ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 3 1 NAME OF THE MEDICINAL PRODUCT CEA-Scan 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Kit for the preparation of 99mTc labelled CEA-Scan. Each 3 mL vial contains 1.25 mg arcitumomab (IMMU-4 Fab anti-CEA monoclonal antibody fragments: consisting mainly of Fab’, but also containing F(ab )2 at ≤5% of total protein, with H and L chain fragments), buffered to pH 5-7, 0.29 mg stannous chloride, sodium chloride, potassium sodium tartrate, sodium acetate, sucrose, argon. 3. PHARMACEUTICAL FORM Powder for injection. 4. CLINICAL PARTICULARS 4.1 Indications After reconstitution with sodium pertechnetate [99mTc] solution, CEA-Scan is indicated only in patients with histologically-demonstrated carcinoma of the colon or rectum for imaging of recurrence and/or metastases. CEA-Scan is employed, in the above mentioned patients, as an adjunct to standard non-invasive imaging techniques, such as ultrasonography or CT scan, in the following situations: ¥ Patients with evidence of recurrence and/or metastatic carcinoma of the colon or rectum, who are undergoing an evaluation for extent of disease, such as prior to surgical resection and/or other therapy. ¥ Patients with suspected recurrence and/or metastatic carcinoma of the colon or rectum in association with rising levels of carcinoembryonic antigen (CEA). 4.2 Posology and Method of Administration CEA-Scan is reconstituted with sodium pertechnetate [99mTc] solution prior to use, and diluted to a total volume of 5-10 mL with isotonic sodium chloride injection. The recommended adult dose is a single dose of 1 mg of Fab fragment labelled with 750-1000 MBq of 99mTc. The radiolabelled solution (5-10 mL) should be administered as a intravenous injection over approximately 30 seconds. Immunoscintigraphy, using planar and SPECT techniques, should be performed preferably at two to five hours after injection. Readministration is discussed in section 4.4.10. 4.3 Contraindications Patients with known allergies or hypersensitivity to mouse proteins. Pregnancy. 4 4.4 Special Warnings and Special Precautions for Use 4.4.1 Use of Radiopharmaceutical Agents • Radiopharmaceutical agents should be used only by qualified personnel with appropriate government authorization for the use and manipulation of radionuclides. • This radiopharmaceutical may be received, used and administered only by authorized persons in designated clinical settings. Its receipt, storage, use, transfer and disposal are subject to the regulations and/or appropriate licenses of local competent official organizations. • 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, complying with the requirements of Good Manufacturing Practices (GMP) for pharmaceuticals. 4.4.2 Reconstitution Immediately prior to use, contents of the vials are reconstituted to prepare CEA-Scan [99mTc]. The contents of the vials are not to be administered directly to patients. 4.4.3 Recommended Imaging Protocol A whole-body planar scan at 2-5 h post-injection can be used to localize sites of colorectal cancer. Planar imaging of the pelvis, abdomen, thorax, and head at 2-5 h post-injection with 500 k counts per view should be made. Image acquisition in analogue and/or digital word-mode and a 128 x 128 matrix is recommended. Single-photon emission computed tomography (SPECT) of the pelvis and abdomen at 2-5 h post-injection should also be employed. SPECT acquisition parameters recommended are: 60 projections in a 360o step-and-shoot technique, 30 s per view in a 64 x 64 matrix. Data processing by filtered backprojection and reconstruction in three planes (transaxial, coronal, and sagittal) is recommended. Variations in this protocol (e.g., additional SPECT of the head) can be performed, depending on the clinical problem. If late imaging is performed (18-24 h), intestinal and gall bladder activity may interfere with true tumor imaging. Therefore, such late images should be compared to those made at earlier times (2-5 h). Due to excretion of the labeled fragment by the urine, the patient should urinate prior to imaging in order to decrease bladder activity. 4.4.4 Tumor Specificity CEA-Scan is not specific for colorectal carcinomas, since CEA is expressed by other carcinomas. These include various carcinomas of the digestive system (e.g., oesophageal, gastric, pancreatic, and bile duct tumors), medullary thyroid cancer, and carcinomas of the lung, breast, ovary, endometrium and cervix. 5 4.4.5 False Positives Among a study of patients with at least one known site of colorectal cancer recurrence or spread, 1 of 122 patients (0.8%) was classified as false-positive. In a study of patients with no other radiological evidence of colorectal cancer, but with clinical or biochemical evidence of recurrence or spread, 11 of 88 patients (12.5%) were classified as false-positive. Areas of potential false-positive readings, particularly with planar imaging, are near the major bloodpool organs (heart, major vessels, etc.) at very early imaging times (1-3 h post-injection), near the sites of antibody fragment metabolism (kidneys and urinary bladder), and in the intestines at late imaging times (18- 24 h post-injection). Accordingly, imaging is recommended at early times, such as 2-5 hours after injection. There is a potential for false-positive results at late (18-24 h) imaging times due to intestinal and gall bladder imaging. If, however, later imaging is needed for comparison to earlier results, then normal activity in the bowel can be recognized by seeing movement of the site of activity in the intestine from the early to the late imaging sessions, suggesting nonspecific localization. With regard to imaging of tumor near the kidneys or urinary bladder, voiding of urine before the study should decrease bladder activity, and careful SPECT imaging near the kidneys and bladder is recommended. 4.4.6 Hot, Rimmed, and Cold Lesions Only hot or rimmed lesions should be considered as positive for tumor, unless other corroborative evidence supports the interpretation of a cold lesion as a site of cancer. Lesions that are rimmed or cold usually fill in as hot or rimmed, respectively, with time. Often, large lesions, due to poor vascularization, will appear to be cold. Of the cold lesions classified as positive for tumor in the studies analyzed, all were confirmed as cancer (18 lesions), indicating that cold lesions in a group of patients with a high suspicion or risk of cancer recurrence or spread have a high probability of being malignant. 4.4.7 Imaging Performance of CEA-Scan CEA-Scan images colorectal cancers, including tumor deposits less than 1 cm in diameter. It has a 98% positive predictive value for recurrence/metastases of colorectal cancer when both CT and CEA-Scan are positive for a lesion, and a negative predictive value of 75% when both tests are negative for a region. • Liver: CEA-Scan provides complementary information to CT when colorectal cancer has resulted in secondaries in the liver. • Extrahepatic Abdomen and Pelvis: CEA-Scan is significantly more sensitive than CT for locating the spread of colorectal cancer in the extrahepatic abdomen and pelvis. • Bone and Brain: Conventional diagnostic techniques other than CEA-Scan should be used to identify possible bone and brain dissemination of colorectal cancer. 4.4.8 Hypersensitivity Anaphylactic and other hypersensitivity reactions are possible whenever mouse protein materials are administered to patients. Appropriate cardiopulmonary resuscitation facilities and trained personnel should be available for immediate use in the event of an adverse reaction. 6 4.4.9 Human Anti-mouse antibody (HAMA) HAMA has been observed before and after single administration of CEA-Scan (see Undesirable Effects). HAMA to fragment was observed to develop in ≤ 1% of patients receiving CEA-Scan. In addition, patients who have previously received murine monoclonal antibody products are more likely to have HAMA. In subjects with HAMA, there may be a greater chance of allergic or hypersensitivity reactions and diminished efficacy in tumor imaging. 4.4.10 Readministration Clinical data reflecting safety and efficacy of multiple injections is only available in 22 patient. In patients whose sera do not contain human anti-mouse antibody (HAMA) in an appropriate assay, readministration may be performed at intervals of not less than three months. The overall radiation dose received by the patient over time should also be taken into account. 4.4.11 Subjects under 21 years of age Studies have not been performed in young patients. 4.4.12 Renal or hepatic disease Formal studies have not been performed in patients with renal or hepatic impairment. However, due to the low dose of protein administered and the short half-life of 99mTc, dosage adjustment is probably not necessary. 4.5 Interactions with Other Medicaments and Other Forms of Interaction Formal drug interaction studies have not been performed, but no drug interactions have been described to date. 4.6 Pregnancy and Lactation 4.6.1 Women of Childbearing Potential When it is necessary to administer radioactive medicinal products to women of childbearing potential, information should always be sought about pregnancy. Any women who has missed a period should be assumed to be pregnant until proven otherwise. When uncertainty exists, it is important that radiation exposure should be the minimum consistent with achieving the desired