Product Information for Helicobacter Test INFAI^®

Helicobacter Test INFAI^®

1  jar  contains: active substance:
¹³C-urea, powder, 75 mg
For excipients see 6.1

Powder for oral solution

Helicobacter Test INFAI^® may be used for in vivo diagnosis of gastroduodenal Helicobacter pylori infection in:
    -  adults,
    -  adolescents, who are likely to have peptic ulcer disease.

Helicobacter Test INFAI ^® INFAI is a breath test. Adolescents from the age 12 and older and adults take the content of 1 jar with 75 mg. The breath test is a single administration.

For performance of the test procedure 200 ml 100 % orange juice or 1g citric acid in 200 ml water for patients from the age of 12 and older (as a pre-administered test meal), as well as tap water (for dissolving the ¹³C-urea powder) are necessary.

The patient has to have fasted for over 6 hours, preferably overnight. The test procedure takes approximately 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 be used after at least four weeks without systemic antibacterial therapy and 4 weeks after last dose of acid antisecretory agents. Both might interfere with the Helicobacter pylori status. This is especially important after Helicobacter eradication therapy.

It is important to follow the instructions for use described in section 6.6 adequately, otherwise the validity of the outcome will become questionable.

The test must not be used in patients with documented or suspected gastric infection or atrophic gastritis, which might interfere with the urea breath test (please refer to section 4.2 - Posology and method of administration).

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

There is insufficient data on the diagnostic liability of the Helicobacter Test INFAI ^® to recommend its use in patients with gastrectomy and in patients younger than 12 years of age.

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 patients vomits during the test procedure, necessitating the repetition of the test, this should be done in fasted condition and not before the following day, as stated in section 4.2.

Helicobacter Test INFAI ^® will be affected by all treatments interfering with Helicobacter pylori status or 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 their use during pregnancy and lactation.

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

None known

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

Pharmacotherapeutic group: Other diagnostic agent, ATC-code: VO4CX

For the amount of 75 mg ¹³C-urea which is administered per unit in the course of the breath test, no pharmacodynamic activity is described.

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

The carbon dioxide diffuses into the blood vessels. From there it is transported as a bicarbonate into the lung 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 (Δδ-value) between the 00-minute- and the 30-minute-values.

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

The cut off point for discriminating Helicobacter pylori-negative and positive patients is determined to be Δδ-value of 4‰, which means that an increase of the Δδ-value by more than 4‰ indicates an infection. In comparison to bioptic diagnostics of an infection with Helicobacter pylori, the breath test achieved, 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%].

In the absence of bacterial urease, the whole amount of the administered urea after absorption from the gastrointestinal tract will be metabolized like the endogenous urea. Ammonia which is produced as described above by the bacterial hydrolysis is included into the metabolism as NH₄⁺.

The orally applied ¹³C-urea is metabolized to carbon dioxide and ammonia or is integrated into the body's own urea cycle. Any increase in ¹³C0₂ will be measured by isotopic analysis.

Absorption and distribution of ¹³CO₂ is faster than the urease reaction. Therefore, the rate limiting step in 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 a significant 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

The shelf life is 3 years

Do not store above 25 °C.

A test set contains the following parts:

1. The test should be performed in the presence of a qualified person.
2. Each patient should be documented according to the provided data sheet. It is recommended to perform 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 containers with the label: "Sampling time: 00-minute-value" out of the test set.
• Remove the stopper from one of the sample containers, unwrap the straw and place the straw into the container.
• Now breathe gently through the straw until the inner surface of the sample container steams up.
• By continuously breathing one must pull out the straw and immediately close the container with its stopper.
  (If the sample container remains open for more than 30 seconds, the test result might be falsified.)
• Hold the sample container upright and stick the bar-code label marked "00-minute-value" round the sample container so that the lines of the bar-code are horizontal.
• Fill up the second sample container (Label: "Sampling time: 00-minute-value") with breath by following the same procedure.
• Now 200 ml of 100 % orange juice or 1 g citric acid in 200 ml water must be drunk without delay.
• Now the preparation of the test solution follows:
• The jar labelled "¹³C-urea powder" is taken from the test set, opened,and filled up to three quarters of its volume with tap water.
• Close the jar and shake it carefully until all the powder is dissolved. Pour the contents into a drinking glass.
• Fill the ¹³C-urea jar to the brim with water for a second and third time and add these contents to the drinking glass (total volume of tap water should be approximately 30 ml).
• This test solution must now be drunk immediately by the patient, and the time of application must be noted.
• Thirty minutes after administration of the test solution (point 7), collect the 30-minute-value samples 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.
• Put the relevant bar-code label on the data sheet for patient documentation. Finally seal the package with the sticker.
• The sample containers have to be sent in the original packaging, for analysis to a qualified laboratory.

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

The analysis of the ¹³C/¹²C-ratio in carbon dioxide of breath is an integrated part of the diagnostic kit Helicobacter Test INFAI. The accuracy of the test strongly depends on the quality of the breath analysis. The specification of mass spectrometer parameters like linearity, stability (reference gas precision), and precision of measurement are fundamental for the accuracy of the system.

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

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

Water is removed from the sample by means of a Nafion water trap or the gas-chromatographic preparation system which separates the individual gases in a gas chromatographic column with Helium as eluent. Passing the column the separated gas species of breath are detected by an ionization detector. The fraction of carbon dioxide gas, identified by its characteristic retention time, is introduced to mass spectrometer.

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

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

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

The mass spectrometer must be capable of:

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

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

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

INFAI, Institut für biomedizinische Analytik & NMR-Imaging GmbH,
Universitätsstraße 142,
D-44799 Bochum
Germany.

EU/97/1/045/001

14. August 1997

23. April 2002