LIMAXETIN 4 MG / ML SOLUTION FOR INJECTION - patient leaflet, side effects, dosage

1. what limaxetin is and what it is used for

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 to determine your liver capacity quantitatively and should be used in conjunction to clinical evaluation.

13 C-Methacetin, the active ingredient of LiMAxetin, is metabolized in liver cells into carbon dioxide, a gas which you exhale, and a small amount of the painkilling agent paracetamol. The resulting carbon dioxide is specifically detected by the FLIP medical device available in your hospital or your doctor’s office. Based on the amount of the exhaled carbon dioxide the FLIP device calculates a value – the LiMAx value – which depends on your liver function and allows your doctor to determine your liver capacity quantitatively.

2. what you need to know before you use limaxetin

Do not use LiMAxetin:

• if you are allergic to 13C-Methacetin, paracetamol (metabolite) or any of the other ingredients of this medicine (listed in section 6).
• if you are allergic to silicone rubber in the LiMAx breathing mask, which is part ofthe pack.

Warnings and precautions

Talk to your doctor or nurse before using LiMAxetin. Please consider the section “Other medicines and LiMAxetin” and tell your doctor if you are taking, have recently taken or might take any other medicines.

Children and adolescents

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.

Other medicines and LiMAxetin

Tell your doctor if you are taking, have recently taken or might take any other medicines.

Some drugs may influence the metabolisation of 13 C-Methacetin.

Please talk to your doctor if you take ciprofloxacin (antibiotic agent), other antibiotics (e. g. enoxacin) or fluvoxamine (antidepressant agent). These active ingredients (strong inhibitors of CYP 1A2-enzyme system) may influence the metabolisation of 13 C-Methacetin.

Please inform your doctor if you take acyclovir (antiviral agent), allopurinol (to treat gout), cimetidine (to treat peptic ulcers), norfloxacin (antibiotic agent), propranolol (to treat high blood pressure and other cardiac disorders), terbinafine (antifungal agent), ticlopidin (anticoagulant agent) or verapamil (to treat cardiac disorders). An influence of these active ingredients (weak inhibitors of CYP 1A2-enzyme system) can not be excluded.

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, FFP (fresh frozen plasma) or amino acids, fats, glucose etc. should not take place shortly before or during the LiMAx test procedure.

LiMAxetin with food and drink

Please do not intake food and carbonated or sugary drinks in the 3 hours before the performance of the LiMAx test as this may negatively influence the test results.

Pregnancy and breast-feeding and fertility

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before this medicine is administered to you.

Driving and using machines

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

LiMAxetin contains Sodium

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.

3. how to use limaxetin

LiMAxetin will always be adminstered to you by a doctor or nurse who is experienced in the use of the product.

The recommended dose is a fixed standard dose of 2 mg/kg body weight and is administered 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.

Your body weight should be determined on a scale prior to the test.

You should abstain from food and sugary drinks for at least 3 hours prior to the test. You are allowed to drink clear water (see section 2 “LiMAxetin with food and drink”).

Information about the LiMAx test:

• 1. Your doctor will ask you to lay down and rest.

• 2. Your doctor will ask you not to talk during the performance of the test.

• 3. The tube of the LiMAx breathing mask will be attached to the FLIP device by your doctor or nurse.

• 4. The LiMAx breathing mask will be adjusted to your face. It needs to fit closely and completely to your face. This is important in order to ensure lossless transfer of exhaled breath to the FLIP device.

• 5. After 5 to 25 minutes of breathing into the mask the measurement preconditions are reached and you will receive an injection of LiMAxetin – you need to continue to breathe into the mask

• 6. Your doctor or nurse will inject LiMAxetin as an intravenous bolus injection in a peripheral or central venous catheter/line.

• 7. After injection of LiMAxetin your doctor will inject an intravenous bolus of 20 ml NaCl solution to rinse the catheter line. In the case of peripheral injections, your doctor might ask you to raise the arm with the venous catheter briefly (for around 5 seconds) in order to empty the arm veins.

• 8. Please continue to rest quiet and breathe, please do not talk.

• 9. After termination of the test within 60 minutes or less the LiMAx breathing mask is removed from your face and the tube is released from the FLIP device.

If you have any further questions on the use of this medicine, ask your doctor or nurse.

4. possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

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

Reporting of side effects

If you get any side effects, talk to your doctor 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: ) 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 limaxetin

Keep this medicine out of the sight and reach of children.

Do not store above 25 °C. Do not refrigerate. Do not freeze.

Do not use this medicine after the expiry date which is stated on the carton after EXP. The expiry date refers to the last day of that month.

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 LiMAxetin contains

• The active substance is 13C-Methacetin
• The other excipients are: Sodium dihydrogen phosphate dihydrate, polyethylene glycol (PEG 400), sodium hydroxide, water for injections

What LiMAxetin looks like and contents of the pack

• LiMAxetin is a clear and colourless ready-to-use solution.
• LiMAxetin is available in 50 ml colourless neutral glass vials with a grey 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

Marketing Authorisation Holder

Humedics GmbH

Bundesallee 23

10717 Berlin, Germany

Manufacturer

Hubertus Apotheke am Salzufer

Salzufer 13/14

10587 Berlin, Germany

This medicinal product is authorised in the Member States of the EEA under the following names:

Austria LiMAxetin 4 mg/ml Injektionslosung

Germany LiMAxetin 4 mg/ml Injektionslosung

United Kingdom LiMAxetin 4 mg/ml solution for injection

This leaflet was last revised in 07/2019.

umedics

THE FOLLOWING INFORMATION IS INTENDED

FOR HEALTHCARE PROFESSIONALS ONLY

LiMAxetin is to be used only under the supervision of experienced and medically qualified healthcare professionals.

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.

Method of administration

• LiMAxetin is administered in an intravenous bolus injection.
• The patients’ weight should be determined on a scale prior to the test.
• The patient should abstain from food and sugary drinks for at least 3 hours prior to the test (clear water allowed; see section 2).
• LiMAxetin is a ready to use formulation in vials with 200 mg 13C-Methacetin/50 ml vial, corresponding to 4 mg 13C-Methacetin/ml.
• The LiMAx test should not be performed more than once per 24 hours.

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 13 CO2:12 CO2 ratio. Each test value presents a specific 13 CO2:12 CO2 ratio at a specific time point (6s).

Change of 6s versus the baseline is displayed as delta over baseline (DOB). To transfer the raw data of 13 CO2:12 CO2 ratio alterations into a single value to easily support diagnostic assessment, the FLIP medical device uses the maximum of the exhaled 13 CO2:12 CO2 ratio (DOB max ) to calculate a single LiMAx value (unit: degradation of test substrate in ng per kg body weight (b. w.) per hour [Mg/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.

Interpretation of the LiMAx test results:

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

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

Surgery planning

Patients under consideration for hepatectomy

• Preoperative LiMAx value < 140 Mg/ kg/ h predicts nonsuitability 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).

Patients under consideration for liver transplantation

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

Post hepatectomy

Postoperative transfer (fast track procedure)

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

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

• Postoperative LiMAx value < 80 Mg/kg/h predicts high mortality (38.1 %) and longer Intensive care and hospital stay and high risk of in-house mortality [Sensitivity 73 %; Specificity 90 %].
• Postoperative LiMAx values > 80 Mg/kg/h or > 150 Mg/kg/h are predicting high chances of survival of the hospital stay [Positive predictive value: 97.5 % and 100 %, respectively].

Post liver transplantation

Postoperative outcome

• Postoperative LiMAx value < 64 Mg/kg/h predicts initial graft dysfunction [Sensitivity 100 %, Specificity 92 %].
• Postoperative LiMAx value < 64 Mg/kg/h (directly after transplantation) and < 42 Mg/kg/ h (1st postoperative day) predicts primary non-function [Sensitivity 100 %, Specificity 100 %].

umedics

THE FOLLOWING INFORMATION IS INTENDED

FOR HEALTHCARE PROFESSIONALS ONLY

LiMAxetin is to be used only under the supervision of experienced and medically qualified healthcare professionals.

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.

Method of administration

• LiMAxetin is administered in an intravenous bolus injection.
• The patients’ weight should be determined on a scale prior to the test.
• The patient should abstain from food and sugary drinks for at least 3 hours prior to the test (clear water allowed; see section 2).
• LiMAxetin is a ready to use formulation in vials with 200 mg 13C-Methacetin/50 ml vial, corresponding to 4 mg 13C-Methacetin/ml.
• The LiMAx test should not be performed more than once per 24 hours.

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 13 CO2:12 CO2 ratio. Each test value presents a specific 13 CO2:12 CO2 ratio at a specific time point (6s).

Change of 6s versus the baseline is displayed as delta over baseline (DOB). To transfer the raw data of 13 CO2:12 CO2 ratio alterations into a single value to easily support diagnostic assessment, the FLIP medical device uses the maximum of the exhaled 13 CO2:12 CO2 ratio (DOB max ) to calculate a single LiMAx value (unit: degradation of test substrate in ng per kg body weight (b. w.) per hour [Mg/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.

Interpretation of the LiMAx test results:

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

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

Surgery planning

Patients under consideration for hepatectomy

• Preoperative LiMAx value < 140 Mg/ kg/ h predicts nonsuitability 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).

Patients under consideration for liver transplantation

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

Post hepatectomy

Postoperative transfer (fast track procedure)

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

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

• Postoperative LiMAx value < 80 Mg/kg/h predicts high mortality (38.1 %) and longer Intensive care and hospital stay and high risk of in-house mortality [Sensitivity 73 %; Specificity 90 %].
• Postoperative LiMAx values > 80 Mg/kg/h or > 150 Mg/kg/h are predicting high chances of survival of the hospital stay [Positive predictive value: 97.5 % and 100 %, respectively].

Post liver transplantation

Postoperative outcome

• Postoperative LiMAx value < 64 Mg/kg/h predicts initial graft dysfunction [Sensitivity 100 %, Specificity 92 %].
• Postoperative LiMAx value < 64 Mg/kg/h (directly after transplantation) and < 42 Mg/kg/ h (1st postoperative day) predicts primary non-function [Sensitivity 100 %, Specificity 100 %].