EndolucinBeta - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

EndolucinBeta 40 GBq/mL radiopharmaceutical precursor, solution

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

1 mL of solution contains 40 GBq Lutetium (177Lu) chloride on activity reference time (ART), corresponding to 10 micrograms of Lutetium (177Lu) (as chloride).

The ART is 12:00 pm (noon) on the scheduled day of radiolabelling as indicated by the customer and can be within 0 to 7 days starting from the day of manufacture.

Each 2 mL vial contains an activity ranging from 3 – 80 GBq, corresponding to 0.73 – 19 micrograms of Lutetium (177Lu), at ART. The volume is 0.075 – 2 mL.

Each 10 mL vial contains an activity ranging from 8 – 150 GBq, corresponding to 1.9 –36 micrograms of Lutetium (177Lu), at ART. The volume is 0.2 – 3.75 mL.

The theoretical specific activity is 4,110 GBq/mg of Lutetium (177Lu). The specific activity of the medicinal product at ART is indicated on the label and always greater than 3,000 GBq/mg.

Non carrier added (n.c.a.) Lutetium (177Lu) chloride is produced by the irradiation of highly enriched (> 99 %) Ytterbium (176Yb) in neutron sources with a thermal neutron flux between 1013 and 1016 cm-2 s-1. The following nuclear reaction is ongoing in the irradiation: 176Yb(n, y) 177Yb ^ 177Lu

The produced Ytterbium (177Yb) with a half-life of 1.9 h decays to Lutetium (177Lu). In a chromatographic process, the accumulated Lutetium (177Lu) is separated chemically from the original target material.

Lutetium (177Lu) emits both medium-energy beta particles and imageable gamma photons, and has a half-life of 6.647 days. The primary radiation emissions of Lutetium (177Lu) are shown in Table 1.

Lutetium (177Lu) decays by emission of beta radiation to stable Hafnium (177Hf).

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

EndolucinBeta is a radiopharmaceutical precursor, and it is not intended for direct use in patients. It is to be used only for the radiolabelling of carrier molecules that have been specifically developed and authorised for radiolabelling with Lutetium (177Lu) chloride.

4.2 Posology and method of administration

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

Posology

The quantity of EndolucinBeta required for radiolabelling and the quantity of

Lutetium (177Lu)-labelled medicinal product that is subsequently administered will depend on the medicinal product 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 paediatric use of Lutetium (177Lu)-labelled medicinal products refer to the Summary of Product Characteristic­s/Package Leaflet of the medicinal product to be radiolabelled.

Method of administration

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

EndolucinBeta should not be administered directly to the patient.

For instructions on 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 EndolucinBeta, refer to the Summary of Product Characteristic­s/Package Leaflet of the 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.

EndolucinBeta is not to be administered directly to the patient, but must be used for the radiolabelling of carrier molecules, such as monoclonal antibodies, peptides, vitamins or other substrates.

Renal impairment and haematological disorders

Careful consideration of the benefit risk ratio in these patients is required since an increased radiation exposure is possible. It is recommended to perform individual radiation dosimetry assessments of specific organs, which may not be the target organ of therapy.

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 Lutetium (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 Lutetium (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.

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.

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.

Radiation protection

Point-source approximation shows that the average dose rate experienced 20 hours after administration of a dose of 7.3 GBq EndolucinBeta labelled radiopharmaceutical (residual radioactivity 1.5 GBq) by a person at 1 meter distance from the patient’s body centre with an abdominal radius of 15 cm is 3.5 ^Sv/h. Doubling the distance to the patient to 2 meters reduces the dose rate by a factor of 4 to 0.9 ^Sv/h. The same dose in a patient with an abdominal radius of 25 cm yields a dose rate at 1 meter of 2.6 ^Sv/h. The generally accepted threshold for discharge of the treated patient from the hospital is 20 ^Sv/h. In most countries, the exposure limit for hospital staff is set the same as for the general public at 1 mSv/year. When taking the 3.5 ^iSv/h dose rate as an average, this would allow hospital staff to work approx. 300 hours/year in close vicinity of patients treated with EndolucinBeta labeled radiopharmace­uticals without wearing radiation protection. Of course, the nuclear medicine staff is expected to wear standard radiation protection.

Any other person in close vicinity of the treated patient should be informed about possibilities to reduce his/her exposure due to radiation emitted from the patient.

Specific warnings

For information concerning special warnings and special precautions for use of Lutetium (177Lu)-labelled medicinal products refer also to the Summary of Product Characteristic­s/Package Leaflet of the medicinal product to be radiolabelled.

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

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies of Lutetium (177Lu) chloride with other medicinal products have been performed.

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 medicinal product to be radiolabelled.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential

When an administration of radiopharmace­uticals 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 due to the risk of ionizing radiation to the foetus (see section 4.3).

Breast-feeding

Before administering radiopharmace­uticals to a mother who is breastfeeding, consideration should be given to the possibility of delaying the administration of radionuclide until the mother has ceased breastfeeding, 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, breastfeeding 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 Lutetium (177Lu)-labelled medicinal products concerning fertility is specified in the Summary of Product Characteristic­s/Package Leaflet of the medicinal product to be radiolabelled.

4.7 Effects on ability to drive and use machines

Effects on ability to drive and to use machines following treatment by Lutetium (177Lu)-labelled medicinal products will be specified in the Summary of Product Characteristic­s/Package Leaflet of the medicinal product to be radiolabelled.

4.8 Undesirable effects

Summary of the safety profile

Adverse reactions following the administration of a Lutetium (177Lu)-labelled medicinal product prepared by radiolabelling with EndolucinBeta will be dependent on the specific medicinal product being used. Such information will be supplied in the Summary of Product Characteristic­s/Package Leaflet of the medicinal product to be radiolabelled.

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.

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).

Tabulated list of adverse reactions

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.

Skin and subcutaneous tissue disorders: 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 EndolucinBeta will lead to increased bone marrow toxicity and haematopoietic stem cell damage. Therefore, in case of an inadvertent administration of EndolucinBeta, 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 EndolucinBeta for labelling 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.

One gram 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 radiotoxicity.

The toxicity of 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: Other therapeutic radiopharmace­uticals, ATC code: V10X

The pharmacodynamic properties of Lutetium (177Lu)-labelled medicinal products prepared by radiolabelling with EndolucinBeta, 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.

Lutetium (177Lu) emits P-particles of moderate maximum energy (0.498 MeV) with a maximum tissue penetration of approximately 2 mm. Lutetium (177Lu) also emits low-energy Y-rays which allow scintigraphic, biodistribution and dosimetry studies with the same Lutetium (177Lu)-labelled medicinal products.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of the studies with EndolucinBeta in all subsets of the paediatric population on grounds that the specific medicinal product does not represent a significant therapeutic benefit over existing treatments for paediatric patients. This waiver does however not extend to any 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 EndolucinBeta, prior to administration, will be dependent on the nature of the medicinal product to be radiolabelled.

Distribution after inadvertent intravenous administration of Lutetium ( 177 Lu) chloride

In the male and female rat, following intravenous administration, Lutetium (177Lu) chloride is rapidly cleared from the blood: at 5 min post injection, only 1.52 % of the injected activity (%ID) is found in blood (corresponding to 0.08 %ID/g) and no activity above background levels remains 1 h post dose. Lutetium (177Lu) chloride distributes mainly to the liver, spleen and bone. After one hour, the amount in the liver is 9.56 % of the injected activity per gram (%ID/g) and in the spleen 5.26 %ID/g. In bone, the content increases from 0.01 %ID/g at 5 min to 0.23 %ID/g after 12 h. For the next 28 days, further uptake of Lutetium (177Lu) can be observed in the bone, which is compensated in part by radioactive decay. Taking into account the radioactive half-life of Lutetium (177Lu) of 6.647 days, the radioactivity remaining in the bone after 28 days is only about 0.06 %ID/g.

Faecal and urinary elimination is slow. As a result of both excretion and radioactive decay, the total radioactivity remaining in the body after 28 days is about 1.8 % of the injected dose.

5.3 Preclinical safety data

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

The toxicity of non-radioactive Lutetium chloride has been studied in different mammalian species and using different administration routes. The intraperitoneal LD50 in mice was found to be approximately 315 mg/kg. In cats, no pharmacological effects on respiration and cardiovascular function were observed up to a cumulative intravenous dose of 10 mg/kg. A high dose of 10 GBq of Lutetium (177Lu)-chloride contains 2.4 ^g Lutetium, corresponding to a human dose of 0.034 ^g/kg. This dose is approximately 7 orders of magnitude lower than the intraperitoneal LD50 in mice and more than 5 orders of magnitude lower than the NOEL observed in cats. Therefore, Lutetium metalion toxicity of EndolucinBeta-labelled medicinal products can be excluded.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Hydrochloric acid, diluted

6.2 Incompatibilities

Radiolabelling of medicinal products, such as monoclonal antibodies, peptides, vitamins 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

Up to 9 days from the date of manufacture.

From a microbiological point of view, unless the method of withdrawal from the vial or any insertion into the vial preclude the risk of microbial contamination, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.

6.4 Special precautions for storage

Store in the original package in order to avoid unnecessary radiation exposure.

Storage of radiopharmace­uticals should be in accordance with national regulation on radioactive materials.

This medicinal product does not require any special temperature storage conditions.

6.5 Nature and contents of container

Colourless type I glass 2 mL or 10 mL vial with a V-shaped and flat bottom, respectively, with a bromobutyl stopper, closed with an aluminium seal.

The vials are placed into a lead container for protective shielding and packed in a metallic can and an outer carton.

Pack size: 1 vial

6.6 Special precautions for disposal and other handling

EndolucinBeta is not intended for direct use in patients.

General warning

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 instructions 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)-labelled 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 exposition there is no 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.

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

7. MARKETING AUTHORISATION HOLDER

ITM Medical Isotopes GmbH

Lichtenbergstrasse 1

D-85748 Garching

Germany

8. MARKETING AUTHORISATION NUMBER(S)

2 mL vial: EU/1/16/1105/001

10 mL vial: EU/1/16/1105/002

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 6 July 2016 Date of latest renewal: