Scintimun - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

Scintimun 1 mg kit for radiopharmaceutical preparation

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial of Scintimun contains 1 mg of besilesomab.

Besilesomab is an anti-granulocyte monoclonal antibody (BW 250/183), produced in murine cells.

The radionuclide is not part of the kit.

Excipients with known effect :

Each vial of Scintimun contains 2 mg of sorbitol.

One mL of the radiolabelled solution contains less than 4 mg of sodium.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Kit for radiopharmaceutical preparation.

Scintimun: white powder

Solvent for Scintimun: white powder

4. CLINICAL PARTICULARS4.1 Therapeutic indications

This medicinal product is for diagnostic use only.

After radiolabelling with sodium pertechnetate ( Tc) solution, the technetium ( Tc) besilesomab solution obtained is indicated in adults for scintigraphic imaging, in conjunction with other appropriate imaging modalities, for determining the location of inflammation/in­fection in peripheral bone in adults with suspected osteomyelitis.

Scintimun should not be used for the diagnosis of diabetic foot infection.

4.2 Posology and method of administration

This medicinal product is for use in designated nuclear medicine facilities only, and should only be handled by authorised personnel.

Posology

Adults

The recommended activity of technetium (99mTc) besilesomab should be between 400 MBq and

800 MBq.

This corresponds to the administration of 0.25 to 1 mg of besilesomab.

For repeated use, see section 4.4.

Elderly

No dose adjustment is required.

Renal impairment / Hepatic impairment

Formal studies have not been performed in patients with renal or hepatic impairment. However, due to the nature of the molecule and the short half-life of technetium (99mTc) besilesomab, dose adjustment is not necessary in such patients.

Paediatric population

The safety and efficacy of Scintimun in children and adolescents have not yet been established.

No data are available.

Method of administration

The radiolabelled solution should be administered intravenously as a single dose only.

This medicinal product should be reconstituted and radiolabelled before administration to the patient. For instructions on reconstitution and radiolabelling of the medicinal product before administration, see section 12.

For patient preparation, see section 4.4.

Image acquisition

Images acquisition should start 3 to 6 hours after administration. An additional acquisition 24 hours after initial injection is recommended. Acquisition can be performed using planar imaging.

4.3 Contraindications

Hypersensitivity to the active substance, to other murine antibodies, to any of the excipients listed in section 6.1 or to any of the components of the labelled radiopharmace­utical.

Positive screening test for human anti-mouse antibody (HAMA).

Pregnancy (see section 4.6).

4.4 Special warnings and precautions for use

Potential for hypersensitivity or anaphylactic reactions

If hypersensitivity or-anaphylactic reactions occur, the administration of the medicinal product must be discontinued immediately and intravenous treatment initiated, if necessary. To enable immediate action in emergencies, the necessary medicinal products and equipment such as endotracheal tube and ventilator must be immediately available.

Since allergic reactions to the murine protein cannot be excluded, cardiovascular treatment, corticosteroids, and antihistamines must be available during administration of the product.

Individual benefit/risk justification

For each patient, the radiation exposure must be justifiable by the likely benefit.

The activity administered should in every case be as low as reasonably achievable to obtain the required diagnostic information.

Patient preparation

Scintimun should be given to sufficiently hydrated patients. In order to obtain images of best quality and to reduce the radiation exposure of the bladder, patients should be encouraged to drink sufficient amounts and to empty their bladder prior to and after the scintigraphic examination.

An interval of at least 2 days must be observed between any previous scintigraphy with other technetium (99mTc)-labelled agents and administration of Scintimun.

Interpretation of images

There are currently no criteria to distinguish infection and inflammation by means of Scintimun imaging. Scintimun images should be interpreted in the context of other appropriate anatomical and/or functional imaging examinations.

Only limited data is available about binding of technetium (99mTc) besilesomab to CarcinoEmbryonic Antigen (CEA) expressing tumours in vivo. In vitro , besilesomab cross-reacts with CEA. False positive findings in patients with CEA expressing tumours cannot be excluded.

False results may be obtained in patients with diseases involving neutrophil defects and to patients with haematological malignancies including myeloma.

After the procedure

Close contact with infants and pregnant women should be restricted during the first 12 hours after the injection.

Specific warnings

Fructose intolerance

Scintimun contains sorbitol therefore patients with rare hereditary problems of fructose intolerance should not be administered this product.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially ‘sodium-free’.

Human Anti-Mouse Antibodies (HAMA)

Administration of murine monoclonal antibodies can lead to the development of Human Anti-Mouse Antibodies (HAMA). Patients who are HAMA positive may have a greater risk for hypersensitivity reactions. Inquiry on possible previous exposure to murine monoclonal antibodies and a HAMA test should be made prior to administration of Scintimun; a positive response would contraindicate the administration of Scintimun (see section 4.3).

Repeated use

Data on repeated dosing of Scintimun are very limited. Scintimun should only be used once in a patient’s lifetime.

4.5 Interaction with other medicinal products and other forms of interaction

Active substances which inhibit inflammation or affect the haematopoietic system (such as antibiotics and corticosteroids) may lead to false negative results.

Such substances should therefore not be administered together with, or a short time before the injection of Scintimun.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential

When an administration of radiopharmace­uticals 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.

Pregnancy

The use of besilesomab is contraindicated in pregnant women (see section 4.3).

Breast-feeding

It is not known if the product is excreted in human milk. A risk to a breast-fed child cannot be excluded.

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 what is the most appropriate choice of radiopharmace­uticals, bearing in mind the secretion of activity in breast milk. If the administration is considered necessary, breast-feeding should be interrupted for three days and the expressed feeds discarded. These three days correspond to 10 half-lives of technetium (99mTc) (60 hours). At that time the remaining activity represents about 1/1000 of the initial activity in the body.

Close contact with infants should be restricted during the first 12 hours after the injection.

4.7 Effects on ability to drive and use machines

Scintimun has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

In the most recent clinical study in which 123 patients were administered Scintimun, the most commonly reported adverse reaction was the development of anti-mouse antibodies (HAMA) in 14 % of the patients, after a single administration (16 positive over 116 assayed one and/or three months after the administration).

The table below reports adverse reactions by MedDRA system organ classes. The frequencies are based on the most recent clinical trial and non interventional safety survey.

The frequency listed below is defined using the following convention:

Very common (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1,000 to < 1/100); rare (> 1/10,000 to < 1/1,000)

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Exposure to ionising radiation is linked with cancer induction and a potential for development of hereditary defects. For diagnostic nuclear medicine investigations the frequency of these adverse reactions is not known. As the effective dose is about 6.9 mSv when the maximal recommended activity of 800 MBq is administered these adverse reactions are expected to occur with a low probability.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in

4.9 Overdose

No case of overdose has been reported.

In the event of administration of a radiation overdose with technetium (99mTc) besilesomab, the absorbed dose to the patient should be reduced where possible by increasing the elimination of the radionuclide from the body by forced diuresis and frequent bladder voiding, and by the use of laxatives to promote faecal excretion.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Diagnostic radiopharmace­uticals, inflammation and infection detection, ATC code: V09HA03

Mechanism of action

Besilesomab is a murine immunoglobulin of IgG1 isotype that specifically binds to NCA-95 (non specific cross-reacting antigen 95), an epitope expressed at the cell membrane of granulocytes and granulocyte precursors. Besilesomab cross-reacts with tumours expressing carcinoembryonic antigen (CEA). Besilesomab has no effect on activation of complement, granulocyte function or platelets.

Pharmacodynamic effects

At the recommended activities, it does not exert any clinically relevant pharmacodynamic effects.

Clinical efficacy

In a randomised cross-over trial comparing blinded reading of Scintimun and 99mTc-White Blood Cells (WBCs) images in 119 patients with suspected osteomyelitis, the agreement rate between the two methods was 83 % (lower 95 % confidence interval limit: 80 %). However, based on the investigator’s di­agnosis after one month of follow-up, Scintimun had a slightly lower specificity (71.8 %) than 99mTc-WBCs (79.5 %).

There are insufficient data on the use of Scintimun for the diagnosis of diabetic foot infection.

5.2 Pharmacokinetic properties

Distribution

Whole blood concentration-time radioactivity curves show a two-phase course, which can be subdivided into an early phase (0–2 h) and a late phase (5–24 h). After correcting for the decay of radionuclide, the calculated half-life of the early phase is 0.5 h whereas the late phase shows a half-life of elimination of 16 h.

Organ uptake

Six hours after injection, about 1.5 % of the whole body radioactivity is found in the liver whereas about 3.0 % is found in the spleen. Twenty-four hours after injection, the percentages of radioactivity are 1.6 % in the liver and 2.3 % in the spleen.

Non pathological unusual accumulations may be observed in the spleen (up to 6 % of the patients), in the bowel (up to 4 % of the patients), in the liver and bone marrow (up to 3 % of the patients), and in the thyroid and kidneys (up to 2 % of patients).

Elimination

Measurement of radioactivity levels in urine shows that up to 14 % of the administered activity is excreted via the bladder during the 24 h post-injection. The low renal clearance of activity (0.2 L/h for a glomerular filtration rate around 7 L/h) indicates that the kidney is not the major route of besilesomab elimination.

5.3 Preclinical safety data

Preclinical toxicity and safety studies were performed using commercial kits reconstituted with decayed technetium (99mTc) and thus the effect of radiation has not been assessed.

Preclinical data obtained with the non-radioactive compound reveal no special hazard for humans based on conventional studies of safety pharmacology, single-dose and repeated-dose toxicity, although antimurine antibodies were found in all dose groups (including controls) in a repeated-dose study in monkeys. Genotoxicity studies conducted to test for potentially genotoxic impurities were also negative. Long-term carcinogenicity studies and toxicity to reproduction have not been carried out.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Scintimun vial:

Sodium dihydrogen phosphate, anhydrous

Disodium monohydrogen phosphate, anhydrous

Sorbitol E420

Under nitrogen atmosphere

Solvent for Scintimun vial:

• 1, 1, 3, 3-propane tetraphosphonic acid, tetrasodium salt, dihydrate (PTP)

Stannous chloride dihydrate

Sodium hydroxide / Hydrochloric acid (for pH adjustment)

Nitrogen

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 12.

6.3 Shelf life

3 years.

After radiolabelling: 3 hours.

Do not store above 25 °C after radiolabelling.

6.4 Special precautions for storage

Store in a refrigerator (2 °C – 8 °C).

Keep the vial in the outer carton in order to protect from light.

For storage conditions after reconstitution and radiolabelling of the medicinal product, see section 6.3.

Storage of radiopharmace­uticals should be in accordance with national regulation on radioactive materials.

6.5 Nature and contents of container

Scintimun v ial:

• 15 mL, colourless, type I glass vial, closed with chlorobutyl rubber stopper and aluminium crimped capsule (green) containing 5.02 mg of powder.

Solvent for Scintimun

• 15 mL, colourless, type I glass vial, closed with chlorobutyl rubber stopper and crimped aluminium capsule (yellow) containing 2.82 mg of powder.

Pack sizes:

Kit of one multidose vial of Scintimun and one vial of solvent.

Kit of two multidose vials of Scintimun and two vials of solvent.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

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.

Contents of the vial are intended only for use in the preparation of technetium(99mTc) besilesomab and are not to be administered directly to the patient without first undergoing the preparative procedure.

For instructions on reconstitution and radiolabelling of the medicinal product before administration, see sections 12.

If at any time in the preparation of this product the integrity of this vial 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 content of the kit before reconstitution is not radioactive. However, after sodium pertechnetate (99mTc) is added, adequate shielding of the final preparation must be maintained.

The administration of radiopharmace­uticals 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 medicinal product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

CIS bio international

B.P.32

F-91192 Gif-sur-Yvette Cedex

France

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/09/602/001

EU/1/09/602/002

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 11 January 2010

Date of latest renewal: 26 August 2014