This information is intended for use by health professionals

1. Name of the medicinal product

LysaKare 25 g/25 g solution for infusion

2. Qualitative and quantitative composition

One 1,000 mL bag contains 25 g of L-arginine hydrochloride and 25 g of L-lysine hydrochloride.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Solution for infusion (infusion).

Clear, colourless solution, free from visible particles

pH: 5.1 – 6.1

Osmolarity: 420 – 480 mOsm/L

4. Clinical particulars
4.1 Therapeutic indications

LysaKare is indicated for reduction of renal radiation exposure during peptide-receptor radionuclide therapy (PRRT) with lutetium (177Lu) oxodotreotide in adults.

4.2 Posology and method of administration

LysaKare is indicated for administration with PRRT with lutetium (177Lu) oxodotreotide therefore, it should only be administered by a health care provider experienced in the use of PRRT.

Posology

Adults

The recommended treatment regimen in adults consists of infusion of full bag of LysaKare concomitantly with lutetium (177Lu) oxodotreotide infusion, even when patients require PRRT dose reduction.

Pre-treatment with an anti-emetic 30 minutes prior to start of LysaKare infusion is recommended to reduce the incidence of nausea and vomiting.

Special populations

Renal impairment

Due to the potential for clinical complications related to volume overload and an increase of potassium in blood associated with the use of LysaKare, this product should not be administered in patients with creatinine clearance <30 mL/min.

Care should be taken with LysaKare use in patients with creatinine clearance between 30 and 50 mL/min. Treatment with lutetium (177Lu) oxodotreotide is not recommended for patients with renal function between 30 and 50 mL/min therefore, the benefit risk for these patients will always need to be weighed carefully, which should include consideration of an increased risk for transient hyperkalaemia in these patients (see section 4.4).

Paediatric population

The safety and efficacy of LysaKare in children less than 18 years have not been established.

No data are available.

Method of administration

For intravenous use.

LysaKare should be administered as a 4-hour infusion (250 mL/hour) starting 30 minutes prior to administration of lutetium (177Lu) oxodotreotide to achieve optimal renal protection.

LysaKare and lutetium (177Lu) oxodotreotide must be given through a separate infusion line.

4.3 Contraindications

• Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

• Pre-existing clinically significant hyperkalaemia if not adequately corrected before starting the LysaKare infusion (see section 4.4).

4.4 Special warnings and precautions for use

Hyperkalaemia

An increase of serum potassium levels may occur in patients receiving arginine and lysine. Serum potassium level increases are generally mild and transient. According to limited available data maximum levels should be reached approximatively by 4 to 5 hours after start of the infusion and should return to normal levels by 24 hours.

Serum potassium levels must be tested before each treatment with LysaKare. In case of hyperkalaemia, patient's history of hyperkalaemia and concomitant medication should be checked. Hyperkalaemia must be corrected accordingly before starting the infusion (see section 4.3).

In case of pre-existing clinically significant hyperkalaemia, a second monitoring prior to LysaKare infusion must confirm that hyperkalaemia has been successfully corrected. The patient should be monitored closely for signs and symptoms of hyperkalaemia, e.g. dyspnoea, weakness, numbness, chest pain and cardiac manifestations (conduction abnormalities and cardiac arrhythmias). An ECG should be performed prior to discharging the patient.

Vital signs should be monitored during the infusion regardless of baseline serum potassium levels. Patients should be instructed to drink substantial quantities of water (at least 1 glass every hour) on the day of infusion to remain hydrated and facilitate excretion of excess serum potassium.

In case hyperkalaemia symptoms develop during LysaKare infusion, appropriate corrective measures must be taken. In case of severe symptomatic hyperkalaemia, discontinuation of LysaKare infusion should be considered, taking into consideration the risk-benefit of renal protection versus acute hyperkalaemia.

Patients with renal impairment

The use of arginine and lysine has not been specifically studied in patients with renal impairment. Arginine and lysine are substantially excreted and reabsorbed by the kidney, and their efficacy in the reduction of renal radiation exposure is dependent on this. Due to the potential for clinical complications related to volume overload and an increase of potassium in blood associated with the use of LysaKare, this product should not be administered in patients with creatinine clearance <30 mL/min. Kidney function (creatinine and creatinine clearance) should be tested before each administration.

Care should be taken with LysaKare use in patients with creatinine clearance between 30 and 50 mL/min. Treatment with lutetium (177Lu) oxodotreotide is not recommended for patients with renal function between 30 and 50 mL/min therefore, the benefit risk for these patients will always need to be weighed carefully, which should include consideration of an increased risk for transient hyperkalemia in these patients.

Patiens with hepatic impairment

The use of arginine and lysine has not been studied in patients with severe hepatic impairment. Liver function (alanine aminotransferase [ALAT], aspartate aminotransferase [ASAT], albumin, bilirubin) should be tested before each administration.

Care should be taken with LysaKare use in patients with severe hepatic impairment and in case of either total bilirubinemia >3 times the upper limit of normal or albuminemia <30 g/L and prothrombin ratio <70% during treatment. Treatment with lutetium (177Lu) oxodotreotide is not recommended in these circumstances.

Heart failure

Due to potential for clinical complications related to volume overload care should be taken with use of arginine and lysine in patients with severe heart failure defined as class III or class IV in the NYHA classification.

Treatment with lutetium (177Lu) oxodotreotide is not recommended for patients with severe heart failure defined as class III or class IV in the NYHA classification therefore, the benefit risk for these patients will always need to be weighed carefully.

Elderly

Because elderly patients are more likely to have decreased renal function, care should be taken in determining eligibility based on creatinine clearance.

Metabolic acidosis

Metabolic acidosis has been observed with complex amino-acid solutions administered as part of total parenteral nutrition (TPN) protocols. Shifts in acid-base balance alter the balance of extracellular-intracellular potassium and the development of acidosis may be associated with rapid increases in plasma potassium.

As LysaKare is administered with lutetium (177Lu) oxodotreotide, please also refer to section 4.4 of the lutetium (177Lu) oxodotreotide SmPC for further warnings specific to treatment with lutetium (177Lu) oxodotreotide.

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

No interaction with other medicinal product is expected since there is no information that other drugs are re-absorbed by the same kidney re-absorption mechanism.

4.6 Fertility, pregnancy and lactation

There is no relevant use of this medicinal product in women of childbearing potential since lutetium (177Lu) oxodotreotide is contraindicated during established or suspected pregnancy or when pregnancy has not been excluded due to the risk associated with the ionizing radiation (see section 4.1).

Pregnancy

There are no data on the use of arginine and lysine in pregnant women.

Animal studies are insufficient with respect to reproductive toxicity (see section 5.3).

Breast-feeding

Arginine and lysine, being naturally occurring amino acids, are excreted in human milk, but effects on the breastfed newborns/infants are unlikely. Breast-feeding should be avoided during treatment with lutetium (177Lu) oxodotreotide.

Fertility

There are no data on the effects of arginine and lysine on fertility.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Summary of the safety profile

There are very limited data on the safety profile of arginine and lysine solution for infusion without concomitant administration of PRRT, which also includes the use of anti-emetics as pre-medication and often the concomitant use of short acting somatostatin analogues.

The main adverse reactions which are related mainly to the amino acid solution are nausea (approximately 25%), vomiting (approximately 10%) and hyperkalaemia. These adverse reactions are mostly mild to moderate.

Tabulated list of adverse reactions

The adverse reactions listed below have been identified in publications of studies with amino acid solutions with the same composition with regards to the amino acid content, involving over 900 patients receiving more than 2,500 doses of arginine and lysine during PRRT with various radiolabelled somatostatin analogues.

The adverse reactions are listed according to the frequency. The frequencies are categorised as follows: 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) and not known (cannot be estimated from the available data).

Table 1 Adverse drug reactions

Adverse drug reaction

Frequency category

Metabolism and nutrition disorders

Hyperkalaemia

Not known

Nervous system disorders

Dizziness

Not known

Headache

Not known

Vascular disorders

Flushing

Not known

Gastrointestinal disorders

Nausea

Very common

Vomiting

Very common

Abdominal pain

Not known

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 national reporting system:

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

In the event of over-hydration or solute overload, the elimination should be promoted by frequent micturition or by forced diuresis and frequent bladder voiding.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: All other therapeutic products, detoxifying agents for antineoplastic treatment, ATC code: V03AF11

Mechanism of action

Arginine and lysine undergo glomerular filtration and, via competition, interfere with renal resorption of lutetium (177Lu) oxodotreotide, reducing the radiation dose delivered to the kidney.

Clinical efficacy and safety

Clinical efficacy and safety for arginine and lysine are based on published literature of studies using solutions with the same arginine and lysine content as LysaKare.

The toxicities that are observed following administration of PRRT are directly due to radiation-absorbed dose to organs. The kidneys are the critical organs for toxicity for lutetium (177Lu) oxodotreotide and dose limiting if amino acids are not administered to reduce renal uptake and retention.

A dosimetry study including 6 patients showed that a 2.5% Lysine-Arginine amino acid solution reduced renal radiation exposure by about 47% as compared to no treatment, without having an effect on tumour uptake of lutetium (177Lu) oxodotreotide. This reduction in renal radiation exposure mitigates the risk for radiation-induced renal injury.

Based on a publication of the largest study using arginine and lysine in the same quantities as LysaKare, the average kidney absorbed dose, as determined by planar imaging dosimetry, was 20.1±4.9 Gy, which is below the established threshold for the occurrence of renal toxicities of 23 Gy.

5.2 Pharmacokinetic properties

Arginine and lysine are naturally occurring amino acids that follow physiological pharmacokinetic steps and biochemical processes after infusion.

Absorption

Due to the intravenous route of administration, LysaKare is 100% bioavailable.

Distribution

Transient elevations in plasma arginine and lysine are observed after intravenous administration, whereupon the highly water soluble amino acids are quickly distributed throughout tissues and body fluid.

Biotransformation

Like other naturally occurring amino acids, arginine and lysine serve as building blocks in protein anabolism and serve as precursors for several other products, including nitric oxide, urea, creatinine, and Acetyl-Coenzyme A.

Elimination

Arginine and lysine are rapidly distributed. Based on a study with 30 g arginine infused over 30 minutes, plasma elimination of amino acids follows at least a biphasic or triphasic decline, with levels returning to baseline within 6 hours post-dose. Initial rapid clearance is through glomerular filtration in the kidney in the first 90 minutes post-infusion. Remaining amino acid is removed by non-renal clearance.

Paediatric population

No pharmacokinetic data are available on the use of arginine and lysine at the same dose as LysaKare and for the same indication in paediatric patients.

5.3 Preclinical safety data

There were no non-clinical studies conducted with LysaKare.

6. Pharmaceutical particulars
6.1 List of excipients

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 Shelf life

2 years

6.4 Special precautions for storage

Store below 25°C.

6.5 Nature and contents of container

Infusion bag made of polyvinyl chloride (PVC) containing 1,000 mL of solution, wrapped in a polyethylene polyamine/aluminium foil.

6.6 Special precautions for disposal and other handling

This medicinal product is for single use only.

Do not remove unit from overwrap until ready to use.

Do not use if overwrap has been previously opened or damaged. The overwrap is a moisture barrier.

Do not reconnect partially used bags.

LysaKare must not be diluted.

Do not use solutions which are cloudy or have deposits. This may indicate that the product is unstable or that the solution has become contaminated.

Once the container has been opened, the contents should be used immediately.

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

7. Marketing authorisation holder

Advanced Accelerator Applications

20 rue Diesel

01630 Saint Genis Pouilly

France

8. Marketing authorisation number(s)

EU/1/19/1381/001

9. Date of first authorisation/renewal of the authorisation

25 July 2019

10. Date of revision of the text

LEGAL CATEGORY

POM