ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS

Transcription

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 3

2 1. NAME OF THE MEDICINAL PRODUCT INDIMACIS 125 Kit for the preparation of the monoclonal antibody Igovomab 111 In infusion. 2. QUALITATIVE AND QUANTITATIVE COMPOSITION The kit for the preparation of the monoclonal antibody Igovomab (OC 125 F(ab') 2 - DTPA) 111 In infusion consists of two ampoules, each containing 1.1 ml of a sterile, pyrogen-free solution with the following composition : Monoclonal antibody Igovomab : 1 mg DTPA (diethylenetriaminopentaacetic acid ) : 9.8 µg 0.1M Saline acetate buffer ph 5.0 : Up to 1 ml This product is to be used after the labelling with a sterile, pyrogen-free indium [ 111 In] chloride solution with a radioactive concentration of 370 MBq/ml at the reference date stated on the label (calibration date). 3. PHARMACEUTICAL FORM Solution for infusion Single-dose ampoules 4. CLINICAL PARTICULARS 4.1. Therapeutic indications Positive diagnosis of relapsing ovarian adenocarcinoma when serum CA 125 is increased without positive results of ultrasound or computerised tomography scan Posology and method of administration The average radioactivity administered is 111 MBq for a 70 kg adult. After labelling the product must be administered slowly over minutes. This may be achieved by injection into a 100 ml 0.9 % sodium chloride infusion bag. Immunoscintigraphy protocol A tomoscintigraphic image of the pelvis and abdomen is acquired 2 to 3 days after the injection. Planar scintigraphy is performed 3 days after injection, and can be repeated between the 4th and 7th day. Acquisition time is 10 minutes per image in the planar mode and 40 minutes in the tomographic mode. In the planar mode, images are as follows : Pelvis : anterior and posterior images Abdomen :anterior and posterior images Two hours before the immunoscintigraphy recording, it is possible to proceed with intravenous injection of 99m Tc oxidronate injection, or 99m Tc medronate injection, to obtain anatomic osseous reference points which 4

3 may facilitate the localisation of an immunoscintigraphic focus. This proceeding results in an additional irradiation of the whole body and skeleton, similar to that produced by a standard scanning Contra-indications The preparation must not be administered to pregnant or nursing women, and to persons with a known history of hypersensitivity to components of the product (particularly hypersensitivity to mouse proteins) Special warnings and special precautions for use This test should not be repeated in the same patient as no data in patients with repeated INDIMACIS 125 imaging are available. The investigation should not be performed within 1 month following therapy of ovarian cancer in order to obtain interpretable results. The per site analysis in patients with elevated serum CA 125 levels shows the following results : at the abdominal site, sensitivity, specificity, positive predictive value and negative predictive value are respectively 80 %, 82 %, 91 % and 66 %; at the pelvic site, they are respectively 91 %, 84 %, 94 % and 78 %. For detection of lesions above 2 cm in patients with elevated serum CA 125 levels, the sensitivity of the INDIMACIS 125 immunoscintigraphy is 93 %. The size of the smallest lesion detected and confirmed is 1.8 cm. False positive responses have been observed in approximately 4.4 % of patients. In case of auto-immunisation by human anti-murine antibodies (HAMA), the determination of serum CA 125 levels can be performed directly on serum samples using IMX CA 125 ABBOTT kit. The use of other tests needs a preliminary HAMA extraction by filtrating serum samples through a protein G column. The preparation is administered by intravenous route by slow infusion under clinical monitoring to prevent and treat any possible hypersensitivity reaction (although no such side-effects have been observed in the clinical context). Radiopharmaceuticals should only be used by qualified personnel with the appropriate government authorisation for the use and manipulation of radionuclides. This radiopharmaceutical may be received, used and administered only by authorised persons in designated clinical settings. Its receipt, storage, use, transfer and disposal are subject to the regulations and/or appropriate licences of the local competent official organisations. Radiopharmaceuticals should be prepared by the user in a manner which satisfies both radiation safety and pharmaceutical requirements. Appropriate aseptic precautions should be taken, complying with the requirements of Good Manufacturing Practice for pharmaceuticals. 5

4 4.5. Interaction with other medicinal products and other forms of interaction No drug interactions have been described to date. For the drugs used in ovarian cancer, there is no transport interaction related to the expression or not of the CA 125 and its level. The potential for interference between INDIMACIS 125 and chemotherapy does not arise because immunoscintigraphy is indicated in patients who have discontinued this treatment for at least one month Use during pregnancy and lactation The preparation must not be administered to pregnant or nursing women. When it is necessary to administer radioactive medicinal products to women of childbearing potential, information should always be sought about pregnancy. Any woman who has missed a period should be assumed to be pregnant until proven otherwise. Where uncertainty exists, it is important that radiation exposure should be the minimum consistent with achieving the desired clinical information. Alternative techniques which do not involve ionising radiation should be considered Effects on ability to drive and use machines Effects on the ability to drive and use machines are not expected Undesirable effects At the clinical level, no severe undesirable effects, related to allergic effects, have been reported in over 400 patients injected with this product. At the biological level, auto-immunisation by human anti-murine antibodies (HAMA) has been reported, in about one quarter of patients, most often on the 30th day after the injection of the product. This autoimmunisation presents no clinical risk for the patient, but presents two potential drawbacks : 1) Possible alteration in the diagnostic performance of subsequent immunoscintigraphies, 2) Possible interference with the serum CA 125 antigen assay, leading to erroneously high levels of this tumour marker. For each patient, exposure to ionising radiation must be justifiable on the basis of likely 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 diagnostic or therapeutic result. Exposure to ionising radiation is linked with cancer induction and a potential for development of hereditary defects. For diagnostic nuclear medicine investigations the current evidence suggests that these adverse effects will occur with low frequency because of the low radiation doses incurred; the EDE (effective dose equivalent) resulting from an administered activity of 111 MBq is 32.2 msv for this product Overdose In the event of the administration of a radiation overdose with the monoclonal antibody Igovomab 111 In, the absorbed dose to the patient should be reduced when possible by increasing the urinary elimination of the radionuclide from the body. 5. PHARMACOLOGICAL PROPERTIES 6

5 5.1. Pharmacodynamic properties Pharmaco-therapeutic group : diagnostic radiopharmaceutical for tumour detection, ATC code: V091 B03. At the chemical concentrations and radioactivities used for diagnostic procedure, the monoclonal antibody Igovomab 111 In does not appear to exert any pharmacodynamic effects Pharmacokinetic properties Serum radioactivity related to the OC 125 F(ab') 2 fragments decreases in keeping with a monoexponential curve, with a distribution volume close to the plasma volume (2.4 litres). Serum radioactivity shows limited extra-plasmatic diffusion. The plasma half-life is 21 ± 8.6 hours. Plasma clearance is slow : litres per hour. This slow plasma clearance accounts for the fact that quality images cannot be obtained before the 3rd and 4th days after administration of the product. 24 hours after injection, a second serum decrease in the labelled antibody is observed, this decay amounts to about 6 % per day. Thirty minutes after intravenous injection, the product is concentrated in the liver, kidneys and spleen. Marked hepatic accumulation occurs instantly, followed by a slow decrease over time (12 % of the injected radioactivity at 24 hours). The high physiological hepatic uptake of 111 In prohibits a reliable judgement of the presence or absence of liver metastases. Splenic and renal bindings rates are respectively 1.1 and 3.6 % at 24 hours. Elimination of the product is urinary at the rate of 0.26 % of the injected radioactivity per hour. Elimination is faster during the first 8 hours, and proceeds via glomerular filtration of the DTPA- 111 In. Subsequent elimination occurs as several metabolites. Radioactivity bound at the target tissue level is relatively low : from 0.08 to % of the injected radioactivity per tumoral gram. Nevertheless, this level appears sufficient in clinical practice for immunoscintigraphy to present adequate contrast with good tumoral detection sensitivity. The tumoral versus non tumoral tissue binding ratios have been estimated at more than 15 in certain cases. Immunoreactivity has not been studied after 5 days Preclinical safety data Toxicological studies with mice have demonstrated that with a single injection of 12.5 mg/kg no deaths were caused. Toxicity with repeated administration of 0.5 mg/kg/day over 14 days in rabbits was not observed. This product is not intended for regular or continuous administration. Mutagenicity studies (AMES test) do not reveal any mutagenic potential. Long-term carcinogenicity studies have not been carried out. 7

6 5.4. Radiation dosimetry Indium [ 111 In] is a cyclotron product emitting X (23 to 26.6 kev, 82.4 %) and γ (171 kev, 90% and 245 kev, 94 %) rays, which decays by electron capture into stable 111 Cd with a period of 2.8 days. The radioactivity due to indium [ 114m In] is not greater than 0.2 % of the total radioactivity. Indium [ 114m In] has a period of 50 days and the main γ rays emitted have energies of kev, kev and kev. The doses absorbed by an adult after the administration of the monoclonal antibody Igovomab 111 In injection are presented in the following table : ORGANS UPTAKE (%) ABSORBED DOSE mgy.mbq -1 LIVER 15.1 ± SPLEEN 1.3 ± KIDNEY 3.5 ± REST OF THE BODY 80.1 ± * Uptake calculated for SPECT imaging (3 days after the administration). For this product the effective dose equivalent resulting from an administered radioactivity of 111 MBq is typically 32.2 msv (per 70 kg individual). For an administered radioactivity of 111 MBq, typical radiation doses to the liver, spleen and kidney are 83, 66 and 54 mgy respectively. 6. PHARMACEUTICAL PARTICULARS 6.1. List of excipients Composition of the 0.1 M saline acetate buffer ph 5.0 : -Sodium acetate trihydrate -Acetic acid -0.9 % sodium chloride solution 6.2. Incompatibilities None known 6.3. Shelf-life The expiry date for this product is 12 months from the day of manufacture. The expiry date is indicated on each vial and on the outer packaging. The expiry date for the labelled product is 24 hours after labelling. 8

7 6.4. Special precautions for storage The product should be stored at a temperature ranging between 2 and 8 C in its original packaging. The labelled product should be stored at a temperature ranging between 15 and 25 C Nature and content of container 2 ml, colourless, European Pharmacopoeia type I glass, self-breaking ampoules Instructions for use, handling and disposal Method of preparation Usual precautions regarding sterility and radioprotection should be respected. Take an ampoule from the kit. Break the neck and, using a hypodermic syringe, remove the monoclonal antibody Igovomab solution and introduce it through the rubber stopper of the vial containing 0.3 ml (111 MBq) of a sterile and pyrogen-free indium [ 111 In] chloride solution (with radioactive concentration of 370 MBq/ml, at the reference date stated on the label). The indium [ 111 In] chloride solution should comply with the specifications laid down in the European Pharmacopoeia draft monograph for «Indium [ 111 In] chloride solution», particularly those concerning metallic elements such as : Cd : 0.40 µg/ml Cu : 0.15 µg/ml Fe : 0.60 µg/ml Stir slowly for about 30 minutes. The obtained preparation is a clear and colourless solution. Before use, limpidity of the solution, radioactivity and gamma spectrum will be checked. The vial should never be opened and must be kept inside its lead shielding. The solution should be removed aseptically through the stopper with a sterile protected syringe. Quality control The quality of labelling (radiochemical purity) can be checked according the following procedure : Method : Instant Thin Layer Chromatography. Materials and reagents : Gelman ITLC SG : Silica gel impregnated glass fibre sheets (20 cm x 2 cm). Trace at 3 cm from one of the ends of the sheet, a fine line called "deposit line", and an other line at 14 cm from the edge called " solvent line". Mobile phase : 0.1M citrate buffer ph 4.0. Glass tank of suitable size for the chromatographic paper used, ground at the top to take a closely fitting lid. At the top of the tank is a device which suspends the chromatographic paper and is capable of being lowered without opening the chamber. 9

8 Miscellaneous : Tongs, scissors, syringes, needles, appropriate counting assembly. Procedure : 1. Place into the glass tank a layer 2 cm deep of the mobile phase. 2. Apply a spot (about 5 µl) of the preparation to the "deposit line" of the sheet using a syringe and needle and dry in air. 3. Using tongs, insert the sheet into the tank and close the lid. Lower the sheet into the mobile phase and allow the solvent to migrate up to the "solvent line". 4. Remove the sheet with tongs and dry in air. 5. Determine distribution of radioactivity with an appropriate detector. Identify each radioactive spot by calculating the Rf. The Rf of monoclonal antibody Igovomab 111 In is 0, and that of DTPA- 111 In is 0.9. Measure the radioactivity of each spot by integration of the peaks. 6. Calculations Calculate the percentage of monoclonal antibody Igovomab 111 In (radiochemical purity) % Igovomab 111 In = Radioactivity of the spot at Rf 0 Total radioactivity of the paper strip The percentage of Igovomab 111 In should be at least 95%. x 100 The administration of radiopharmaceuticals creates risks for other persons from external radiation or contamination from spill or urine, vomiting, etc. Radiation protection precautions in accordance with national regulations must therefore be taken. Waste must be disposed of according to national regulations. 7. MARKETING AUTHORIZATION HOLDER CIS bio international B.P GIF-SUR-YVETTE Cedex FRANCE 8. NUMBER IN THE COMMUNITY REGISTER OF MEDICINAL PRODUCTS 9. DATE OF FIRST AUTHORIZATION/RENEWAL OF THE AUTHORIZATION 10. DATE OF REVISION OF TEXT 10

9 ANNEX II HOLDER(S) OF THE MANUFACTURING AUTHORISATION(S) RESPONSIBLE FOR BATCH RELEASE AND CONDITIONS OF THE MARKETING AUTHORISATION 11

10 A. HOLDERS OF THE MANUFACTURING AUTHORISATIONS Manufacturers of the active substance Manufacturer of the OC 125 F(ab ) 2 murine monoclonal antibody fragment: Centocor B.V. Einsteinweg P.O. Box AG Leiden - Netherlands Manufacturing Authorisation issued on the 1st January 1995 by De Minister van Volksgezondheid, Welzijn en Sport, Postbus 5046, NL-2280 HK, Rijswijk, Netherlands. Manufacturer of OC 125 F(ab ) 2 :-DTPA CIS bio international B.P Gif sur Yvette Cedex - France Manufacturing Authorisation issued on the 11th September 1991 by le Ministre Delegue a la Sante, Direction de la Pharmacie et du Medicament, 1 Place Fontenoy, F-75350, Paris. Manufacturer of the finished medicinal product and site where the batch release takes place CIS bio international B.P Gif sur Yvette Cedex - France Manufacturing Authorisation issued on the 11th September 1991 by le Ministre Delegue a la Sante, Direction de la Pharmacie et du Medicament, 1 Place Fontenoy, F-75350, Paris. B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to non-renewable restricted medical prescription. C. COMMITMENTS MADE BY THE MARKETING AUTHORISATION HOLDER C.1 Post-authorisation commitments The applicant, after having been consulted agreed to submit to the EMEA, within the defined timeframe, the information requested by the CPMP (letter dated 30/5/96),. Chemical, pharmaceutical and biological aspects: 1. Additional data to justify the maximum limit for fermentation (27 days) have to be provided by 30th November Clarification regarding the production strategy has to be provided by 30th November 1996 justification for such variable perfusion rate and optimisation of this parameter; justification and stability data to support the proposed 3-year storage period of the concentrates. 3. Regarding the use and reuse of the columns the following has to be submitted by 30th November 1996 clarification of the terms used: batches in the answer and run in the SOPs; additional data on the performances of the columns after a significant number of runs; exact explanation when the entire cleaning procedure for the Protein-A column takes place and how the column is regenerated between two cycles. 4. Justification and setting of a maximum time for the digestion step (e.g. 17 h) and commitment to discarding the product if the specification (i.e. not more than 5% intact IgG) is not met at that time, have to be submitted by 30th November

11 5. Regarding the reprocess strategy, clarification, for the various steps, of the criteria for which reprocessing will be allowed, has to be submitted by 30th November The terminology technical failure or inadequate performance is too vague. 6. Reduction of the limit for BSA content in OC 125 F(ab ) 2, in line with batch analysis data provided, has to be submitted by 30th November Regarding bioburden testing, performed at CIS bio international, clarification of the method(s) used among the three described in Attachment 64.3, as well as the justification to what extent the validation data submitted for these methods, performed by Centocor, apply to CIS bio international, have to be provided by 31st October Unless otherwise justified, performance of bioburden testing on the DTPA solution and 1 M sodium bicarbonate solution prior to use and limits have to be submitted by 31st October The same applies for any other buffers or diluents used in the manufacturing process. 9. A proposal of a clear protocol to prepare and qualify any new working standard has to be submitted by 31st October This protocol should particularly insist on the statistical analysis to determine the value to be assigned to the standard. As a new ELSA II-CA 125 is now used, which is claimed to be more sensitive, clarification to what extent the improvement of sensitivity affects the results of the tests, particularly the confidence limit (i.e log) has to be submitted by 31st October In line with experience gained using the new ELSA II-CA 125, a new immunoreactivity specification has to be proposed by 31st October Unless otherwise justified, the specifications for immunoreactivity (immobilised antigen) and limulus amoebocyte lysate (LAL), on the finished product, have to be tightened, in line with batch analysis data, by 31st October Clinical aspects 11. The applicant is committed to provide further data to confirm the diagnostic procedure by the performance of a European multicentre study including 100 patients by 31st December C.2 Batch release testing protocol Pursuant to Article 4 of Council Directive 89/342/EEC of 3 May 1989 on immunological medicinal products, this product is subject to batch release, to be carried out by the competent National Control Authority. The batch release testing protocol was agreed by the Committee as follows: 1. National Control Authority involved: Direction des Laboratoires et des Contrôles, Agence du Médicament, France. 13

12 2. Product to be tested: INDIMACIS 125 finished product. 3. List of tests to be performed: ph osmolality LAL test identity: immunoreactivity (ELISA test) purity: SDS PAGE (non reducing condition, Coomassie Blue staining) HPLC Gel Filtration (% monomer) assay: Total Protein content (UV spectro 280 nm) Immunoreactivity (ELISA test). The specifications to be applied are those currently approved in the dossier. 4. Proposed duration of the Batch Release Procedure: For the next five consecutive finished product batches with yearly reports. Depending on the consistency of the results obtained, extension of this procedure could be envisaged after discussion within the Biotechnology Working Party. 5. Distribution on the market of the next five batches is conditional to a positive batch release certificate by the Agence du Médicament, France. 6. The Batch Release certificates as well as the yearly report should be provided to the CPMP, the European Commission and the Company. 14

13 ANNEX III LABELLING AND USER PACKAGE LEAFLET 15

14 A. LABELLING 16

15 Reference text for the label of the ampoule CIS CIS bio international, B.P. 32, GIF-SUR-YVETTE Cedex, FRANCE INDIMACIS 125 Igovomab 1 mg/1 ml Batch N : Expiry : For I.V. infusion after labelling 17

16 Reference text for the outer packaging CIS CIS bio international, B.P. 32, GIF-SUR-YVETTE Cedex, FRANCE INDIMACIS 125 Kit for the preparation of the monoclonal antibody Igovomab 111 In infusion Contains 2 ampoules Composition per ampoule : - Monoclonal antibody Igovomab : 1 mg - DTPA (diethylenetriaminopentaacetic acid) : 9.8 µg - 0.1M saline acetate buffer ph 5.0 : Up to 1 ml Saline acetate buffer contains sodium acetate trihydrate, acetic acid and 0.9% sodium chloride solution Solution for infusion Batch N : Expiry : For intravenous infusion after labelling with Indium [ 111 In] chloride solution Keep out of reach of children Store between 2 and 8 C. Store the labelled product between 15 and 25 C. Use within 24 hours after labelling Marketing authorisation holder : CIS bio international, B.P. 32, GIF-SUR-YVETTE Cedex, FRANCE Marketing authorisation number : Medicinal product subject to medical prescription For detailed instructions regarding administration, special warnings and precautions for elimination : read package leaflet before use 18

17 B. PACKAGE LEAFLET 19

18 PACKAGE LEAFLET INDIMACIS 125 (Igovomab) Ampoule 1mg/ml 1. IDENTIFICATION OF THE MEDICINAL PRODUCT Name of the medicinal product INDIMACIS 125 Kit for the preparation of the monoclonal antibody Igovomab 111 In infusion. Qualitative composition The active ingredient is a monoclonal antibody which has been derived from mouse proteins and purified for human use. It is then coupled with a chelating agent (DTPA). The product also contains sodium acetate trihydrate, acetic acid and 0.9 % sodium chloride solution. Quantitative composition Each vial contains 1 mg of the monoclonal antibody Igovomab (OC 125 F(ab') 2 - DTPA). Pharmaceutical form Solution for infusion. Pharmaco-therapeutic group This product is used in the preparation of a diagnostic radiopharmaceutical. After preparation and administration, the radiopharmaceutical temporarily collects in particular organs and tissues of the body (liver, spleen, kidneys and ovarian tissue). Because the substance contains a small amount of radioactivity it can be detected from outside the body using special cameras, and pictures, known as scans, can be taken. These scans will show exactly the distribution of the radiopharmaceutical within the organs and the target tissues. This gives the physician valuable information for the diagnosis of the disease. Name and address of the holder of the marketing authorisation and manufacturer CIS bio international B.P GIF-SUR-YVETTE Cedex FRANCE 2. THERAPEUTIC INDICATIONS INDIMACIS 125 is used, after it has been marked with indium [ 111 In] chloride, to perform scans of the abdomen and the pelvis. This will help your physician to investigate these parts of the body, during the follow-up of the ovarian tumour. This diagnostic procedure needs to be used when ultrasound and CT-scan do not give clear results. 20

19 3. LIST OF INFORMATION WHICH IS NECESSARY BEFORE TAKING THE MEDICINAL PRODUCT Contra-indications Because the preparation may not be administered to pregnant or nursing women, and to persons with a known history of hypersensitivity, you should tell your physician if there is any possibility that you are pregnant or breast-feeding, and if you have any allergic disease (particularly if you have hypersensitivity to any protein which comes from a mouse). IN CASE OF DOUBT IT IS ESSENTIAL TO CONSULT YOUR PHYSICIAN Special warnings The use of INDIMACIS 125 does involve administration of small amounts of radioactivity. The risk this involves is very small and your physician will not consider carrying out the investigation unless he believes that the risk is outweighed by the potential benefit of the study. This test should not be repeated in the same patient as no data in patients with repeated INDIMACIS 125 imaging are available. Precautions for use INDIMACIS 125 is administered by intravenous route by slow infusion under clinical monitoring to prevent and treat any possible allergic effect (although no such undesirable effects have been observed). Because there are strict laws covering the use, handling and disposal of radioactivity, INDIMACIS 125 will always be used, handled and administered by people who are trained and qualified in the safe handling of radioactive material. Your physician will inform you if you need to take any special precautions before or after the injection of the product. If you have ever received any product made from a mouse antibody, your physician should take a sample of blood for testing to be sure that you have not developed an allergy to it. IN CASE OF DOUBT DO NOT HESITATE TO CONSULT YOUR PHYSICIAN Interactions with other medicinal products and other forms of interaction IN ORDER TO AVOID POSSIBLE INTERACTIONS WITH OTHER MEDICINAL PRODUCTS, ANY OTHER CURRENT MEDICATION MUST BE NOTIFIED TO YOUR PHYSICIAN. Pregnancy-lactation The preparation must not be administered to pregnant or nursing women. Any possibility of pregnancy must be ruled out before using this product. Effects on ability to drive or to operate machinery Effects on the ability to drive and use machines are not expected. 21

20 List of those excipients, knowledge of which is important for the safe use of the medicinal product in certain patients This product contains no excipients which might necessitate special consideration being given to its use for particular types of patients. 4. INSTRUCTIONS FOR PROPER USE Dosage Your physician will decide on the amount of radioactive INDIMACIS 125 to be used. For a 70 kg adult, the average indium [ 111 In] activity administered is 111 megabecquerel (becquerel is the unit in which radioactivity is measured). This dose of radioactivity is safe and will be gone from the body in about 8 days. Method and route of administration After labelling the product must be administered slowly over minutes. This may be achieved by injection into a 100 ml 0.9 % sodium chloride infusion bag. Two hours before INDIMACIS 125 scans, it is possible to proceed with intravenous injection of a diagnostic radiopharmaceutical ( 99m Tc oxidronate or 99m Tc medronate), to obtain bone scans to help your physician to interpret the results. Duration of treatment Scans may be taken 2 or 3 days after the injection of the INDIMACIS 125. Additional scans may be performed between 4 days and 7 days after the injection of the preparation. Action to be taken in the case of an overdose Since INDIMACIS 125 is administered by a physician under strictly controlled conditions, the chances of a possible radiation overdose are small. Your physician will recommend that you drink plenty of fluids to increase the urinary elimination of the radionuclide from the body. 5. UNDESIRABLE EFFECTS No severe undesirable effects, related to allergic effects, have been reported in over 400 patients injected with this preparation. As a biological undesirable effect, a production of antibodies against INDIMACIS 125 has been reported in about one quarter of the patients. INFORM YOUR PHYSICIAN IF YOU EXPERIENCE ANY ILL-EFFECTS 22

21 6. STORAGE The product label includes the appropriate storage conditions and the expiry date for the batch of product. Hospital personnel will ensure that the product is stored correctly and not administered to you after the stated expiry date. The expiry date for this product is 12 months from the day of manufacture. The expiry date is indicated on each vial and on the outer packaging. The product should be stored at a temperature ranging between 2 and 8 C in its original packaging. The expiry date for the labelled product is 24 hours after labelling. The labelled product should be stored at a temperature ranging between 15 and 25 C. 7. INSTRUCTIONS FOR USE, HANDLING AND DISPOSAL Read directions for use thoroughly before starting the preparation procedure. All procedures should be conducted using aseptic techniques and standard precautions for handling radionuclides. Use of radiopharmaceutical agents Radiopharmaceuticals should only be used by qualified personnel with the appropriate government authorisation for the use and manipulation of radionuclides. This radiopharmaceutical may be received, used and administered only by authorised persons in designated clinical settings. It s receipt, storage, use, transfer and disposal are subject to the regulations and/or appropriate licences of the local competent official organisations. Radiopharmaceuticals should be prepared by the user in a manner which satisfies both radiation safety and pharmaceutical requirements. Appropriate aseptic precautions should be taken, complying with the requirements of Good Manufacturing Practice for pharmaceuticals. Method of preparation Usual precautions regarding sterility and radioprotection should be respected. Take an ampoule from the kit. Break the neck and, using a hypodermic syringe, remove the monoclonal antibody Igovomab solution and introduce it through the rubber stopper of the vial containing 0.3 ml (111 MBq) of a sterile and pyrogen-free indium [ 111 In] chloride solution (with radioactive concentration of 370 MBq/ml, at the reference date stated on the label). The indium [ 111 In] chloride solution should comply with the specifications laid down in the European Pharmacopoeia draft monograph for «Indium [ 111 In] chloride solution», particularly those concerning metallic elements such as : Cd : 0.40 µg/ml Cu : 0.15 µg/ml Fe : 0.60 µg/ml Stir slowly for about 30 minutes. The obtained preparation is a clear and colourless solution. Before use, limpidity of the solution, radioactivity and gamma spectrum will be checked. 23

22 The vial should never be opened and must be kept inside its lead shielding. The solution should be removed aseptically through the stopper with a sterile protected syringe. Quality control The quality of labelling (radiochemical purity) can be checked according to the following procedure : Method : Instant Thin Layer Chromatography. Materials and reagents : Gelman ITLC SG : Silica gel impregnated glass fibre sheets (20 cm x 2 cm). Trace at 3 cm from one of the ends of the sheet, a fine line called "deposit line", and another line at 14cm from the edge called " solvent line". Mobile phase : 0.1M citrate buffer ph 4.0. Glass tank of suitable size for the chromatographic paper used, ground at the top to take a closely fitting lid. At the top of the tank is a device which suspends the chromatographic paper and is capable of being lowered without opening the chamber. Miscellaneous : Tongs, scissors, syringes, needles, appropriate counting assembly. Procedure : 1 Place into the glass tank a layer 2 cm deep of the mobile phase. 2 Apply a spot (about 5 µl) of the preparation to the "deposit line" of the sheet using a syringe and needle and dry in air. 3 Using tongs, insert the sheet into the tank and close the lid. Lower the sheet into the mobile phase and allow the solvent to migrate up to the "solvent line". 4 Remove the sheet with tongs and dry in air. 5 Determine distribution of radioactivity with an appropriate detector. Identify each radioactive spot by calculating the Rf. The Rf of monoclonal antibody Igovomab 111 In is 0, and that of DTPA- 111 In is 0.9. Measure the radioactivity of each spot by integration of the peaks. 6 Calculations Calculate the percentage of monoclonal antibody Igovomab 111 In (radiochemical purity) % Igovomab 111 In = Radioactivity of the spot at Rf 0 Total radioactivity of the paper strip x

23 The percentage of Igovomab 111 In should be at least 95%. The administration of radiopharmaceuticals creates risks for other persons from external radiation or contamination from spill or urine, vomiting, etc. Radiation protection precautions in accordance with national regulations must therefore be taken. After use, the container and the other radioactive waste should be disposed of according to national regulations. 8. DATE OF LAST REVISION OF THE PACKAGE LEAFLET 25