CHOLEDIAM - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

CHOLEDIAM

Kit for the preparation of technetium [99mTc] mebrofenin injection

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

CHOLEDIAM, kit for the preparation of technetium [99mTc] mebrofenin injection, consists of 1 or 5 multidose vials, each containing the following sterile, pyrogen-free, freeze-dried product under nitrogen:

Mebrofenin (I.N.N.)                    :    40.0 mg

Stannous chloride dihydrate              :     0.6 mg

The product contains no antimicrobial preservative.

The product is to be used after reconstitution by the addition of sterile, pyrogen-free, isotonic sodium pertechnetate [99mTc] injection, allowing the preparation of technetium [99mTc] mebrofenin injection (technetium [99mTc] N-(2,4,6 trimethyl 3 bromophenyl­carbamoyl-methyl) iminodiacetic acid, i.e. technetium [99mTc] trimethyl-bromo-IDA).

The radionuclide is not part of the kit.

3. PHARMACEUTICAL FORM

Powder for injection.

4. CLINICAL PARTICULARS

4.1. Therapeutic Indications

After reconstitution with sodium pertechnetate [99mTc] injection :

– Hepatobiliary imaging.

– Hepatobiliary function studies.

4.2. Posology and Method of Administration

The solution is administered intravenously, to patients fasting for 6 hours prior to examination.

In adults, the dose is 150 to 300 MBq (4.1 to 8.1 mCi), other doses may be justifiable.

The dose to be administered in a child should be a fraction of the adult dose calculated from the body weight according to the following table:

Fraction of adult dose:

(Paediatric Task Group, EANM)

In very young children (up to 1 year), a minimum dose of 20 MBq (0.5 mCi) is necessary to obtain images of sufficient quality.

The examination as sequential or functional scintigraphy may be started immediately after injection.

Cholecystokinins or a fatty meal may be used to contract the gall bladder.

4.3. Contra-Indications

There are no specific contra-indications.

4.4. Special Warnings and Special Precautions for Use

This radiopharmaceutical may be used and administered only by authorised persons.

Radiopharmace­uticals intended for administration to patients should be prepared by the user in a manner which satisfies both radiological safety and pharmaceutical quality requirements.

The biliary tree may not be adequately visualised in the following circumstances :

– Parenteral nutrition

– Prolonged dieting

– After a meal : the test should be performed with the patient fasted for six hours

– Hepatocellular insufficiency

– Hepatitis

4.5. Interactions with other Medicinal Products and other Forms of Interaction

– Opiate analgesics and barbiturates cause spasm in the Sphincter of Oddi and increased

intrabiliary pressure. This increases biliary – bowel transit time and may enhance activity

in the gall bladder.

– Nicotinic acid is toxic to hepatocytes and may impair uptake and excretion of technetium

[99mTc] mebrofenin in bile.

– Gall bladder visualisation may be adversely affected in patients receiving chemotherapy

via an indwelling hepatic artery catheter, since a chemical cholecystitis has been described.

– Cholecystokinin and sincalide stimulate gall bladder emptying and secretion of the

radiotracer into the duodenum.

– Atropine and somatostatin may impair gall bladder emptying.

4.6. Pregnancy and Lactation

When it is necessary to administer radioactive medicinal products to a woman 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.

Radionuclide procedures carried out on pregnant women also involve radiation doses to the foetus. Only imperative investigations should be carried out during pregnancy, when the likely benefit exceeds the risk incurred by mother and foetus.

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, the breast feeding should be interrupted for 12 hours and the expressed feeds discarded. 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.

4.7. Effects on Ability to Drive and Use Machines

No effects on the ability to drive and operate machines are to be expected after use of this product.

4.8 Undesirable effects

Very rare cases of allergic type reactions may appear after administration of Mebrofenin.

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 these adverse effects will occur with low frequency because of the low radiation dose incurred.

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

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 Yellow Card Scheme at www.mhra.gov.uk/yellowcard.

4.9. Overdose

In the event of the administration of an overdose of a radiopharmace­utical, the absorbed dose to the patient should be reduced where possible by increasing the elimination of the radionuclide from the body.

In the event of an overdose of this technetium [99mTc] labelled compound, laxatives to aid faecal clearance are recommended.

In the event of biliary obstruction or significant parenchymal liver disease, overall tissue radiation may be reduced by implementing a regime of forced diuresis.

5. PHARMACOLOGICAL PROPERTIES

5.1. Pharmacodynamic Properties

At doses used for diagnostic procedures, technetium [99mTc] mebrofenin does not appear to exert any pharmacodynamic effects.

5.2. Pharmacokinetic Properties

Following intravenous injection, technetium [99mTc] mebrofenin is bound to plasma proteins and carried to the liver. It is cleared rapidly from the plasma, less than 1% of administered activity remaining 1 hour after injection. Technetium [99mTc] mebrofenin is taken up by active transport into hepatocytes in a manner similar to bilirubin, reaching peak activity in the liver in 12 minutes. The liver T1/2 is 25–30 minutes in healthy subjects but this may be influenced by plasma albumin concentration, hepatic blood flow and hepatocyte function. Tracer can be excreted unchanged into bile or bound to bile salts either within the hepatocyte or immediately after excretion. Small amounts only are excreted in the urine unless there is significant biliary obstruction.

In healthy subjects, the biliary tree is visualised within 5 – 20 minutes of injection and the gall bladder within 10 – 40 minutes.

5.3. Preclinical Safety Data

Toxicity after single administration

Trials of the acute intravenous tolerance of trimethyl-bromo-iminodiacetic acid have demonstrated:

– LD50 of 285 mg/kg body weight in mice

– LD50 of 250 mg/kg body weight in rats.

The maximum amount of technetium [99mTc] mebrofenin given to patients is approximately 0.6 mg/kg. This is a factor 500 lower than the animal LD50.

Toxicity after repeated administrations

No significant variations were observed in blood tests or histological studies of the major organs after daily injection of mebrofenin for 14 consecutive days in rats.

Mutagenicity or reproduction studies and long-term carcinogenicity studies have not been carried out.

5.4 Radiation dosimetry

According to publication N°53 by the ICRP (International Commission on Radiological Protection), the radiation doses absorbed, compared with the doses of technetium [99mTc] mebrofenin administered are the following in healthy adults :

– Gallbladder          : 1.1 × 10–1 mGy/MBq

– Liver               : 1.5 × 10–2 mGy/MBq

– Haematopoietic tissue : 7 × 10–3   mGy/MBq

– Kidneys             : 6.3 × 10–3 mGy/MBq

Technetium [99mTc] disintegrates with the emission of gamma radiation with an energy of 140 keV and a half life of 6.02 hours to technetium [99Tc] which can be regarded as quasi stable.

Tc-LABELLED IMINODIACETIC ACID

(IDA) DERIVATIVES

99mTc T1/2 = 6.02 hours

Healthy subject

Gastrointestinal tract

For this product, the effective dose equivalent resulting from an administered activity of 300 MBq is typically 7.2 mSv (per 70 kg individual).

Parenchymal liver disease

For this product, in case of parenchymal liver disease, the effective dose equivalent resulting from an administered activity of 300 MBq is typically 3.9 mSv (per 70 kg individual).

Occlusion of the cystic duct

For this product, in case of occlusion of the cystic duct, the effective dose equivalent resulting from an administered activity of 300 MBq is typically 5.4 mSv (per 70 kg individual).

Occlusion of the common bile duct

(mSv/MBq)

For this product, in case of occlusion of the common bile duct, the effective dose equivalent resulting from an administered activity of 300 MBq is typically 2.9 mSv (per 70 kg individual)

Newborns, congenital biliary atresia

6. PHARMACEUTICAL PARTICULARS

6.1. List of Excipients

Stannous chloride dihydrate

6.2. Incompatibilities

None known

6.3. Shelf-Life

The expiry date for this kit is 12 months from the day of manufacture. The expiry date is indicated on the outer packaging and on each vial.

The labelled product must be injected within 4 hours after reconstitution.

6.4. Special Precautions for Storage

The freeze-dried product is to be stored at a temperature ranging between +2°C and +8°C.

The reconstituted product is to be stored at a temperature ranging between +15°C and +25°C. Storage should be in accordance with national regulations for radioactive material.

6.5 Nature and contents of container

15 ml, colourless, European Pharmacopoeia type I, drawn glass vials, closed with chlorobutyl rubber stoppers and aluminium capsules.

Box of 1 or 5 multidose vials.

6.6. Instruction for Use, Handling and Disposal

– Method of preparation

Usual precautions regarding sterility and radioprotection should be respected.

Take a vial from the kit and put it in an appropriate lead shielding.

Using a hypodermic syringe, introduce through the rubber stopper 1 to 5 ml of sterile and pyrogen-free sodium pertechnetate [99mTc] injection, activity varying as a function of the volume from 0.74 to maximum 3.7 GBq (from 20 to maximum 100 mCi). Sodium pertechnetate [99mTc] injection should comply with European Pharmacopoeia specifications.

Do not use a breather needle as the contents are under nitrogen : after introduction of the volume of sodium pertechnetate [99mTc] injection, without removing the needle, let the piston rise into the syringe so as to reduce the excess of pressure.

Invert a few times the vial to dissolve the freeze-dried product, and then allow to stand for about 30 minutes at ambient temperature.

The obtained preparation is a clear and colourless solution, with a pH ranging between 4.0 and 6.0.

Limpidity of the solution after preparation, pH, radioactivity and gamma spectrum should be checked before use.

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 lead protected syringe.

7   MARKETING AUTHORISATION HOLDER

21 AVENUE DE VERDUN

59700 MARCQ-EN-BAROEUL FRANCE

8. MARKETING AUTHORISATION NUMBER

PL 22879/0001