HELICOBACTER TEST INFAI 75mg powder for oral solution medication leaflet

Helicobacter Test INFAI 75 mg powder for oral solution

One jar contains 75 mg of 13C-urea powder.

For the full list of excipients, see section 6.1.

White, crystalline powder for oral solution.

Helicobacter Test INFAI may be used for in vivo diagnosis of gastroduodenal Helicobacter pyloriinfection in:

- adults,

- adolescents, who are likely to have peptic ulcer disease.

This medicinal product is for diagnostic use only.

This medicinal product should be administered by a healthcare professional and under appropriatemedical supervision.

Helicobacter Test INFAI is a breath test for single administration. Patients from the age of 12 musttake the contents of 1 jar with 75 mg.

For performance of the test, 200 ml 100 % orange juice or 1 g citric acid in 200 ml water for patientsfrom the age of 12 and older (as a pre-administered test meal), as well as tap water (for dissolving the13C-urea powder) are necessary.

The patient must have fasted for over 6 hours, preferably overnight. The test procedure takesapproximately 40 minutes.

In case it is necessary to repeat the test procedure, this should not be done until the following day.

The suppression of Helicobacter pylori might give false negative results. Therefore the test shall beused after at least four weeks without systemic antibacterial therapy and two weeks after last dose ofacid antisecretory agents. Both might interfere with the Helicobacter pylori status. This is especiallyimportant after Helicobacter eradication therapy.

It is important to follow the instructions for use adequately (see section 6.6), otherwise the reliabilityof the outcome will become questionable.

The test must not be used in patients with documented or suspected gastric infection or atrophicgastritis, which might interfere with the urea breath test (see section 4.2).

A positive test alone does not constitute indication for eradication therapy. Differential diagnosis withinvasive endoscopic methods might be indicated in order to examine the presence of any othercomplicating conditions, e.g. ulcer, autoimmune gastritis and malignancies.

There is insufficient data on the diagnostic liability of the Helicobacter Test INFAI to recommend itsuse in patients with gastrectomy.

For children from the age of 3, Helicobacter Test INFAI for children aged 3 to 11 is available.

In individual cases of A-gastritis (atrophic gastritis) the breath test may have false positive results;other tests may be required to confirm the Helicobacter pylori status.

If the patient vomits during the test procedure, necessitating the repetition of the test, this should bedone in fasted condition and not before the following day (see section 4.2).

Helicobacter Test INFAI will be affected by all treatments interfering with Helicobacter pylori statusor urease activity.

It is not expected that the test procedure may be harmful during pregnancy or lactation.

It is recommended to take notice of the product information of eradication therapy products for theiruse during pregnancy and lactation.

Helicobacter Test INFAI has no influence on the ability to drive and use machines.

None known.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Due to the fact that only 75 mg of 13C-urea is delivered, an overdose is not expected.

Pharmacotherapeutic group: Other diagnostic agents, ATC code: VO4CX

For the amount of 75 mg 13C-urea, which is administered per unit in the course of the breath test, nopharmacodynamic activity is described.

After oral ingestion the labelled urea reaches the gastric mucosa. In the presence of Helicobacterpylori the 13C-urea is metabolised by the enzyme urease of Helicobacter pylori.

2H 132N( CO)NH + 2H O Enzyme urease2 2 4NH3 + 213CO2

The carbon dioxide diffuses into the blood vessels. From there it is transported as bicarbonate into thelung and liberated as 13CO2 with the exhaled air.

In the presence of bacterial urease the ratio of the 13C/12C-carbon isotopes is significantly changed.

The portion of 13CO2 in the breath samples is determined by isotope-ratio-mass-spectrometry (IRMS)and stated as an absolute difference (∆δ-value) between the 00-minute- and the 30-minute-values.

Urease is produced in the stomach only by Helicobacter pylori. Other urease producing bacteria wereseldom found in the gastric flora.

The cut off point for discriminating Helicobacter pylori-negative and positive patients is determined tobe ∆δ-value of 4 ‰, which means that an increase of the ∆δ-value by more than 4 ‰ indicates aninfection. In comparison to bioptic diagnostics of an infection with Helicobacter pylori, the breath testachieved in clinical trials on 457 patients, a sensitivity in the range of 96.5 % to 97.9 % [95 %-CI:94.05 %-99.72 %], and a specificity range from 96.7 % to 100 %. [95 %-CI: 94.17 %-103.63 %],whereas in clinical trials on 93 adolescents from the age 12-17, a sensitivity of 97.7 % [90 %-CI:91.3 %], and a specificity of 96.0 % [90 %-CI: 89.7 %] were achieved.

In the absence of bacterial urease, the whole amount of the administered urea after absorption from thegastrointestinal tract will be metabolised like the endogenous urea. Ammonia which is produced asdescribed above by the bacterial hydrolysis is included into the metabolism as NH +4 .

The orally applied 13C-urea is metabolised to carbon dioxide and ammonia or is integrated into thebody’s own urea cycle. Any increase in 13CO2 will be measured by isotopic analysis.

Absorption and distribution of 13CO2 is faster than the urease reaction. Therefore, the rate-limiting stepin the whole process is the cleavage of 13C-urea by Helicobacter's urease.

Only in Helicobacter pylori-positive patients does the administration of 75 mg labelled urea lead to asignificant increase of 13CO2 in the breath sample within the first 30 minutes.

No concerns in relation to the clinical use of the product.

None.

Not applicable.

3 years

Do not store above 25 °C.

A test set contains the following parts:

No. Component Quantity

Jar (10 ml volume, polystyrene with polyethylene snap cap)1 containing 75 mg 13C-urea powder for oral solution 1

Labelled sample glass- or plastic- containers for sampling, storing2 and transporting the breath samples for analysis:

Sampling time: 00-minute-value 2

Sampling time: 30-minute-value 23 Bendable straw for collection of the breath samples into thecorresponding sample containers 14 Data sheet for patient documentation 15 Package leaflet 16 Page of barcode labels and sticker 1

1. The test is to be performed in the presence of a qualified person.2. Each patient should be documented according to the provided data sheet. It is recommended toperform the test with the patient being in a resting position.3. The test starts with the collection of samples for the determination of baseline-value (00-minute-value):

* Take the straw and the two sample tubes with the label“Sampling time: 00-minute-value” out of the test set.

* Remove the stopper from one of the sample tubes, unwrap the straw and place the strawinto the container.

* Now the patient breathes gently through the straw until the inner surface of the sampletube steams up.

* By continuously breathing the patient must pull out the straw and immediately close thesample tube with its stopper.(If the sample tube remains open for more than 30 seconds, the test result might befalsified.)

* Hold the sample tube upright and stick the bar-code label marked “00-minute-value”round the sample tube, so that the lines of the bar-code are horizontal.

4. Fill up the second sample tube (Label “Sampling time: 00-minute-value”) with breath byfollowing the same procedure.

5. Now 200 ml of 100 % orange juice or 1 g citric acid in 200 ml water must be drunk by thepatient without delay.

6. Now the preparation of the test solution follows:

* The jar labelled “13C-urea powder” is taken from the test set, opened, and filled up tothree quarters of its volume with tap water.

* Close the jar and shake it carefully until all the powder is dissolved. Pour the contentsinto a drinking glass.

* Fill the 13C-urea jar to the brim with water for a second and third time and add thesecontents to the drinking glass (total volume of tap water should be approximately 30 ml).

7. This test solution must now be drunk immediately by the patient, and the time of applicationmust be noted.

8. Thirty minutes after administration of the test solution (point 7), collect the 30-minute-valuesamples in the two containers which are left in the test package (Label “Sampling time:30-minute-value”), as described under steps 3 to 4. Use the bar-code labels marked “30-minute-value” for these samples.

9. Put the relevant bar-code label on the data sheet for patient documentation. Finally seal thepackage with the sticker.

10. The sample tubes have to be sent in the original packaging, for analysis, to a qualifiedlaboratory.

Analysis of breath samples and testing specification for laboratories

The breath samples, collected in 10 ml glass- or plastic sample tubes, are analysed by isotope ratiomass spectrometry (IRMS).

The analysis of the 13C/12C-ratio in carbon dioxide of breath is an integrated part of the diagnostic test

Helicobacter Test INFAI. The accuracy of the test strongly depends on the quality of the breathanalysis. The specification of breath analysis parameters like linearity, stability (reference gasprecision), and precision of measurement are fundamental for the accuracy of the system.

It has to be ensured that the analysis is carried out by a qualified laboratory. The method validated inthe application is as follows:

* Sample preparation for (IRMS)

To determine the 13C/12C-ratio of carbon dioxide in breath by mass spectrometric analysis the carbondioxide must be separated from the breath and introduced into the mass spectrometer. The automaticpreparation system for isotope mass spectrometers which is dedicated for breath test analysis is basedon a gas-chromatographic continuous flow separation technique.

Water is removed from the sample by means of a Nafion water trap or the gas-chromatographicpreparation system that separates the individual gases in a gas chromatographic column with Heliumas eluent. Passing the column the separated gas species of breath are detected by an ionisationdetector. The fraction of carbon dioxide gas, identified by its characteristic retention time, isintroduced into mass spectrometer.

* Mass spectrometric analysis

To analyse the separated carbon dioxide sample gas its molecules must be ionised, formed into abeam, accelerated by an electric field, deflected in a magnetic field, and finally detected. These fiveprocesses take place in the analyser of a mass spectrometer, which consists of three separate sections:the source, flight tube, and collector. Ionisation, beam formation and acceleration all occur in thesource, magnetic deflection takes place in the flight tube and detection takes place in the collector.

* Sample inlet

For introduction of the carbon dioxide into the analyser many sample inlet systems are available. Forbreath test analysis the individual balancing of the carbon dioxide of the sample to a referencestandard gas is essential. This ensures the high accuracy of this system, as calculation of the isotopiccontent in carbon dioxide is done with respect to an independent standard.

* Specifications for determining 13C/12C-ratios

The breath test concept relies on the administration of a specifically 13C-labelled urea whosemetabolite utilisation is monitored by measuring 13CO2 in the expired breath gas.

* The mass spectrometer must be capable of:

Multiple replicate analyses: Minimum of 3 replicate analyses of the same sample during operation

Security access: Storing of operating parameters and of results under security access toavoid later manipulation

Adjustment: 13C/12C-ratio with respect to Pee Dee Beliminate (PDB)

Sample loop: < 200 µl

The principal tests to verify the specifications are linearity, stability (reference gas precision), andprecision of measurement.

* All mass spectrometers for breath analysis must comply with the following specifications:

Linearity: ≤ 0.5 ‰ for breath samples varying between 1 % and 7 %

CO2-concentration

Stability: ≤ 0.2 ‰ on 10 consecutive pulses

Precision of measurement: ≤ 0.3 ‰ for 13C at natural abundance using a 10 ml breath sample tubewith 3 % CO2 breath concentration

Helicobacter pylori infection is present if the difference in 13C/12C of baseline-value and 30-minute-value exceeds 4.0 ‰.

Alternatively, any other suitable-validated method may be used, carried out by any objectivelyqualified laboratory.

INFAI GmbH

An der Kohlenbahn 39

D-58135 Hagen

Germany

EU/1/97/045/001

Date of first authorisation: 14 August 1997

Date of latest renewal: 14 August 2007

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.