SUMMARY OF PRODUCT CHARACTERISTICS

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 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.
• The product has been formulated to function only when the required amount of Tc 99m pertechnetate is added to the complete content of each vial. Any change in the ratio of the ingredients, adulteration of the vial’s content, including extreme temperature changes for storage after opening the vial, or reduction of the administered dose, will likely result in an ineffective product.

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 360^o 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.

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.

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 clinical information. Alternative techniques which do not involve ionizing radiation should be considered.

4.6.2 Pregnancy

Radionuclide procedures carried out on pregnant women also involve radiation doses to the fetus. 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 fetus 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 the Ability to Drive and Use Machines

No known effect.

4.8 Undesirable Effects

1. The following minor, self-limiting adverse effects have been reported: 1) Transient eosinophilia; 2) nausea; 3) bursitis; 4) urticaria; 5) generalized itching; 6) headache; 7) upset stomach; and 8) fever.

2. There has been a single report, out of a total of over 500 patients receiving the product to date, 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). While no hypersensitivity reactions to CEA-Scan have been observed to date, it is possible that such reactions could occur, resulting in hypersensitivity reactions, anaphylactic shock, serum sickness or death.

For each patient, exposure to ionizing 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 ionizing 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.

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.

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 mutagenicity, carcinogenicity, or potential effects on reproductive activity.

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).

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

Argon

6.2 Incompatibilities

Not known.

6.3 Shelf Life

The expiratory date for this kit stored at 2-8°C is 36 months from the day of manufacture.

Following reconstitution and radiolabelling, the material can be held at room temperature (15-25°C) and must be used within four hours following reconstitution.

6.4 Special Precautions for Storage

Store labelling kit at 2-8°C.

6.5 Nature and Contents of Container

Materials included:

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

Vials comply with the requirements for glass type I.

The vial is closed with a bromobutyl rubber stopper with a blue flip-off seal.

6.6 Instructions for Use/Handling-Disposal

Read complete directions thoroughly before starting the preparation procedure.

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

6.6.1 Method of Preparation and Quality Contol

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

3. Swirl and shake the vial 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.

5. Prior to administration, the solution should be inspected visually for particulate matter and discoloration. If either are present, the product should be discarded.

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 fiber 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 analyzer. Calculate the percent free technetium as follows:

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 B.V.
European Headquarters
Haarlemmerstraat 30
2181 HC Hilegom,
The Netherlands

8. MARKETING AUTHORIZATION NUMBER

EU/1/97/032/009

9. DATE OF FIRST AUTHORIZATION/RENEWAL OF THE AUTHORIZATION

14 February 1997

10. DATE OF REVISION OF THE TEXT

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