healthy subjects, pantoprazole's half-life is short. Only very

small amounts of pantoprazole can be dialyzed. Although the main metabolite has a moderately

delayed half-life (2

3h), excretion is still rapid and thus accumulation does not occur. However, the

daily dose of 40 mg pantoprazole should not be exceeded in patients with impaired renal function.

Although for patients with liver cirrhosis (classes A and B according to Child) the half-life values

increased to between 3 and 6 h and the AUC values increased by a factor of 3

5, the maximum serum

concentration only increased slightly by a factor of 1.3 compared with healthy subjects.

A slight increase in AUC and Cmax in elderly volunteers compared with younger counterparts is also

not clinically relevant.

5.3

Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety

pharmacology, repeated dose toxicity and genotoxicity.

In a two-year carcinogenicity study in rats, neuroendocrine neoplasms were found. In addition,

squamous cell papillomas were found in the forestomach of rats. The mechanism leading to the

formation of gastric carcinoids by substituted benzimidazoles has been carefully investigated and

allows the conclusion that it is a secondary reaction to the massively elevated serum gastrin levels

occurring in the rat during chronic high-dose treatment.

In two-year rodent studies an increased number of liver tumours was observed in rats (in one rat study

only) and in female mice and was interpreted as being due to pantoprazole's high metabolic rate in the

liver.

A slight increase of neoplastic changes of the thyroid was observed in the group of rats receiving the

highest dose (200 mg/kg) in one 2 year study. The occurrence of these neoplasms is associated with the

pantoprazole-induced changes in the breakdown of thyroxine in the rat liver. As the therapeutic dose in

man is low, no side effects on the thyroid glands are expected.

From mutagenicity studies, cell transformation tests and DNA binding studies it is concluded that

pantoprazole has no genotoxic potential.

Investigations revealed no evidence of impaired fertility or teratogenic effects. Penetration of the

placenta was investigated in the rat and was found to increase with advanced gestation. As a result,

concentration of pantoprazole in the foetus is increased shortly before birth.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

The core of tablet:

Mannitol

Crospovidone (type B)

Sodium carbonate, anhydrous

Sorbitol (E420)

Calcium stearate

The film-coating:

Hypromellose

Povidone (K25)

Titanium dioxide (E171)

Iron oxide, yellow (E172)

Propylene glycol

Methacrylic acid - ethyl acrylate copolymer

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Sodium lauryl sulphate

Polysorbate 80

Macrogol 6000

Talc

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

2 years.

6.4

Special precautions for storage

Blister pack: Store in the original package in order to protect from moisture.

Container: Keep the container tightly closed in order to protect from moisture.

6.5

Nature and contents of container

Perforated blister pack (OPA/Aluminium/PVC film and aluminium foil) in a carton box.

Pack-sizes of 7, 14, 15, 28, 30, 56, 60, 84, 98, 100, 100 x 1, 112 or 140 gastro-resistant tablets.

HDPE containers with a silica gel desiccant in a tamper evident PP screw-cap.

Pack-size of 250 gastro-resistant tablets.

Not all pack sizes may be marketed.

6.6

Special precautions for disposal

No special requirements.

Any unused product or waste material should be disposed of in accordance with local requirements.

7

MARKETING AUTHORISATION HOLDER

KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia

8

MARKETING AUTHORISATION NUMBER(S)

PL 01656/0022

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DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

21/09/2007

10

DATE OF REVISION OF THE TEXT

24/10/2007

10

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