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. It should therefore only be administered by a healthcare professional experienced in the use of PRRT.

Posology

Adults

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

Antiemetics

Pre-treatment with an antiemetic 30 minutes prior to the start of LysaKare infusion is recommended to reduce the incidence of nausea and vomiting. In case of severe nausea or vomiting during the infusion of LysaKare despite administration of a preventive antiemetic, an antiemetic of a different pharmacological class can be administered.

Please refer to the full prescribing information of the antiemetic for administration instructions.

Special populations

Elderly

There are limited data on the use of LysaKare in patients aged 65 years or above.

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

Hepatic impairment

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

Renal impairment

Due to the potential for clinical complications related to volume overload and an increase in serum potassium associated with the use of LysaKare, this medicinal 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, due to a potential increased risk of transient hyperkalaemia in these patients. The pharmacokinetic profile and safety of lutetium (177Lu) oxodotreotide in patients with baseline severe renal impairment (creatinine clearance <30 mL/min by Cockcroft-Gault formula) or end-stage renal disease have not been studied. Treatment with lutetium (177Lu) oxodotreotide in patients with kidney failure with creatinine clearance <30 mL/min is contraindicated. Treatment with lutetium (177Lu) oxodotreotide in patients with baseline creatinine clearance <40 mL/min (using Cockcroft-Gault formula) is not recommended. No dose adjustment is recommended for renally impaired patients with baseline creatinine clearance ≥40 mL/min and the benefit/risk balance for these patients will therefore always need to be weighed carefully. This 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 aged less than 18 years have not been established.

No data are available.

Method of administration

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.

Infusion of LysaKare and lutetium (177Lu) oxodotreotide through a separate venous access in each of the patient's arms is the preferred method. However, if two intravenous lines are not possible due to poor venous access or institutional/clinical preference, LysaKare and lutetium (177Lu) oxodotreotide may be infused through the same line via a three-way valve, taking into consideration flow rate and maintenance of venous access. The dose of the amino acid solution should not be decreased even if a reduced dose of lutetium (177Lu) oxodotreotide is administered.

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

A transient increase in serum potassium levels occurs in most patients receiving LysaKare, with maximum serum potassium levels reached approximately 4 to 5 hours after the start of infusion and usually returning to normal levels by 24 hours after the start of the amino acid solution infusion. Such increases are generally mild and transient. Patients with reduced creatinine clearance may be at increased risk for transient hyperkalaemia (see “Renal impairment” in section 4.4).

Serum potassium levels must be tested before each administration of LysaKare. If hyperkalaemia is determined, the patient's history of hyperkalaemia and any concomitant medicinal product should be checked. Hyperkalaemia must be corrected accordingly before the infusion is started (see sections 4.3 and 5.1).

In case of clinically significant hyperkalaemia, patients should be retested prior to LysaKare infusion to confirm that hyperkalaemia has been successfully corrected (see section 5.1). Patients 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 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 encouraged to remain hydrated and to urinate frequently before, on the day of and the day after administration (e.g. 1 glass of water every hour) to facilitate elimination of excess serum potassium.

If 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.

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 in serum potassium associated with the use of 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 each administration.

Care should be taken with LysaKare use in patients with creatinine clearance between 30 and 50 mL/min, due to a potential increased risk of transient hyperkalaemia in these patients. The pharmacokinetic profile and safety of lutetium (177Lu) oxodotreotide in patients with baseline severe renal impairment (creatinine clearance <30 mL/min by Cockcroft-Gault formula) or end-stage renal disease have not been studied. Treatment with lutetium (177Lu) oxodotreotide in patients with kidney failure with creatinine clearance <30 mL/min is contraindicated. Treatment with lutetium (177Lu) oxodotreotide in patients with baseline creatinine clearance <40 mL/min (using Cockcroft-Gault formula) is not recommended. No dose adjustment is recommended for renally impaired patients with baseline creatinine clearance ≥40 mL/min and the benefit/risk balance for these patients will therefore always need to be weighed carefully. This should include consideration of an increased risk for transient hyperkalaemia in these patients.

Hepatic impairment

The use of arginine and lysine has not been studied in patients with severe hepatic impairment. Liver function (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 of either total bilirubinaemia >3 times the upper limit of normal or a combination of albuminaemia <30 g/L and international normalised ratio (INR) >1.5 during treatment. Treatment with lutetium (177Lu) oxodotreotide is not recommended in these circumstances.

Heart failure

Due to the 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 IV in the New York Heart Association (NYHA) classification.

Treatment with lutetium (177Lu) oxodotreotide is not recommended for patients with severe heart failure defined as class III or IV in the NYHA classification. The benefit/risk balance for these patients will therefore always need to be weighed carefully, taking into consideration the volume and osmolality of LysaKare solution.

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. Metabolic acidosis was also observed with LysaKare based on laboratory parameters only, which usually resolved within 24 hours of administration, and without clinical symptoms.

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

4.6. Fertility, pregnancy and lactation

Women of childbearing potential

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

Contraception in males and females

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

Pregnancy

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 when pregnancy has not been excluded due to the risk associated with the ionising radiation. Please also refer to section 4.6 of the lutetium (177Lu) oxodotreotide SmPC for further guidance specific to treatment with lutetium (177Lu) oxodotreotide.

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

Breast-feeding

Arginine and lysine, being naturally occurring amino acids, are excreted in human milk, but effects on breast-fed 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 limited data on the safety profile of arginine and lysine solution for infusion without concomitant administration of PRRT (see section 5.1), 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 involving amino acid solutions that had the same composition as LysaKare with regard to amino acid content. These studies included 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 MedDRA system organ class and by 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 reactions

Adverse 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, elimination should be promoted by forced diuresis and frequent bladder voiding.