Cuprymina 925 MBq/mL radiopharmaceutical precursor, solution
1 mL of solution contains 925 MBq of copper (64Cu) chloride at calibration time (01h00 a.m. Central European Time (CET)), corresponding to at least 0.25 micrograms of 64Cu. The calibration time is set between the end of the synthesis time and the expiry time. Each vial contains an activity ranging from 925 MBq to 2,770 MBq (at calibration time) which corresponds to an amount of 0.25 to 0.75 micrograms of Copper-64. The volume varies from 1 to 3 mL. The minimal specific activity is 3,700 MBq Copper-64/micrograms of Copper at the expiry date and time. Copper-64 has a half-life of 12.7 hours. Copper-64 decays by an emission of b+ (17.6 %) with a maximum energy of 0.66 MeV, an emission of b- (38.5 %) with a maximum energy of 0.58 MeV and electronic capture (43.9 %). Copper-64 decays in stable Nickel 64Ni (61 %) by an emission of b+ (18 %) or by an electronic capture (43 %). Copper-64 decays also in stable Zinc (64Zn) by emission of b- (39 %). For the full list of excipients, see section 6.1.
Radiopharmaceutical precursor, solution. Clear, colourless solution, free of particulate matter.
Cuprymina is a radiopharmaceutical precursor. It is not intended for direct use in patients. This medicinal product must be used only for the radiolabelling of carrier molecules, which have been specifically developed and authorised for radiolabelling with this radionuclide.
Cuprymina is only to be used by specialists experienced with in vitro radiolabelling
Posology
The quantity of Cuprymina required for radiolabelling and the quantity of 64Cu-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
64Cu-labelled medicinal products should not be used in children and adolescents up to 18 years. For more information concerning paediatric use of 64Cu-labelled medicinal products refer to the Summary of Product Characteristics/package leaflet of the radiolabelled medicinal product.
Method of administration
Cuprymina is intended for in vitro radiolabelling of medicinal products, which are subsequently administered by the approved route. Cuprymina should not be administered directly to the patient. For instruction on preparation of the product, see section 12.
Cuprymina is contraindicated in the following cases:
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 64Cu-labelled medicinal products prepared by radiolabelling with Cuprymina refer to the Summary of Product Characteristics/package leaflet of each particular medicinal product to be radiolabelled.
Individual benefit/risk justification
Cuprymina 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 organisation. 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 special precautions for use of 64Cu-labelled medicinal products refer to the Summary of Product Characteristics/package leaflet of the medicinal product to be radiolabelled. It must be considered that the radiolabelled medicinal product emits high intensity Auger electrons. Regarding the dose for a person in close contact with the patient, this is entirely due to the gamma rays (Cuprymina emits 2 gamma rays at 511.0 Kev and 1,345.77 Kev), because b+ and b- emissions have no role due to their very short range. The 64Cu gamma dose constant is 3.6 x 10-5 mSv x MBq-1 x h at a distance of 1 meter. Assuming the worst case that the whole maximum activity (2,770 MBq) is injected to the patient and 64Cu is labelled to a molecule with infinite biological half-life (no disposal by the patient) the person is continuously exposed at a distance of 2 meters. With these assumptions the estimated dose for a person in close contact with the patient is 0.46 mSv, which is less than one half of the limit of not exposed people (1 mSv/year). Special precautions for relatives, carers and hospital staff are provided in section 6.6.
Disappearance of radioactivity
Considering that each MBq of 64Cu causes a dose rate of 9 nSv/h (at a distance of 2 meters) and that the maximum injected activity is of 2,770 MBq, the initial dose rate is 24,930 nSv/h. Assuming that the environmental background value is of 150 nSv/h, and requiring that the dose rate due to 64Cu is lower than the environmental background the condition of negligible radioactivity in the patient is reached, in practice, 4 days after injection (dose rate 132 nSv/h) as shown in table 1. Table 1 - Condition of negligible radioactivity in the patients
| Days after injection (2,770 MBq) | 0 | 1 | 2 | 3 | 4 | 5 |
| Dose rate (nSv/h) | 24,930 | 6,727 | 1,815 | 490 | 132 | 37 |
No interactions studies of Copper-64 chloride with other medicinal products have been performed. The possible use of chelating therapies could interfere with the use of 64Cu-labelled medicinal products. For information concerning interactions associated with the use of 64Cu-labelled medicinal products refer to the Summary of Product Characteristics/package leaflet of the radiolabelled medicinal product.
Women of childbearing potential
When an administration of radioactive medicinal products 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 64Cu-labelled medicinal products, pregnancy should be excluded using an adequate/validated test.
Pregnancy
The use of 64Cu-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 the choice of the most appropriate radiopharmaceuticals, bearing in mind the secretion of activity in breast milk. If the administration is considered necessary, a breast-feeding mother should be advised to stop breast-feeding. The duration of stopping will depend on the particular radiolabelled medicinal product. Further information concerning the use of 64Cu-labelled medicinal products in pregnancy and breast- feeding is specified in the Summary of Product Characteristics of the medicinal product to be radiolabelled.
Fertility
According to literature reports, it may be considered that both spermatogenetic and genetic damage in male testis are unlikely at the dose of 1,000 MBq. Further information concerning the effect on fertility of the use of 64Cu-labelled medicinal products is specified in the Summary of Product Characteristics of the medicinal product to be radiolabelled.
Effects on ability to drive and to use machines following treatment by 64Cu-labelled medicinal products is specified in the Summary of Product Characteristics/package leaflet of the particular medicinal product to be radiolabelled.
Adverse reactions following the intravenous administration of 64Cu-labelled medicinal products prepared by radiolabelling with Cuprymina, 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 result. The radiation dose to the patient resulting from exposure after administration 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. Exposure to ionising radiation is linked with cancer induction and a potential for development of hereditary defects.
The presence of free copper (64Cu) chloride in the body after an inadvertent administration of Cuprymina will lead to increased hepatotoxicity. Therefore, in case of an inadvertent administration of Cuprymina, the radiotoxicity for the patient must be reduced by immediate (i. e. within 1 hour) intravenous 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 Cuprymina for labelling of carrier molecules:
Ca-DTPA (Trisodium calcium diethylenetriaminepentaacetate) or
Ca-EDTA (Calcium disodium ethylenediaminetetraacetate)
These chelating agents help elimination of copper radiotoxicity by an exchange between the calcium ion and the copper due to their capacity of forming water soluble complexes with the chelating ligands (DTPA, EDTA). These complexes 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 dextrose, 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, even if 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 damages. The toxicity of the free 64Cu due to in vivo release from the labelled biomolecule in the body during therapy could be reduced by post-administration of chelating agents.
Pharmacotherapeutic group:
Not yet assigned
, ATC code:
Not yet assigned
The pharmacodynamic properties of 64Cu-labelled medicinal products prepared by radiolabelling with Cuprymina, 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 Cuprymina in all subsets of the paediatric population on grounds of lack of significant therapeutic benefit over existing treatments. This waiver does however not extend to any diagnostic or therapeutic uses of the product when linked to a carrier molecule.
The pharmacokinetic properties of 64Cu-labelled medicinal products prepared by radiolabelling with Cuprymina, prior to administration, will be dependent on the nature of the medicinal product to be radiolabelled. Pharmacokinetics of Cuprymina was investigated in mice. Following intravenous administration, at the beginning most organs contained an amount of radioactivity which represented their content of 64Cu-laden blood. Liver, kidney and the intestinal tract reached their maximal content of 64Cu within the first few hours, and then radioactivity steadily diminished. Part of the decrease can be attributed to excretion of 64Cu into the bile, urine and faeces. Blood radioactivity decreased from 60.3 % to 3.4 % after 1 hour, and then it decreased of 1 % after 6 hours, and increased to 5.6 % and 4.9 % after 12-24 hours. Copper chloride (64CuCl2) is distributed mainly in the liver and kidney and the pattern of radioactivity in the blood parallels the pattern of radioactivity in the liver. Almost the entire 64CuCl2 rapidly leaves the blood and enters the liver and kidney. Maximum liver uptake was 4 hours after injection with 57.7 %. Then copper re-emerges in plasma and is distributed to other organs.
Pharmacokinetic data on Cuprymina relate to free copper
When the precursor is bound to a carrier molecule the content of radioactive free copper 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.
The toxicological properties of 64Cu-labelled medicinal products prepared by radiolabelling with Cuprymina prior to administration will be dependent on the nature of the medicinal product to be radiolabelled. No animal toxicity studies were conducted with Cuprymina. Toxicity of copper compounds has been extensively investigated both in human and in animals. Liver, gastrointestinal tract and kidney are the target organs for copper toxicity after single and repeated doses administration. Many international bodies assessed copper genotoxicity and carcinogenicity concluding that there is no conclusive evidence that copper may be mutagenic or carcinogenic The Scientific Committee on Food of the European Commission (2003) recommend a Dietary Allowances of 0.9 mg copper/day in adult males and females and established a Tolerable Upper Uptake level of 5 mg/day, allowing a huge safety margin in comparison to copper amount administered by Cuprymina. Non-clinical data reveal no special hazard for humans based on available published data.
Hydrochloric acid 0.1 N.
Water for injections.
Radiolabelling of carrier molecules, such as peptides, monoclonal antibodies, or other substrates, with Copper (64Cu) 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 compound 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.
24 hours from date and time of End of Synthesis (EOS).
Store in the original package that provides protection from radiation. Storage of radiopharmaceuticals should be in accordance with national regulation on radioactive materials.
The radiopharmaceutical precursor solution is packaged in colourless, type I glass 10 mL vial, closed with bromobutyl rubber stopper and aluminium overseal. The volume of one vial ranges from 1 to 3 mL solution (corresponding to 925 to 2,770 MBq at calibration time). The vials are packed into a tungsten container for protective shielding. Each pack contains 1 vial in a tungsten container.
Cuprymina is not intended for direct use in patients. Cuprymina is a sterile solution.
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 instruction on preparation of the product, see section 12. If at any time in the preparation of this 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 64Cu-radiopharmaceuticals. The use of television monitor systems to monitor the patients is recommended. Given the long half-life of 64Cu 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 with 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.
SPARKLE S.r.l. Contrada Calo snc 73042 Casarano (LE) - Italy Tel: 0039.0833.211348 or 0039.0733.560354 Fax: 0039.0899.831005 or 0039.0733.560376 E-mail: info @sparklepet.it
EU/0/00/000/000
Date of first authorisation: DD/MM/YYYY
MM/YYYY
The radiation dose received by the various organs following intravenous administration of a 64Cu- labelled medicinal product is dependent on the specific molecule being radiolabelled. Information on radiation dosimetry of each different medicinal product following administration of the radiolabelled preparation is available in the Summary of Product Characteristics/package leaflet of the particular medicinal product to be radiolabelled. The dosimetry table below is presented in order to evaluate the contribution of non-conjugated 64Cu to the radiation dose following the administration of 64Cu-labelled medicinal product or resulting from an accidental intravenous injection of Cuprymina. The dosimetry estimates were based on a mouse distribution study and the calculations were effected using OLINDA - Organ Level INternal Dose Assessment Code (see Table 2). Time points for measurements were 2 minutes, 30 minutes, 1 hour, 4 hours, 6 hours, 12 hours, 24 hours, 2 days, 4 days, 6 days. Table 2: Absorbed dose per unit activity administered
| absorbed dose per unit activity administered (mGy/MBq) | |||||||
| organ | adult male (70 kg) | adult female (60 kg) | 15 years | 10 years | 5 years | 1 years | newborn |
| adrenals | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 |
| brain | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 |
| breasts | 0.000596 | 0.000730 | 0.000732 | 0.00133 | 0.00204 | 0.00384 | 0.00776 |
| gallbladder wall | 0.00192 | 0.00230 | 0.00219 | 0.00278 | 0.00453 | 0.00917 | 0.0158 |
| LLI wall | 0.0149 | 0.0160 | 0.0195 | 0.0340 | 0.0569 | 0.112 | 0.291 |
| small Intestine | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 |
| stomach Wall | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 |
| ULI wall | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 |
| heart wall | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 |
| kidneys | 0.00885 | 0.00969 | 0.0107 | 0.0151 | 0.0224 | 0.0401 | 0.106 |
| liver | 0.0211 | 0.0282 | 0.0283 | 0.0436 | 0.0649 | 0.126 | 0.294 |
| lungs | 0.00178 | 0.00233 | 0.00245 | 0.00351 | 0.00526 | 0.00999 | 0.0240 |
| muscle | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 |
| ovaries | 0.00 | 0.00314 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 |
| pancreas | 0.00267 | 0.00310 | 0.00365 | 0.00716 | 0.00955 | 0.0199 | 0.0637 |
| red marrow | 0.00581 | 0.00565 | 0.00670 | 0.0118 | 0.0242 | 0.0586 | 0.198 |
| osteogenic cells | 0.00202 | 0.00269 | 0.00263 | 0.00426 | 0.00718 | 0.0172 | 0.0549 |
| skin | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 |
| spleen | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 |
| testes | 0.0463 | 0.00 | 0.114 | 0.907 | 1.05 | 1.41 | 2.02 |
| thymus | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 |
| thyroid | 0.000129 | 0.000156 | 0.000189 | 0.000292 | 0.000593 | 0.00113 | 0.00178 |
| urinary bladder wall | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 |
| uterus | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 |
| effective dose ( Sv/1 GBq administered) | |||||||
| adult male | adult female | 15 years | 10 years | 5 years | 1 years | newborn | |
| 0.0962 | 0.0712 | 0.168 | 0.854 | 1.05 | 1.56 | 2.73 | |
For this product, the effective dose resulting from an intravenously injected activity of 925 MBq is 65.86 mSv for a 60-kg female adult and 88.99 mSv for a 70-kg male adult.
Before use, packaging and radioactivity must be checked. Activity may be measured using an ionisation chamber. 64Cu is a beta emitter. Activity measurements using an ionisation chamber are very sensitive to geometric factors and, therefore, should be performed only under geometric conditions which have been appropriately validated. Usual precautions regarding sterility and radioactivity must be respected. The vial should never be opened and must be kept inside its tungsten shielding. The product must be aseptically withdrawn through the stopper using sterilised single-use needle and syringe after disinfecting the stopper. Appropriate aseptic precautions must be taken, in order to maintain the sterility of Cuprymina and to maintain sterility throughout the labelling procedures. The administration of radioactive medicinal products creates risks for other persons from external radiation or contamination from spills of urine, vomiting, etc. Radiation protection precautions in accordance with national regulations must therefore be taken. Any unused product or waste material must be disposed of in accordance with local requirements. Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu
ANNEX II
MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
Name and address of the manufacturer(s) responsible for batch release
ACOM S.p.A (Advanced Center Oncology Macerata) Localita Cavallino IT-62010 MONTECOSARO (MC) Italy
CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product Characteristics, section 4.2).
OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance presented in Module 1.8.1. of the Marketing Authorisation is in place and functioning before and whilst the medicinal product is on the market.
Risk Management Plan (RMP)
The MAH shall perform the pharmacovigilance activities detailed in the Pharmacovigilance Plan, as agreed in the Risk Management Plan presented in Module 1.8.2. of the Marketing Authorisation and any subsequent updates of the RMP agreed by the Committee for Medicinal Products for Human Use (CHMP). As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the updated RMP should be submitted at the same time as the next Periodic Safety Update Report (PSUR). In addition, an updated RMP should be submitted
When new information is received that may impact on the current Safety Specification, Pharmacovigilance Plan or risk minimisation activities
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being reached
At the request of the European Medicines Agency.
PSURs
The PSUR cycle for the medicinal product should follow the standard requirements.
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.