Lumark - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

Lumark 80 GBq/mL radiopharmaceutical precursor, solution

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each mL of solution contains 80 GBq lutetium (177Lu) chloride at activity reference time (ART), corresponding to at most a maximum of 160 microgram of lutetium. The ART is defined as the end of production.

Each vial contains a volume varying from 0.1 to 5 mL corresponding to an activity ranging from 8 to

400 GBq (at ART).

The minimal specific activity is 500 GBq/mg lutetium (177Lu) at the ART.

Lutetium (177Lu) has a half-life of 6.647 days. Lutetium (177Lu) is produced by neutron irradiation of enriched lutetium (176Lu). Lutetium (177Lu) decays by P–emission to stable Hafnium (177Hf), with the most abundant P- (79.3%) having a maximum energy of 0.497 MeV. Also low gamma energy is emitted, for instance at 113 keV (6.2%) and 208 keV (11%).

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Radiopharmaceutical precursor, solution.

Clear, colourless solution.

4. CLINICAL PARTICULARS4.1 Therapeutic indications

Lumark is a radiopharmaceutical precursor. It is not intended for direct use in patients. It must be used only for the radiolabelling of carrier molecules, which have been specifically developed and authorised for radiolabelling with this radionuclide.

4.2 Posology and method of administration

Lumark is only to be used by specialists experienced with in vitro radiolabelling.

Posology

The quantity of Lumark required for radiolabelling and the quantity of the medicinal product to be radiolabelled with lutetium(177Lu) that is subsequently administered will depend on the medicinal product to be radiolabelled and its intended use. Refer to the Summary of Product Characteristic­s/package leaflet of the particular medicinal product to be radiolabelled.

Paediatric population

For more information concerning the paediatric use of lutetium (177Lu)-labelled medicinal products refer to the Summary of Products Characteristic­s/package leaflet of the the particular medicinal product to be radiolabelled.

Method of administration

Lumark is intended for in vitro radiolabelling of medicinal products, which are subsequently administered by the approved route.

Lumark should not be administered directly to the patient.

Lumark is for single-use only.

For instructions on extemporary preparation of the medicinal product before administration, see section 12.

4.3 Contraindications

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

• – Established or suspected pregnancy or when pregnancy has not been excluded (see section 4.6).

For information on contraindications to particular lutetium (177Lu)-labelled medicinal products prepared by radiolabelling with Lumark, refer to the Summary of Product Characteristic­s/package leaflet of each particular medicinal product to be radiolabelled.

4.4 Special warnings and precautions for use

Individual benefit/risk justification

For each patient, the radiation exposure must be justifiable by the likely benefit. The activity administered should in every case be as low as reasonably achievable to obtain the required therapeutic effect. Lumark is not to be administered directly to the patient but must be used for the radiolabelling of carrier molecules, such as monoclonal antibodies, peptides or other substrates.

General warnings

Radiopharmace­uticals should be received, used and administered only by authorised persons in designated clinical settings. Their receipt, storage, use, transfer and disposal are subject to the regulations and/or appropriate licences of the competent official authorities.

Radiopharmace­uticals should be prepared by the user in a manner which satisfies both radiation safety and pharmaceutical quality requirements. Appropriate aseptic precautions should be taken.

For information concerning special warnings and precautions for use of 177Lu-labelled medicinal products refer to the Summary of Product Characteristic­s/package leaflet of the medicinal product to be radiolabelled.

Radiation protection

Administration of a high activity (7.400 MBq) of the lutetium(177Lu)-labelled medicinal product results in an average radiation dose rate at 1 m distance from the patient of 4–11 ^Sv/h after 24 hours. This is below the threshold considered acceptable for discharge from the clinic (20 |aSv/h). For a person in the vicinity of the patient, assuming continuous exposure at 2 m and infinite biological half-life (no disposal by the patient after discharge from the hospital), this dose rate will result in an overall dose of approximately 0.6 mSv, which is approximately one half of the dose limit set for general public (1 mSv/year).

Precautions with respect to relatives, carers and hospital staff are provided in section 6.6.

Renal impairment and haematological disorders

Myelodysplastic syndrome and acute myeloid leukaemia

Myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML) have been observed after treatment with lutetium (177 Lu) peptide receptor radionuclide therapy for neuroendocrine tumours (see section 4.8). This should be taken into account when considering the benefit/risk, especially in patients with possible risk factors like prior exposure to chemotherapeutic agents (such as alkylating agents).

Myelosuppression

Anaemia, thrombocytopenia, leucopenia, lymphopenia, and less commonly neutropenia may occur during radioligand therapy with lutetium (177Lu). Most events are mild and transient, but in some cases patients have required blood and platelet transfusions. In some patients more than one cell line may be affected and pancytopenia requiring treatment discontinuation has been described. A blood count should be taken at baseline and monitored regularly during treatment, in accordance with clinical guidance.

Renal irradiation

Radiolabelled somatostatin analogues are excreted by the kidney. Radiation nephropathy has been reported following peptide receptor radionuclide therapy for neuroendocrine tumours using other radioisotopes. Renal function including glomerular filtration rate (GFR) should be assessed at baseline and during treatment and renal protection should be considered, in accordance with clinical guidance of the radiolabelled medicinal product.

Hepatotoxicity

Cases of hepatotoxicity have been reported in the post-marketing setting and in the literature in patients with liver metastases undergoing treatment with 177Lu peptide receptor radionuclide therapy for neuroendocrine tumours. Liver function should be monitored regularly during treatment. Dose reduction may be necessary in affected patients.

Hormone release syndromes

There have been reports of carcinoid crisis and other syndromes associated with release of hormones from functional neuroendocrine tumours following 177Lu peptide receptor radionuclide therapy, which may be related to irradiation of tumour cells. Reported symptoms include flushing and diarrhoea associated with hypotension. Observation of patients by overnight hospitalisation should be considered in some cases (e.g. patients with poor pharmacologic control of symptoms). In case of hormonal crises, treatments may include: intravenous high dose somatostatin analogues, intravenous fluids, corticosteroids, and correction of electrolyte disturbances in patients with diarrhoea and/or vomiting.

Extravasation

There have been reports of extravasation of lutetium (177Lu) labelled ligands in the post-marketing setting. In case of extravasation, infusion of the medicinal product should be immediately ceased, and the nuclear medicine physician and the radiopharmacist should be promptly informed. Management should be in accordance with local protocols.

Tumour lysis syndrome

Tumour lysis syndrome has been reported following Lutetium (177Lu) radioligand therapy. Patients with a history of renal insufficiency and high tumour burden may be at greater risk and should be treated with increased caution. Renal function as well as electrolyte balance should be assessed at baseline and during treatment.

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies of lutetium (177Lu) with other medicinal products have been performed. The possible use of chelating therapies could interfere with the use of lutetium(177Lu)-labelled medicinal products.

For information concerning interactions associated with the use of lutetium (177Lu)-labelled medicinal products refer to the Summary of Product Characteristic­s/package leaflet of the radiolabelled medicinal product.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential

When an administration of radiopharmaceutical to a woman of childbearing potential is intended, it is important to determine whether or not she is pregnant. Any woman who has missed a period should be assumed to be pregnant until proven otherwise. If in doubt about her potential pregnancy (if the woman has missed a period, if the period is very irregular, etc.), alternative techniques not using ionising radiation (if there are any) should be offered to the patient. Before the use of 177Lu -labelled medicinal products, pregnancy should be excluded using an adequate/vali­dated test.

Pregnancy

The use of lutetium (177Lu)-labelled medicinal products is contraindicated during established or suspected pregnancy or when pregnancy has not been excluded (see section 4.3).

Breast-feeding

Before administering radiopharmace­uticals to a mother who is breast-feeding, consideration should be given to the possibility of delaying the administration of radionuclide until the mother has ceased breast-feeding, and to what is the most appropriate choice of radiopharmace­uticals, bearing in mind the secretion of activity in breast milk. If the administration is considered necessary, breast-feeding should be interrupted and the expressed feeds discarded.

Fertility

According to literature reports and taking a conservative approach (maximum patient dose of 10 GBq, average labeling yield and no additional measures), it may be considered that 177Lu-labelled medicinal products do not lead to reproductive toxicity including spermatogenetic damage in male testes or genetic damage in male testes or female ovaries.

Further information concerning the use of 177Lu-labelled medicinal products is specified in the Summary of Product Characteristics of the medicinal product to be radiolabelled.

4.7 Effects on ability to drive and use machines

Effects on ability to drive or use machines following treatment by lutetium (177Lu)-labelled medicinal products is specified in the Summary of Product Characteristic­s/package leaflet of the particular medicinal product to be radiolabelled.

4.8 Undesirable effects

Summary of the safety profile

Adverse reactions following the intravenous administration of lutetium (177Lu)-labelled medicinal products prepared by radiolabelling with Lumark will be dependent on the specific medicinal product being used. Such information is supplied in the Summary of Product Characteristic­s/package leaflet of the medicinal product to be radiolabelled.

For each patient, exposure to ionising radiation must be justifiable on the basis of likely clinical benefit. The activity administered must be such that the resulting radiation dose is as low as reasonably achievable bearing in mind the need to obtain the intended therapeutic result.

Exposure to ionising radiation is linked with cancer induction and a potential for development of hereditary defects. The radiation dose resulting from therapeutic exposure may result in higher incidence of cancer and mutations. In all cases, it is necessary to ensure that the risks of the radiation are less than from the disease itself.

Tabulated list of adverse reactions

Adverse reactions are divided into groups according to the MedDRA convention frequencies: 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).

Adverse drug reaction	Frequency category
Neoplasms benign, malignant and unspecified (including cysts and polyps)
Refractory cytopenia with multilineage dysplasia (Myelodysplastic syndrome) (see section 4.4)	Common
Acute myeloid leukaemia (see section 4.4)	Uncommon
Blood and lymphatic system disorders
Anaemia	Very common
Thrombocytopenia
Leukopenia
Lymphopenia
Neutropenia	Common
Pancytopenia	Not Known
Endocrine disorders
Carcinoid crisis	Not known
Metabolism and nutrition disorders
Tumour lysis syndrome	Not known
Gastrointestinal disorders
Nausea	Very common
Vomiting
Dry mouth	Not Known
Skin and subcutaneous tissue disorders
Alopecia	Very common

Description of selected adverse reactions

Dry mouth has been reported among patients with metastatic castration resistant prostate cancer receiving PSMA-targeted lutetium (177Lu)-labelled radioligands and has been transient.

Alopecia, described as mild and temporary, has been observed among patients receiving lutetium (177Lu) peptide receptor radionuclide therapy for neuroendocrine tumours.

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 listed in

4.9 Overdose

The presence of free lutetium (177Lu) chloride in the body after an inadvertent administration of Lumark will lead to increased bone marrow toxicity and haematopoetic stem cell damage. Therefore, in case of an inadvertent administration of Lumark, the radiotoxicity for the patient must be reduced by immediate (i.e. within 1 hour) administration of preparations containing chelators like Ca-DTPA or Ca- EDTA in order to increase the elimination of the radionuclide from the body.

The following preparations must be available in medical institutions, which use Lumark for radiolabelling of carrier molecules for therapeutic purposes:

• – Ca-DTPA (Trisodium calcium diethylenetri­aminepentaace­tate) or

• – Ca-EDTA (Calcium disodium ethylenediami­netetraacetate)

These chelating agents help with the elimination of lutetium (177Lu) radiotoxicity by an exchange between the calcium ion in the complex and the lutetium (177Lu) ion. Due to the capacity of the chelating ligands (DTPA, EDTA) of forming water soluble complexes, the complexes and bound lutetium(177Lu) are rapidly eliminated by the kidneys.

1 g of the chelating agents should be administered by slow intravenous injection over 3–4 minutes or by infusion (1 g in 100–250 mL of glucose, or sodium chloride 9 mg/mL (0.9%) solution for injection).

The chelating efficacy is greatest immediately or within one hour of exposure when the radionuclide is circulating in or available to tissue fluids and plasma. However, a post-exposure interval >1 hour does not preclude the administration and effective action of chelator with reduced efficiency. Intravenous administration should not be protracted over more than 2 hours.

In any case the blood parameters of the patient have to be monitored and the appropriate actions immediately taken if there is evidence of damage to the blood marrow.

The toxicity of the free lutetium (177Lu) due to in vivo release from the labelled biomolecule in the body during therapy could be reduced by post-administration of chelating agents.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Not yet assigned, ATC code: Not yet assigned

Lutetium (177Lu) chloride is produced by irradiation of 176Lu with neutrons. It decays by emission of beta radiation of maximal 498 keV to 177Hf-Hafnium. 177Lu-lutetium has a half-life of 6.647 days.

The pharmacodynamic properties of lutetium (177Lu)-labelled medicinal products prepared by radiolabelling with Lumark, prior to administration, will be dependent on the nature of the medicinal product to be radiolabelled. Refer to the Summary of Product Characteristic­s/package leaflet of the particular medicinal product to be radiolabelled.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of the studies with Lumark in all subsets of the paediatric population on grounds that the specific medicinal product is likely to be ineffective or unsafe in part or all of the paediatric population and on grounds that the specific medicinal product does not represent a significant therapeutic benefit over existing treatments for the paediatric patients. This waiver does however not extend to any diagnostic or therapeutic uses of the medicinal product when linked to a carrier molecule (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

The pharmacokinetic properties of lutetium (177Lu)-labelled medicinal products prepared by radiolabelling with Lumark, prior to administration, will be dependent on the nature of the medicinal product to be radiolabelled.

Distribution

Pharmacokinetics of lutetium (177Lu) was investigated in rats and mice. The distribution and mineral concentrations in the organs were investigated at low (9–10 mg/kg) and high (19–20 mg/kg) doses administered intravenously to rats. It appeared that more than 78% of the doses was distributed into liver, bone and spleen. For lutetium (177Lu) the different dose levels did not result in significantly different uptake with 65% appearing in the liver, 5.3% in the spleen and 13% in the bones at one day after administration. With respect to the distribution pattern in blood it appeared that 2 h after administration 15% of the lutetium as being present in blood, had entered the blood cells with the remaining 85% still being present in the serum.

A more detailed study of the biodistribution of lutetium (177Lu) chloride in mice confirms the relatively high uptake in the liver, kidneys and bone marrow The results indicated that lutetium (177Lu) chloride is accumulated in the bone marrow and emphasizes the importance of all lutetium (177Lu) to be peptide-bound at injection, as well as the in-vivo stability of the radionuclide-chelate-complex during therapy.

Pharmacokinetic data on Lumark related to free lutetium

When the precursor is bound to a carrier molecule the content of radioactive free lutetium (177Lu) is supposed to be less than the stated amounts depending on the carrier used. Relevant data is included in the Summary of Product Characteristics of the labelled medicinal products.

5.3 Preclinical safety data

The toxicological properties of lutetium (177Lu)-labelled medicinal products prepared by radiolabelling with Lumark prior to administration, will be dependent on the nature of the medicinal product to be radiolabelled.

No animal toxicity studies were conducted with Lumark.

The toxicity of lutetium (177Lu) chloride has been studied in different mammals and using different administration routes. Intraperitoneal administration resulted in generalised peritonitis with adhesion and accumulation of some ascetic fluid. By intraperitoneal route, the LD50 is approximately 300 mg/kg in mice and rats. By intravenous route, the LD50 in rats and mice ranges between 30 and 60 mg/kg. Intravenously administrated doses resulted in varying effects on the blood pressure and a decreased heart rate. Electrocardiograms showed no irregularities in cardiac rhythm or conduction. Effects of the respiration were slight and variable. No gross differentiating changes were found of the tissues demonstrating no evidence of acute damage resulting from the experiment. The studies suggest that the intravenous toxicity of the ionic compounds of the rare earth elements would decrease with atomic weight resulting in lutetium (177Lu) being the least toxic of the series.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Hydrochloric acid

Water for injections

6.2 Incompatibilities

Radiolabelling of carrier molecules, such as monoclonal antibodies, peptides or other substrates, with lutetium (177Lu) chloride is very sensitive to the presence of trace metal impurities.

It is important that all glassware, syringe needles, etc., used for the preparation of the radiolabelled medicinal product are thoroughly cleaned to ensure freedom from such trace metal impurities. Only syringe needles (for example non-metallic) with proven resistance to dilute acid should be used to minimise trace metal impurity levels.

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

6.3 Shelf life

8 days from the date of ART (= end of production).

6.4 Special precautions for storage

Store in the original package in order to protect from radiation.

Storage of radiopharmace­uticals should be in accordance with national regulations for radioactive materials.

6.5 Nature and contents of container

The radiopharmaceutical precursor solution is packaged in a colourless type I glass vial of 10 mL, closed with a bromobutylrubber stopper and aluminium overseal.

Each vial contains a volume varying from 0.1 to 5 mL corresponding to an activity ranging from 8 to 400 GBq at the ART.

The vials are placed in a lead container for protective shielding and packed in a plastic jar.

Each pack contains one vial in a lead container.

6.6 Special precautions for disposal and other handling

Lumark is not intended for direct use in patients.

Radiopharmace­uticals should be received, used and administered only by authorised persons in designated clinical settings. Their receipt, storage, use, transfer and disposal are subject to the regulations and/or appropriate licences of the competent official organisation.

Radiopharmace­uticals should be prepared in a manner, which satisfies both radiation safety and pharmaceutical quality requirements. Appropriate aseptic precautions should be taken.

For instruction on extemporary preparation of the medicinal product before administration, see section 12.

If at any time in the preparation of this medicinal product the integrity of this container is compromised it should not be used.

Administration procedures should be carried out in a way to minimise risk of contamination of the medicinal product and irradiation of the operators. Adequate shielding is mandatory.

The surface dose rates and the accumulated dose depend on many factors. Measurements on the location and during work are critical and should be practiced for more precise and instructive determination of overall radiation dose to the staff. Healthcare personnel are advised to limit the time of close contact with patients injected with lutetium (177Lu)-radiopharmace­uticals. The use of television monitor systems to monitor the patients is recommended. Given the long half-life of lutetium (177Lu) it is specially recommended to avoid internal contamination. For this reason it is mandatory to use protective high quality (latex/nitrile) gloves in any direct contact with the radiopharmaceutical (vial/syringe) and with the patient. For minimising radiation exposure resulting from repeated exposure, there is no specific recommendation except the strict observance of the above ones.

The administration of radiopharmace­uticals creates risks for other persons from external radiation or contamination from spill of urine, vomiting, etc. Radiation protection precautions in accordance with national regulations must therefore be taken.

Lumark is for single use only.

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

7. MARKETING AUTHORISATION HOLDER

I.D.B. Holland B.V.

Weverstraat 17

5111 PV Baarle-Nassau

The Netherlands

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/15/1013/001

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 19 June 2015

Date of latest renewal: 23 April 2020