Annex I Summary of Product Characteristics

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ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS 1. NAME OF THE MEDICINAL PRODUCT

CEA-Scan 1.25 mg, powder for solution for injection

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-murine Fab´ anti-CEA monoclonal antibody fragments) for the preparation of 99mTc labelled CEA-Scan. The kit does not include the radioisotope.

3. PHARMACEUTICAL FORM

Powder for solution for injection.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

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 for diagnostic use only, 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, or

• 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 an intravenous injection over approximately 30 seconds.

Safety and diagnostic accuracy in persons under 21 years of age have not been established.

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.

Readministration is discussed in section 4.4.10.

4.3 Contraindications

Patients with known allergies or hypersensitivity to mouse proteins

2 Pregnancy

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 authorised 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 organisations.

· 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 unreconstituted contents of the vials are not to be administered directly to patients.

4.4.3 Recommended Imaging Protocol

Immunoscintigraphy, using planar and SPECT techniques, should be performed preferably at two to five hours after injection.

A whole-body planar scan at 2-5 h post-injection can be used to localise 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 tumour 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 Tumour 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 tumours), medullary thyroid cancer, and carcinomas of the lung, breast, ovary, endometrium and cervix.

3 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 recognised by seeing movement of the site of activity in the intestine from the early to the late imaging sessions, suggesting nonspecific localisation.

With regard to imaging of tumour 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. Better image quality in the pelvis may require bladder catheterization.

4.4.6 Hot, Rimmed, and Cold Lesions

Only hot or rimmed lesions should be considered as positive for tumour, 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 tumour in the studies analysed, 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 tumour 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.

4 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 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 tumour imaging.

4.4.10Readministration

Clinical data reflecting safety and efficacy of multiple injections is available in 44 patients. 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.

4.5 Interaction with other medicinal products and other forms of interaction

Formal drug interaction studies have not been performed, but no drug interactions have been described to date.

4.6 Use during 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 clinical information. Alternative techniques, which do not involve ionising radiation, should be considered.

4.6.2 Pregnancy

Radionuclide procedures carried out on pregnant women also involve radiation doses to the foetus. CEA-Scan is contraindicated in pregnancy. Administration of 740 MBq CEA-Scan will give an estimated absorbed dose of 4.1 mGy to an embryo or foetus at an early stage.

4.6.3 Lactation

Before administering a radioactive medicinal product to a mother who is breast feeding, consideration should be given as to whether the investigation could be reasonably delayed until the mother has ceased breast-feeding and as to whether the most appropriate choice of radiopharmaceutical has been made, 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. It is usual to advise that breast-feeding can be restarted when the level in the milk will not result in a radiation dose to the child greater than 1 mSv. Due to the short six-hour, half-life of 99mTc, a dose of less than 1 mSv in mother’s milk can be expected 24 hours after the administration of CEA-Scan [99mTc].

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. No known effect.

5 4.8 Undesirable effects

1. The following rare adverse effects have been reported: 1) Transient eosinophilia; 2) nausea; 3) bursitis; 4) urticaria; 5) generalised itching; 6) headache; 7) upset stomach; 8) fever; and 9) hypersensitivity and anaphylactoid reactions.

2. There has been a single report of an apparent grand mal epileptic seizure that was "possibly related" to CEA-Scan infusion.

3. HAMA: The presence of HAMA and human anti-mouse fragment have been reported in patients before and after receiving CEA-Scan (£1% of patients develop HAMA to the antibody fragment).

4. 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 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 the adverse effects will occur with low frequency because of the low radiation doses incurred.

5. For most diagnostic investigations using a nuclear medicine procedure, the radiation dose delivered (effective dose/EDE) is less than 20 mSv. Higher doses may be justified in some clinical circumstances.

4.9 Overdose

Intravenous administration of intact IgG and F(ab´)2 of IMMU-4 in therapeutic doses of up to 25 mg has not shown any serious adverse reactions. Fab´ fragments have been demonstrated to be less immunogenic than intact IgG or F(ab´)2 fragments.

In the unlikely event of the administration of a radiation overdose with CEA-Scan, the absorbed dose to the patient may be reduced by increased oral or intravenous intake of fluids to promote excretion of the radiolabel.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Diagnostic Radiopharmaceutical for Tumour Detection, ATC V09I A01.

At the concentrations and activities used for diagnostic procedures, CEA-Scan [99mTc] does not appear to exert any pharmacodynamic effects. CEA-Scan [99mTc] is not specific for colorectal carcinoma, since CEA is expressed by other carcinomas (see Section 4.4.4).

5.2 Pharmacokinetic properties

Pharmacokinetic studies were performed after the intravenous administration of the product. At one hour after infusion, the blood level was 63% of baseline, 23% at five hours, and 7% of baseline at 24 hours. The distribution half-life was approximately one hour; the elimination half-life was 13 ± 4 hours with 28% of the radiolabel excreted in urine over the first 24 hours after administration.

6 5.3 Preclinical safety data

Only very limited preclinical studies have been performed with either the labelled or unlabelled agent. These revealed no remarkable findings. It should be noted, however, that these studies did not assess genotoxicity, carcinogenic potential, or toxicity to reproduction.

5.4 Radiation dosimetry

For this product, the effective dose equivalent resulting from an administered activity of 750 MBq is typically 9.8 mSv for a 70 kg individual.

Technetium [99mTc] disintegrates with the emission of gamma radiation with an energy of 140 keV and a half-life of 6 hours to technetium [99Tc], which can be regarded as quasi stable.

Radiation dosimetry for individual organs revealed a generally low level of activity. As might be expected for a small molecular-sized antibody fragment, it was highest in the kidney. The values were calculated according to Medical Internal Radiation Dosimetry (MIRD). Data represent the mean of ten patients, with the exception of kidney (nine patients), ovary (eight patients), and testes (two patients).

Summary of Normal Organ Dosimetry (µGy/MBq) CEA-Scan [99mTc] Organ Mean ± SD Bladder 16.6 3.6 Kidney 100.3 31.7 Spleen 15.9 4.5 Liver 10.4 2.9 Red Marrow 9.9 2.0 Lung 7.7 1.9 Ovary 7.7 1.5 Total Body 4.6 0.8 Testes 4.5 0.6 Effective dose equivalent 13.1 µSv/MBq Effective dose 9.1 µSv/MBq

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Stannous chloride, dihydrate Sodium Chloride Acetic Acid, Glacial Hydrochloric Acid Potassium Sodium Tartrate, Tetrahydrate Sodium Acetate, Trihydrate Sucrose Nitrogen

6.2 Incompatibilities

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

7 6.3 Shelf-life

Kit - 48 months. Reconstituted and radiolabelled material - 4 hours.

6.4 Special precautions for storage

Kit - Store at 2ºC - 8ºC (in a refrigerator). Do not freeze. Reconstituted/radiolabelled material - Do not store above 25ºC. Do not refrigerate or freeze.

6.5 Nature and content of container

One vial prepared so as to contain 1.25 mg lyophilised CEA-Scan monoclonal antibody fragment.

Pack size: one vial per carton container.

6.6 Instructions for use and handling, and disposal (if appropriate)

Read complete directions thoroughly before starting the preparation procedure.

All procedures should be conducted using aseptic technique and standard precautions for handling radionuclides.

Reconstituted radiopharmaceuticals should be handled using waterproof gloves, adequate shielding of radioactivity, and aseptic technique. Following reconstitution, unused radiopharmaceutical and vial should be handled as radioactive waste and disposed of in accordance with local requirements.

6.6.1 Method of Preparation and Quality Control

6.6.1.1 Method of Preparation

1. Obtain 925-1110 MBq/ml sodium-pertechnetate [99mTc] (from any commercial source) in sodium saline injection.

2. Resuspend the lyophilised material by injecting the 925-1110 MBq of [99mTc] sodium- pertechnetate in a shielded vial of CEA-Scan.

3. Swirl the vial gently for approximately 30 seconds making sure all sodium-pertechnetate [99mTc] is in contact with the antibody. Allow the labelling reaction to proceed for at least five minutes. Add 1 ml of isotonic sodium chloride injection in order to facilitate easy removal. Assay the product in a suitable dose calibrator.

4. Based on the activity measured in the activity calibrator, withdraw a sufficient amount of the product to provide the desired activity (750-1000 MBq of 99mTc, see Dosage and Administration). CEA-Scan [99mTc] can be used after five minutes and should be used within four hours after preparation. CEA-Scan [99mTc] can be stored at room temperature after formulation.

6.6.1.2 Quality Control

1. After radiolabelling the antibody, dilute a 10 µl sample with 1.5 mL saline. Determine the radiochemical purity by Instant Thin Layer Chromatography on silica gel impregnated glass fibre strips, 1 × 9 cm using acetone as the solvent. When the solvent front is within 1 cm of the top of the strip, remove it, cut it in half and place each into a glass tube. Count each tube in a gamma scintillation counter, dose calibrator or radiochromatogram analyser. Calculate the percent free technetium as follows:

8 % Free Technetium = Activity in top half of strip × 100 Total Activity

The radiolabeled product should not contain more than 10% free technetium.

6.6.2 Disposal

After use, the container should be disposed of as radioactive waste.

7. MARKETING AUTHORIZATION HOLDER

Immunomedics GmbH Otto-Röhm-Straße 69 D-64293 Darmstadt Germany

8. NUMBER IN THE COMMUNITY REGISTER OF MEDICINAL PRODUCTS

EU/1/96/023/001

9. DATE OF FIRST AUTHORIZATION/RENEWAL OF THE AUTHORIZATION

4 October 1996

10. DATE OF REVISION OF THE TEXT

9 ANNEX III

LABELLING AND PACKAGE LEAFLET

10 A. LABELLING

11 Container Package Label

CEA-Scan Arcitumomab Kit for the Preparation of 99mTc arcitumomab For Intravenous Use

PACKAGE CONTAINS One vial, arcitumomab powder for injection Each vial contains 1.25 mg of arcitumomab, buffered to pH 5-7, stannous chloride, sodium chloride, potassium sodium tartrate, sodium acetate, sucrose, nitrogen

Store at 2-8°C (in a refrigerator) Batch No. Do not freeze Expiry Date 00/00/00 EU/96/023/001

Medicinal Product subject to medical prescription.

Keep out of the reach of children.

Dispose of as radioactive waste in accordance with local law.

Immunomedics GmbH Otto-Röhm-Straße 69 D-64293 Darmstadt Germany

12 Vial Label

CEA-Scan - arcitumomab Contains 1.25 mg lyophilized arcitumomab, stannous chloride and stabilizers.

For Intravenous Use Only. Rehydrate with sterile, non-pyrogenic 99mTc Na pertechnetate.

Store at 2-8°C (in a refrigerator) Batch No. Do not freeze Expiry Date 00/00/00 EU/1/96/023/001

Immunomedics GmbH Otto-Röhm-Straße 69 D-64293 Darmstadt Germany

13 B. PACKAGE LEAFLET

14 PACKAGE LEAFLET

Please read this leaflet carefully. It does not contain all the information about your medicine that you may need to know, so please refer to the Summary of Product Characteristics or ask your doctor or nurse if you have any questions. This leaflet only applies to CEA-Scan.

NAME OF YOUR MEDICINE

CEA-Scan 1.25 mg powder for solution for injection is the trade name of your medicine. Arcitumomab is the common name.

COMPOSITION: WHAT YOUR MEDICINE CONTAINS

Each 3-mL vial (glass container) contains 1.25 mg of active substance, arcitumomab, buffered to pH 5-7. The other ingredients are stannous chloride, sodium chloride, potassium sodium tartrate, sodium acetate, sucrose, nitrogen.

NAME AND ADDRESS OF THE MARKETING AUTHORIZATION HOLDER AND MANUFACTURER

Immunomedics GmbH Otto-Röhm-Straße 69 D-64293 Darmstadt Germany

1. WHAT CEA-SCAN IS AND WHAT IT IS USED FOR

An antibody is a natural substance made by the body which binds to foreign substances to help remove them from your body. You produce many different kinds of antibodies. CEA-Scan (arcitumomab) is a special kind of antibody which binds to the surface of certain kinds of tumour cells. It is produced in mice and purified so that it can be used in humans. When it is combined to the radioactive technetium isotope and injected, it finds certain tumours and attaches to them. This helps your doctor make a diagnosis and evaluate the extent of your illness. The doctor does this by using a special imaging camera that reveals areas of radioactivity.

Pharmaceutical Form: What CEA-Scan consists of

Powder for injection.

Therapeutic Group: How CEA-Scan works

CEA-Scan is used to determine the presence of tumours in the body derived from the colon or rectum. Shortly after mixing the CEA-Scan with the radioactive technetium isotope, the doctor will inject it into your vein. Two to five hours later you will be placed on a special table and pictures will be taken with standard nuclear cameras to see where the tumour(s) are located. Before undergoing the scanning procedure, you should empty your bladder by urinating. You may be asked to come back the next day for some additional pictures to be taken.

Indications: When CEA-Scan is used

CEA-Scan is an antibody fragment which is linked to a radioactive substance called technetium. CEA-Scan is used in patients with tumours of the colon or rectum that have been diagnosed after examination under the microscope. The antibody is able to bind to the surface of certain kinds of tumours producing a tumour marker, carcinoembryonic antigen (CEA). When the radioactive antibody

15 binds to the tumour, your doctor can determine where it is located by using a special imaging camera that reveals areas of radioactivity. The doctor can also determine how much disease there is and if it has spread to other areas of the body. This will help the doctor determine whether to operate or what other kind of treatment to use.

2. BEFORE YOU USE CEA-SCAN

Contraindications: When you should not use CEA-Scan

If you know that you are allergic to any protein which comes from a mouse, tell your doctor. You should then not be given CEA-Scan, unless your doctor takes certain precautions and believes that the potential benefit exceeds any risk. You should not be given CEA-Scan if you are pregnant.

Interactions with other medications and other forms of interaction

No interactions have been described to date.

Special Warnings: Things you should know before you are given CEA-Scan

It is possible to have a serious allergic reaction to CEA-Scan. Therefore, your doctor should keep you under close observation for a short time after he has given you this drug.

If you have ever received CEA-Scan or another product made from a mouse antibody, your doctor should take a sample of blood for testing to be sure that you have not developed an allergy to it.

If you are breast-feeding, you should stop breast feeding your baby for at least 24 hours after you have been given CEA-Scan.

If the prepared solution of CEA-Scan appears discoloured or contains particles, it should not be used.

Use of Radiopharmaceutical Agents

· Radiopharmaceutical agents should be used only by qualified personnel with appropriate government authorization for the use and manipulation of radionuclides.

· After use, the container should be disposed of as radioactive waste.

3. HOW TO USE CEA-SCAN

Dosage: The Amount of medicine given

You will receive a single dose of 1 mg of CEA-Scan. It will contain the radioactive technetium isotope in an amount called 750-1000 MBq.

Method and Route of Administration: How the injection is given to you

16 Your doctor will prepare the CEA-Scan and the radioactive isotope technetium in a volume of 5-10 ml. One mg of CEA-Scan will be labelled with 750-1000 MBq of technetium. This material will then be injected into your vein. This dose of radioactivity is safe and will be gone from the body in about 24 hours.

Frequency of Administration: How often you will be given CEA- Scan

CEA-Scan is prepared for a single injection. If your doctor decides to give it to you again after several weeks or several months, your blood should be tested first to see if you have developed an allergy to CEA-Scan.

4. POSSIBLE SIDE EFFECTS

Some side effects, although not common, have been reported. These include nausea, upset stomach, headache, itching, fever, a rough patch on the skin, a small increase in the number of certain white blood cells called eosinophils (but without any apparent symptoms). If you experience any of these or any other unwanted effect after you are given this drug, tell your doctor.

Overdose

Intravenous administration of intact IgG and F(ab¢)2 of IMMU-4 in therapeutic doses of up to 25 mg has not shown any serious adverse reactions. Fab¢ fragments have been demonstrated to be less immunogenic than intact IgG or F(ab¢)2 fragments.

5. STORING CEA-SCAN

Shelf Life: How long CEA-Scan can be kept

Kit - 48 months.

Special precautions for storage: How it is stored

Kit - Store at 2ºC-8ºC (in a refrigerator). Do not freeze.

Reconstituted and radiolabelled material - Do not store above 25ºC. Do not refrigerate or freeze.

DATE ON WHICH THE PACKAGE LEAFLET WAS LAST REVISED: