LIMAXETIN 4 MG / ML SOLUTION FOR INJECTION - summary of medicine characteristics

This medicinal product is subject to additional monitoring This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

1 NAME OF THE MEDICINAL PRODUCT

LiMAxetin 4 mg/ml Solution for injection

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 1 ml of solution for injection contains 4 mg of 13C-Methacetin.

Excipient with known effect: Each milliliter of solution for injection contains 0.46 –0.47 mg of sodium.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Solution for injection.

LiMAxetin is a sterile, clear and colourless ready-to-use solution.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

This medicinal product is a diagnostic agent.

LiMAxetin is used with the LiMAx test for the quantitative assessment of liver capacity in adults under evaluation for liver surgery. The LiMAx test can be used pre-and post-surgery for predicting and monitoring postoperative outcome in liver resection and transplantation.

The LiMAx test is a non-invasive breath test and should be used in conjunction to clinical evaluation.

4.2 Posology and method of administration

Posology

LiMAxetin is administered in a fixed standard dose of 2 mg/kg b.w. as an intravenous bolus injection per one LiMAx test.

Any intravenous access (central or peripheral) can be used, as long as it affords rapid bolus administration.

Paediatric population

LiMAxetin should not be used in children and adolescents under the age of 18 years as safety and efficacy have not yet been established in the paediatric population.

Method of administration

LiMAxetin is administered in an intravenous bolus injection.

The patient's weight should be determined on a scale prior to the test.

The patient should abstain from food and sugary drinks at least 3 hours prior to the test (clear water allowed; see section 4.5).

LiMAxetin is a ready to use formulation in vials with 200 mg 13C-Methacetin/50 ml vial, corresponding to 4 mg 13C-Methacetin/ml.

For details on the interpretation of the LiMAx test results please refer to section 4.4.

For details on the performance of the LiMAx test please refer to section 6.6.

The LiMAx test should not be performed more than once per 24 hours.

The Elderly:

There is no clinically relevant effect of age described for the metabolism of LiMAxetin, therefore no adjustment of the dosage or administration in patients over the age of 65 years is required.

Hepatic impairment:

No adjustment of dosage or administration is required in patients with hepatic impairment.

Renal Impairment

No adjustment of dosage or administration is required in patients with renal impairment.

4.3 Contraindications

Hypersensitivity to the active substance 13C-Methacetin, paracetamol (metabolite), or to any of the excipients listed in section 6.1.

Hypersensitivity to silicone rubber in the LiMAx breathing mask (part of the pack).

4.4 Special warnings and precautions for use

To be used only under the supervision of experienced and medically qualified healthcare

professionals.

Drugs affecting the CYP 1A2 system

Strong inhibitors affecting the CYP 1A2 system – such as e.g. ciprofloxacin, fluvoxamine or enoxacin

– may have an impact on the 13C-Methacetin degradation in liver and therefore on the LiMAx test

results. Please refer to section 4.5.

Hepatic impairment:

No specific toxicity for 13C-Methacetin has been described. LiMAxetin can therefore be used

without restriction in hepatic impairment.

Renal Impairment:

No specific toxicity for 13C-Methacetin has been described. LiMAxetin can therefore be used

without restriction in renal impairment.

Paediatric population

LiMAxetin should not be used in children and adolescents under the age of 18 years as safety and efficacy have not yet been established in the paediatric population.

Paracetamol

LiMAxetin is metabolized to paracetamol.

While paracetamol is typically administered orally, an intravenous formulation is marketed for use in certain circumstances. In adults, the i.v. formulation is usually administered at a dose of 1 g with peak plasma concentrations around 20 gg/ml. These levels are much higher than those seen immediately after a standard i.v. dose of LiMAxetin given that the doses typically used in the LiMAx test (100 mg to 200 mg, depending on body weight), are several times lower than therapeutic doses of i.v. paracetamol. Therefore, no special warnings and precautions have to be considered with regard to the paracetamol concentration.

Instructions for use of the medical devices LiMAx breathing mask and the FLIP device must be followed absolutely.

LiMAx breathing mask (part of pack)

The LiMAx breathing mask is made of latex-free silicone rubber. This material is used as standard in clinical settings because of its high level of safety when coming into contact with patients. Nevertheless, in a small number of cases patients may display intolerance to silicones when the LiMAx breathing mask is used. In such cases, special precautionary measures, such as the application of a protective gel (e.g. hydrocolloid dressings) between the mask and the patient’s face, may be required in order to perform the LiMAx test.

FLIP device – Serious lung infection with highly multi-resistant microbes or open tuberculosis

If a LiMAx test is deemed medically necessary in cases of urgent indication and suspected serious lung infection with highly multi-resistant microbes or open tuberculosis, an adequate, standard bacteria filter must be fitted between the tube of the LiMAx breathing tube and the connection to the FLIP measurement device.

Interpretation of the LiMAx test results:

LiMAx test results should be considered in relation to a reference normal LiMAx value of 315 gg/kg/h as described in the literature.

LiMAx cut-off values for adults under evaluation for liver surgery are presented below.

Surgery planning

o Patients under consideration for hepatectomy

■ Preoperative LiMAx value <140 gg/kg/h predicts non-suitability for surgery

■ Residual liver function can be predicted preoperatively by combination of the LiMAx test and liver / tumor volumetry (due to high correlation between predicted post-operative liver volume and residual liver function).

o Patients under consideration for liver transplantation

■ LiMAx value <55 ^g/kg/h predicts high risk of death within 6 months without transplantation [Sensitivity 56%, Specificity 81%]

Post hepatectomy

o Postoperative transfer (fast track procedure)

■ Postoperative LiMAx value >150 ^g/kg/h predicts suitability for transfer directly from recovery room to general ward [Sensitivity 90%, Specificity 100%].

o Postoperative outcome (in-hospital mortality, Intensive care and hospital stay)

■ Postoperative LiMAx value < 80 ^g/kg/h predicts high mortality (38.1 %), longer Intensive care and hospital stay and high risk of inhouse mortality [Sensitivity 73%; Specificity 90%].

■ A postoperative LiMAx value of > 80 ^ig/kg/h (respectively > 150 ^g/kg/h) predicts high chances of survival of the hospital stay with a Positive predictive value of 97.5% (respectively 100%).

Post liver transplantation

o Postoperative outcome

■ Postoperative LiMAx value < 64 ^g/kg/h predicts initial graft dysfunction [Sensitivity 100%, Specificity 92%].

■ Postoperative LiMAx value < 64 ^g/kg/h (directly after transplantation) and < 42 ^g/kg/h (1st postoperative day) predicts primary non-function [Sensitivity 100%, Specificity 100%].

Excipients:

This medicinal product contains 1 mmol (23 mg) – 1.02 mmol (23.5 mg) sodium per 50 ml vial. To be taken into consideration by patients on a controlled sodium diet.

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

However, it is to be expected that drugs affecting the CYP 1A2 system – strong inhibitors such as e.g. ciprofloxacin, fluvoxamine or enoxacin – may have an impact on the 13C-Methacetin degradation in liver and therefore on the LiMAx test results.

The influence of weak inhibitors of CYP 1A2 (e.g. acyclovir, allopurinol, cimetidine, norfloxacin, propranolol, terbinafine, ticlopidin, verapamil) on the LiMAx test result is not known.

Caution should be exercised if drugs which are known to affect the CYP 1A2 system are administered concomitantly.

Clinical data indicate that there is an effect (induction) of smoking on the CYP 1A2 system. However, the shift in LiMAx values was not statistically significant.

Use of paracetamol-containing products prior to the LiMAx test does not influence the outcome of the LiMAx test.

To minimise effects which might result in an unstable baseline measurement, uncontrolled carbon or sugary intake needs to be avoided. Therefore, administration of infusions, drugs, FFPs (fresh frozen plasma), amino acids, fats, glucose etc. should not take place shortly before or during the LiMAx test procedure. Intake of food and carbonated or sugary drinks should be avoided in the 3 hours prior to the test.

4.6 Fertility, pregnancy and lactation

Pregnancy

Data from the use of 13C-Methacetin in pregnant women are limited. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity.

The metabolite of 13C-Methacetin is paracetamol, which is an analgesic drug which has showed no negative effects during pregnancy in standard oral dosages.

However, LiMAxetin should only be used during pregnancy with caution and should be limited to cases in which other alternative diagnostic processes are not available.

Patients should then be monitored extensively.

Breastfeeding

It is unknown whether 13C-Methacetin is excreted in human milk. However, the metabolite paracetamol is excreted in breast milk. Up to now no adverse effects of paracetamol after oral adminstration have been reported.

Nevertheless breastfeeding should be discontinued during treatment with LiMAxetin.

Fertility

No data is available.

4.7 Effects on ability to drive and use machines

LiMAxetin is expected to have no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

The information below lists reported adverse reactions, ranked using 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).

No undesirable effects have been reported during long-term practical clinical experience of the application of 13C-Methacetin to assess liver function by breath tests, or in published literature.

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

No clinical information on overdose is available for LiMAxetin. The drug is administered exclusively by healthcare professionals. The dose is adjusted to body weight. The FLIP device used for determination of the maximum liver capacity automatically calculates and displays the recommended amount of LiMAxetin for administration.

Incorrect calculation of the dose can bias the LiMAx test result. This might occur due to incorrect estimation of the body weight by history. Therefore, the patient’s weight should be determined using a scale prior to the test.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Tests for liver functional capacity, ATC code: V04CE03.

13C-Methacetin is used to assess the maximal liver function capacity based on the liver-specific Cytochrome P450 1A2 metabolism by means of the LiMAx test method. 13C is a stable isotope of the naturally occurring carbon and is therefore not associated with any exposure to radioactivity.

Clinical efficacy

One open-label, randomised, controlled clinical trial was conducted with the LiMAx test versus a standard of care control group in 148 liver tumor patients undergoing partial liver resection to identify low risk patients after partial liver resection to enable direct transfer of patients with sufficient liver functional status from the recovery room to general ward (‘fast-track procedure’). Based on the determination of a postoperative LiMAx cut-off value of > 150 pg/kg/h in the recovery room 85% of patients in the LiMAx group could be safely transferred to the general ward (sensitivity 90%, specificity 100%, positive predictive value 100%). The negative predictive value was low due to the number of negative cases in the LiMAx group indicating that the chosen cut-off of > 150 pg/kg/h was conservative enough to exclude an inappropriate transfer of a patient to the general ward after surgery. Based on the standard transfer practice only 1.7% of the patients could be safely transferred to the general ward after surgery. There was a high correlation between residual liver function as determined in LiMAx values and post-operative residual liver volume, indicating that the LiMAx test can be used to predict residual liver function and individual postoperative outcome after hepatectomy.

Mechanism of action

In humans, 13C-Methacetin undergoes O-demethylation through the hepatic mixed function oxidase system, exclusively by the activity of CYP 1A2 which is distributed throughout the entire liver acinus and is ubiquitously active throughout the liver. This rate-limiting reaction step leads to the formation of paracetamol and formaldehyde which is immediately oxygenated in the cytosol (formaldehyde dehydrogenase) or mitochondria (aldehyde dehydrogenase) to methanoic acid and finally to 13CO2. 13CO2 is exhaled and is used for quantitative measurement with the FLIPdevice, reflecting the liver function. CYP 1A2 activity allows a clear discrimination between normal function and liver disease independent of cholestasis.

Pharmacodynamic effects

No pharmacodynamic effect specific for 13C-Methacetin is described.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with LiMAxetin in all subsets of the paediatric population in the condition “diagnosis of liver disease” as per Paediatric Investigation Plan (PIP) decision, for the granted indication (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

Absorption

13C-Methacetin is administered as intravenous bolus injection.

Distribution

No clinical information is available on the volume of distribution of 13C-Methacetin.

Peak blood concentration is achieved on average after 10 minutes. Serum halflife is approximately 30 min.

Biotransformation

13C-Methacetin undergoes O-demethylation through the hepatic mixed function oxidase system, exclusively by the activity of CYP 1A2. The final metabolic products of this rapid single step enzymatic reaction are 13CO2 and paracetamol.

Elimination

The metabolite paracetamol is renally excreted after being further metabolized. The other metabolite 13CO2 is exhaled in the breath and is used to perform the LiMAx test.

5.3 Preclinical safety data

In a 1-month repeated dose toxicity study in rats at the highest technically feasible dose, which corresponded to a 3-fold higher dose than the regular clinical dose for humans (based on body surface area), slight clinical signs were observed, which did not represent clear toxicity.

13C-Methacetin was not genotoxic in standard genotoxicity studies and did not affect embryofoetal development in preclinical studies.

No local effects of 13C-Methacetin were observed in animals upon single paravenous injection and upon repeated daily intravenous injection.

6.1 List of excipients

Sodium dihydrogen phosphate dihydrate

Polyethylene Glycol (PEG 400)

Sodium hydroxide

Water for injections

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3

2 years

6.4 Special precautions for storage

Do not store above 25°C.

Do not refrigerate.

Do not freeze.

6.5 Nature and contents of container

LiMAxetin is available in 50 ml colourless neutral glass vials with a grey bromobutyl rubber stopper and with an aluminium cap with plastic seal.

LiMAxetin is available in packs with

– one 50 ml glass vial and a CE-marked LiMAx breathing mask together with its instructions for use

– two 50 ml glass vials and a CE-marked LiMAx breathing mask together with its instructions for use.

6.6 Special precautions for disposal

To be used only under the supervision of experienced and medically qualified healthcare

professionals.

Performance of the LiMAx test:

For the performance of the LiMAx test with LiMAxetin the LiMAx breathing mask (provided together with LiMAxetin) and a FLIP (Fast Liver Investigation Package) medical device are needed.

Instructions for use of the medical devices LiMAx breathing mask and the FLIP device must be followed absolutely.

The following provides only a short summary on how to perform the LiMax test.

Deviations from the standard arrangement and procedure described in the FLIP and LiMAx breathing mask instructions for use may adversely affect the results of the liver function measurement leading to an incorrect assessment of the liver function capacity.

1. Prepare the LiMAx test as outlined in the FLIP device and LiMAx breathing mask instructions for use.

2. Place the patient in a supine position; inform the patient to refrain from talking while the measurement is performed.

3. Attach the tube of the LiMAx breathing mask to the FLIP device.

4. Adjust the LiMAx breathing mask to the patient’s face. Please make sure that it fits closely and completely to the face of the patient in order to ensure lossless transfer of all exhaled CO2 to the FLIP device.

5. Proceed according to the instructions provided by the FLIP device user interface to determine the baseline within the next 5 to 25 minutes.

6. Prior to starting the test, the patient should be fitted with a sufficiently sized peripheral venous cannula (min. 20 gauge, preferably 18 gauge) in the antecubital fossa or more centrally. Where a central venous catheter is available, it should be used.

Note: Access points on the distal forearm or hand should not be used.

7. Prepare the syringes needed for conduct of the injections (one 50 ml syringe per vial LiMAxetin; one 20 ml syringe with 0.9% sodium chloride (NaCl) physiological saline solution for flushing the injection tubes) as described in the instructions for use of the FLIP device.

8. When indicated by the FLIP device, confirm beginning of the injection at the FLIP device screen.

9. Inject LiMAxetin as an intravenous bolus injection in a peripheral or central venous catheter/line in no more than 20 seconds.

10. Proceed as described in the instructions for use for the FLIP device taking the following steps:

a.Immediately after the application of LiMAxetin flush by intravenous administration of 20 ml 0.9% sodium chloride (NaCl) physiological saline solution.

In the case of peripheral injections, the arm with the venous catheter can ideally be raised briefly (for around 5 seconds) in order to empty the arm veins.

b. Follow the instructions provided by the FLIP device user interface and instructions for use until the LiMAx value has been determined and the measurement is terminated. This will last no longer than 60 minutes.

c.Remove the LiMAx breathing mask from the patient’s face.

Analysis of breath samples:

The non-invasive procedure is based on continuous real-time breath analysis with the FLIP medical device after intravenous administration of LiMAxetin. The exhaled air transferred via the LiMAx breathing mask into the FLIP medical device is used to calculate the 13CO2:12CO2 ratio. Each test value presents a specific 13CO2:12CO2 ratio at a specific time point (3s). Change of 4 versus the baseline is displayed as delta over baseline (DOB). To transfer the raw data of 13CO2:12CO2 ratio alterations into a single value to easily support diagnostic assessment, the FLIP medical device uses the maximum of the exhaled 13CO2:12CO2 ratio (DOBmax) to calculate a single LiMAx value (unit: degradation of test substrate in ^g per kg body weight (b.w.) per hour |^g/kg/h|) by a standardized LiMAx formula. The LiMAx value is reported by the FLIP medical device as a direct outcome parameter of the LiMAx test.

The measuring technique of the FLIP medical device is based on the absorption of light detected in CO2 gas and uses infrared spectroscopy.

Prerequisite for valid conduct of the LiMAx test is the use of the CE-certified FLIP medical device and the CE-certified LiMAx breathing masks.

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

Humedics GmbH Bundesallee 23 10717 Berlin Germany

8 MARKETING AUTHORISATION NUMBER(S)

PL 45726/0001

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

16/10/2017