LYSAKARE 25g / 25g infusion solution medication leaflet

LysaKare 25 g/25 g solution for infusion

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.

Solution for infusion

Clear, colourless solution, free from visible particlespH: 5.1 to 6.1

Osmolarity: 420 to 480 mOsm/L

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

LysaKare is indicated for administration with PRRT with lutetium (177Lu) oxodotreotide. It shouldtherefore only be administered by a healthcare professional experienced in the use of PRRT.

The recommended treatment regimen in adults consists of infusion of a full bag of LysaKareconcomitantly with lutetium (177Lu) oxodotreotide infusion, even when patients require PRRT dosereduction.

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

No studies have been performed in patients aged 65 years or above.

Elderly patients are more likely to have decreased renal function, and care should therefore be taken indetermining eligibility based on creatinine clearance (see section 4.4).

The use of arginine and lysine has not been specifically studied in patients with severe hepaticimpairment (see section 4.4).

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

Care should be taken with LysaKare use in patients with creatinine clearance between 30 and50 mL/min. Treatment with lutetium (177Lu) oxodotreotide is not recommended for patients with renalfunction between 30 and 50 mL/min, and the benefit/risk balance for these patients will thereforealways need to be weighed carefully. This should include consideration of an increased risk fortransient hyperkalaemia in these patients (see section 4.4).

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

No data are available.

For intravenous use.

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

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

* 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).

An increase in serum potassium may occur in patients receiving arginine and lysine. Such increasesare generally mild and transient. According to limited available data maximum levels should bereached by approximately 4 to 5 hours after the start of infusion and should return to normal levels by24 hours.

Serum potassium levels must be tested before each treatment with LysaKare. If hyperkalaemia isdetermined, the patient’s history of hyperkalaemia and any concomitant medicinal product should bechecked. Hyperkalaemia must be corrected accordingly before the infusion is started (see section 4.3).

In patients with pre-existing clinically significant hyperkalaemia the serum potassium level must betested again prior to LysaKare infusion to confirm that hyperkalaemia has been successfully corrected.

Patients should be monitored closely for signs and symptoms of hyperkalaemia, e.g. dyspnoea,weakness, numbness, chest pain and cardiac manifestations (conduction abnormalities and cardiacarrhythmias). An electrocardiogram (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 theday of infusion to remain hydrated and facilitate excretion of excess serum potassium.

If hyperkalaemia symptoms develop during LysaKare infusion, appropriate corrective measures mustbe taken. In case of severe symptomatic hyperkalaemia, discontinuation of LysaKare infusion shouldbe considered, taking into consideration the risk-benefit of renal protection versus acutehyperkalaemia.

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 thereduction of renal radiation exposure is dependent on this. Due to the potential for clinicalcomplications related to volume overload and an increase in blood potassium associated with the useof LysaKare, this medicinal product should not be administered in patients with creatinine clearance<30 mL/min. Kidney function (creatinine and creatinine clearance) should be tested before eachadministration.

Care should be taken with LysaKare use in patients with creatinine clearance between 30 and50 mL/min. Treatment with lutetium (177Lu) oxodotreotide is not recommended for patients with renalfunction between 30 and 50 mL/min, and the benefit/risk balance for these patients will thereforealways need to be weighed carefully. This should include consideration of an increased risk fortransient hyperkalemia in these patients.

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

Care should be taken with LysaKare use in patients with severe hepatic impairment and in the event ofeither total bilirubinaemia >3 times the upper limit of normal or albuminaemia <30 g/L andprothrombin ratio <70% during treatment. Treatment with lutetium (177Lu) oxodotreotide is notrecommended in these circumstances.

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

York Heart Association (NYHA) classification.

Treatment with lutetium (177Lu) oxodotreotide is not recommended for patients with severe heartfailure defined as class III or IV in the NYHA classification. The benefit/risk balance for these patientswill therefore always need to be weighed carefully.

Metabolic acidosis has been observed with complex amino-acid solutions administered as part of totalparenteral 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 inplasma potassium.

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

No interaction studies have been performed.

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

There is no relevant use of this medicinal product in women of childbearing potential (see section 4.1).

No animal studies of developmental toxicity have been conducted with LysaKare. Since LysaKare isused with lutetium (177Lu) oxodotreotide, males and females of reproductive potential should beadvised to use effective contraception during treatment with lutetium (177Lu) oxodotreotide. Pleasealso refer to section 4.6 of the lutetium (177Lu) oxodotreotide SmPC for further guidance specific totreatment with lutetium (177Lu) oxodotreotide.

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

There is no relevant use of this medicinal product in pregnant women. Lysakare is used with lutetium(177Lu) oxodotreotide, which is contraindicated during established or suspected pregnancy and whenpregnancy has not been excluded due to the risk associated with the ionising radiation. Please alsorefer to section 4.6 of the lutetium (177Lu) oxodotreotide SmPC for further guidance specific totreatment with lutetium (177Lu) oxodotreotide.

No studies on animal reproductive function have been conducted (see section 5.3).

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

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

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

There are very limited data on the safety profile of arginine and lysine solution for infusion withoutconcomitant administration of PRRT, which also includes the use of anti-emetics as pre-medicationand 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 aremostly mild to moderate.

The adverse reactions listed below have been identified in publications of studies involving amino acidsolutions that had the same composition as LysaKare with regard to amino acid content. These studiesincluded over 900 patients receiving more than 2 500 doses of arginine and lysine during PRRT withvarious radiolabelled somatostatin analogues.

The adverse reactions are listed according to MedDRA system organ class and by frequency. Thefrequencies 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 beestimated from the available data).

Table 1 Adverse drug reactions

Adverse drug reaction Frequency category

Hyperkalaemia Not known

Dizziness Not known

Headache Not known

Flushing Not known

Nausea Very common

Vomiting Very common

Abdominal pain Not 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.

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

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

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

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

The toxicities that are observed following administration of PRRT are directly due to the radiation-absorbed dose to organs. The kidneys are the critical organs for lutetium (177Lu) oxodotreotide toxicityand 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 solutionreduced renal radiation exposure by about 47% as compared to no treatment, without having an effecton tumour uptake of lutetium (177Lu) oxodotreotide. This reduction in renal radiation exposuremitigates 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, was20.1±4.9 Gy, which is below the established threshold for the occurrence of renal toxicities of 23 Gy.

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

Lysakare is intended for intravenous use and is therefore 100% bioavailable.

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 bodyfluid.

Like other naturally occurring amino acids, arginine and lysine serve as building blocks in proteinanabolism and as precursors for several other products, including nitric oxide, urea, creatinine andacetyl-coenzyme A.

Arginine and lysine are rapidly distributed. Based on a study with 30 g arginine infused over30 minutes, plasma elimination of amino acids follows at least a biphasic or triphasic decline, withlevels returning to baseline within 6 hours post-dose. Initial rapid clearance is through glomerularfiltration in the kidney in the first 90 minutes post-infusion. Remaining amino acid is removed by non-renal clearance.

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

There were no non-clinical studies conducted with LysaKare.

Water for injections

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

2 years

Store below 25°C.

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

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 unstableor 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 localrequirements.

Advanced Accelerator Applications8-10 Rue Henri Sainte-Claire Deville92500 Rueil-Malmaison

France

EU/1/19/1381/001

Date of first authorisation: 25 July 2019

Date of latest renewal:

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

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