1. NAME OF THE MEDICINAL PRODUCT

Multibone (EDTMP, Ethylene-diamine-tetramethylene-phosphonate) in vivo kit for preparation of radiopharmaceutical product (Sm-IK-26)

The pharmaceutical is to be prepared on the location of use (hospital or clinical laboratory) by mixing the content of the product and the ¹⁵³Sm-chloride labelling product.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

a.) Composition of the Multibone in vivo kit:

b.) Composition of 153Sm-chloride labelling product:

c.) Composition of 153Sm-Multibone radioactive injection:

3. PHARMACEUTICAL FORM

Pharmaceutical form of EDTMP in vivo kit: Powder for injection
Pharmaceutical form of ¹⁵³Sm-chloride: Sterile solution, not to be applied directly
as pharmaceutical
Pharmaceutical form of ¹⁵³Sm-Multibone: Radioactive, sterile injection

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

This medical product is for THERAPY purposes only.

Field of indication: pain killing, palliative treatment of previously localised bone lesions, especially recommended in the following cases:
– Palliative treatment of painful bone metastases of breast cancer
– Palliative treatment of bone metastases of prostate cancer
– Palliative treatment of bone metastases of other tumors

4.2 Posology and mode of administration

The quantity of ¹⁵³Sm-EDTMP prepared at one labelling represents a single dose of one patient. Labelling is to be carried out in the activity range of 1500-2500 MBq ¹⁵³Sm. Depending upon the weight of the patient, the number, size and prevalence of the bone metastases 1500-2500 MBq ¹⁵³Sm-Multibone is to be administered.

Recommended mode of administration:

¹⁵³Sm-Multibone is to be administered slowly as intravenous injection. Thereafter the patient is to be hydrated per os with 10 ml/kg body weight and/or the circulation is to be increased with slow injection of 20 ml physiology saline solution. The patient is to be kept under medical attendance for several hours. Urine excreted during this period is to be treated as radioactive waste.

4.3 Contraindications

RELATIVE CONTRAINDICATIONS
The use of the product is generally contraindicated
– at the age below 18 years except the expected therapy effect prevails the risk originating from the radiation exposure,
in case of patient with seriously impaired bone marrow since the risk of the therapy would be higher than the advantageous effect expected. The contraindication is especially valid if the following quantitative parameters of the patient are above/below the given limits:

ABSOLUTE CONTRAINDICATIONS
The use of the product is absolutely contraindicated
– in case of pregnant or lactating women,
– if the patient does not provide an oral or written consent of being treated with the radionuclide.

4.4 Special warnings and special precautions for use

The product is a radioisotope containing pharmaceutical. The rules for handling, transportation and storage of radioactive materials are applicable for the product.

The medicinal product can only be applied by properly qualified and trained personnel within designated clinical settings, which possess the appropriate government authorisation for the use and manipulation of radioisotopes.

The ¹⁵³Sm-Multibone therapy can be carried out in case of outpatients as well. After administration the patient is to be kept under medical attendance for several hours because the activity not bound to the bone lesions leaves during this period. The urine is to be handled as radioactive waste. It is advantageous that the physical half life of ¹⁵³Sm is 47 hours, after ten fold of the half life (3 weeks) the radioactivity can be considered as decayed.

4.5 Interactions with other medicinal products and other forms of interaction

No interaction has been reported.

4.6 Application during pregnancy and lactation

In general, application of the product during pregnancy and lactation is prohibited.

4.7 Effect of the product on ability to drive and on working in circumstances of significant accident risk

The product has no direct influence on ability of car driving or working in hazardous circumstances. In occurrence of unexpected side effects the ability to drive and the aptitude to work amidst accident risk are to be reconsidered.

4.8 Undesirable effects

The incidentally occurring temporary undesirable effects are divided into two groups:

Early side effects:

Late side effects:

– Temporary myelosuppression, which returns to normal after two weeks.

4.9 Overdose

There is no information available about any actually occurred overdose. Should still such a case occur the treatment should be directed towards the support of vital functions.

Administration of higher activity than prescribed results in unnecessary absorbed radiation dose on the patient and her/his environment, which is to be avoided. However, should such an event occur as the result of an error or a mistake of the personnel first of all the actually injected activity value of Tc-99m is to be determined. Then the absorbed dose (concerning both the whole body and the individual organs) is to be calculated based on the dosimetry table in paragraph 5.4. The table shows the absorbed dose values in µGy caused by introduction of 1 MBq Sm-153 isotope, which is to be multiplied by the MBq value of the actually injected activity so that the required absorbed dose is obtained. Whether the patient should undergo a treatment and/or an administrative radiation safety procedure is to be decided according to the calculated values.

If administered as prescribed one patient gets the content of one Multibone powder ampoule labelled with one ampoule of Sm-153 precursor, which represents 25 mg ¹⁵³Sm-EDTMP. If the content of two ampoules were administered mistakenly to a patient, whose probability is extremely slight, it equals to 50 mg.

Pursuant to intravenous acute toxicity experiments on mice no clinical symptoms can be observed up to 50 mg/kg body. In case of normal dosage and 70 kg body weight as average only 0.72% of the symptom free limit quantity is administered (0.357 mg/kg body). If as the result of an error a double treatment were occurred it would correspond to 0.714 mg/kg body i.e. 1.44% of the symptom free limit quantity.

Consequently, no toxic effect is expectable even in case of a doubled dose.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

ATC code: V10B X 02

EDTMP can be labelled with three different radionuclides: Labelled with ^99mTc it is suitable to follow up bone metastases, while in case of Sm-153 or Y-90 labelling palliative treatment of the same bone metastases can be carried out.

¹⁵³Sm-EDTMP active agent quickly leaves the bloodstream and is accumulated first of all in the bone lesions, in a less degree in the healthy bone and a negligible quantity appears in the soft tissues. The mechanism of the uptake is precipitation and chemisorption in the inorganic matrix of the bone (hydroxy-apatite of ionic nature, Ca₁₀(PO₄)₆(OH)₂), mostly in the lesions. Such in a place scilicet
– the blood supply of the bone and
– the bone formation (osteoblast) activity
increase.

Therefore, an increased radioactivity is observed in the lesions (primer tumours, metastases), which facilitates a selective, local radionuclide therapy. 47-77% of ¹⁵³Sm-EDTMP (in the activity range of 1500-2500 MBq) appears in the bone and bone lesions and the bone lesion / normal bone activity ratio may reach 16:1 even. In case of several and extensive lesions binding of ¹⁵³Sm-EDTMP is even more increased.

¹⁵³Sm-Multibone not bound to the bones is excreted with the urine, excretion through the hepatobiliary system is negligible.

The beta particles of 710 keV energy emitted by Sm-153 radionuclide display the therapy effect of ¹⁵³Sm-Multibone because they are absorbed in the tissues (including bone metastases) within 0.6 mm average distance. The maximum limit of the absorption range is 3 mm. The beta particles transmit their full energy to the tissues, bone lesions, in which they are absorbed. This energy is the agent that causes the palliative effect by the destruction of the tissues of the metastases. If treatment is performed by applying 1500-2500 MBq activity per patient, relatively low myelosuppressio can be observed within 1-2 weeks from the administration and the blood composition is fully regenerated within 3-4 weeks, supposed the activity of the administered Sm-153 does not exceed 40 MBq/kg body weight.

5.2 Pharmacokinetic properties

Sm-153-EDTMP introduced intravenously leaves the bloodstream quickly, 88-90% of the activity is eliminated within half an hour and 98% within 4 hours. The excretion can be characterised with four parallel processes described with exponential curves:
– Quick phase T_1/2 = 14 min
– Slow phase T_1/2 =11.5 hours

The activity necessary to achieve the therapy effect appears in the bone lesions 1-2 hours after administration. During that time 47-77% of the injected radioactivity is localised in the bone and bone lesions, in case of several and more extensive lesions the localisation is higher.

The non-bound activity proceeds to the kidneys and the urinary bladder (70% 2 hours after being injected, 90% after 4 hours and 100% after 12 hours). A negligible quantity appears in the liver and the intestines.

5.3 Preclinical safety data

Pursuant to intravenous acute toxicity experiments on mice no clinical symptoms can be observed up to 50 mg/kg body. Conducting the labelling procedure is easy and safe with the application of the Multibone (EDTMP) powder ampoule and the ¹⁵³Sm-chloride radioactive labelling product. The preparative made of the content of one Multibone powder ampoule and one ampoule of the labelling agent represents one single dose of one patient. In case of normal dosage and 70 kg body weight as average only 0.72% of the symptom free limit quantity is administered (0.357 mg/kg body).

Consequently, the application of the medicinal product is to be considered as safe.

Further advantage of the product is that the activity of the applied Sm-153 radionuclide (in the recommended range of 1500-2500 MBq) actually present has no effect on the quantity of the radiochemical impurities, i.e. their total quantity always remains below 5% permitted. Therefore, application of the medical product can be considered safe from the point of view of labelling.

5.4 Radiophysical properties of the radionuclide and the absorbed dose values

A single dose of a patient contains 1500-2500 MBq activity. In case of 70 kg average weight 1 MBq of the injection induces the following absorbed doses in the listed organs:

6. PHARMACEUTICAL PARTICULARS

6.1 List of Excipients

Excipients in the Multibone in vivo kit:

Excipients in the radioactive ¹⁵³Sm-chloride labelling product:

6.2 Incompatibilities

The Multibone in vivo kit is incompatible with any alkaline of higher quantity than the buffer capacity of the product since it increases the pH value when dissolving the content of the ampoule. Labelling takes place with a poorer efficiency in alkaline medium, therefore, the radiochemical purity of the preparative may decrease below the prescribed limit. Consequently, the cap and the plug of the ampoules can only be removed right before the radioactive labelling, which should be carried out strictly according to the instructions for use of the product.

The ¹⁵³Sm-Samarium-chloride labelling product is incompatible with any alkaline because it would cause hydrolysis of ¹⁵³Sm³⁺ cation before the formation of the complex, i.e. influences the circumstances of complex compound formation and this way the radiochemical purity of the preparative.

No interaction with other pharmaceuticals has been reported.

6.3 Shelf life

Shelf life of the Multibone in vivo kit (lyophilised non-radioactive components in glass ampoules closed with a rubber plug and an aluminium cap) is 12 months from the day of production.

One paper box contains 6 ampoules. Radioactive labelling of the content of the individual ampoules can be done at different occasions within the expiry date shown on the label of the ampoule and the paper box.

Shelf life of the radioactive Sm-153 labelling product is 5 days from the day of production, which is shown on the label of the ampoule, the lead pot and the external can.

The ¹⁵³Sm-EDTMP injection (Multibone labelled with ¹⁵³Sm radionuclide) is to be used within 24 hours from labelling.

6.4 Special precautions for storage

The Multibone in vivo kit is to be stored in a refrigerator at 2-8°C in its original paper box.

The Sm-153 labelling product is to be stored at room temperature in its original container.

Tc-99m-EDTMP injection is to be stored at room temperature (15-25oC) in accordance with the regulations on radioactive materials.

6.5 Nature and composition of the packaging

The Multibone in vivo kit in vivo kit contains the components shown in paragraph 2.a and 6.1 as sterile, pyrogen-free freeze dried material. Each ampoule (BEKA type vial of 6 ml) is labelled and closed with a rubber plug and an aluminium cap equipped with a removable plastic top.

6 labelled ampoules are placed in a white cardboard box of 150×100×60 mm dimensions. The box is lined with a spacer insert made of the same material as the box, which secures the ampoules safely. One box contains 6 ampoules, enough for 6 labellings (one labelling each).

The cardboard box is fastened with a celluloid shrinking foil. By removing the shrinking foil and lifting up the upper part of the box the ampoules are available.

The Sm-153 labelling product is packed in a labelled ampoule (BEKA type lyophilising vial of 6 ml) closed with a rubber plug and an aluminium cap. A labelled lead pot (type KT1 - KT6), which is capped with a lead cover and lined with a paper cylinder as spacer, serves as radiation shielding. The glass vial is placed in the paper cylinder and this way in the lead container as well. The labelled lead container is put in a sealed and labelled metal can containing plastic foam spacers.

Mode of opening the packaging of the radioactive product:

The product is a radioactive preparation, which should be opened truly according the following instructions:

During the operation the radiation safety regulations should be kept.

Tear off the top panel of the metal can. Remove the upper part of the plastic foam spacer. Lift the lead container out of the metal can and put it on the working area. Remove the seal strip and then the upper part of the lead pot. This way the glass vial containing the radioactive material is readily accessible.

6.6 Instruction for use and handling

The Multibone in vivo kit must not be used directly as an injection, only ¹⁵³Sm-EDTMP (EDTMP of the kit labelled with the ¹⁵³Sm-chloride labelling product) can be administered. ¹⁵³Sm-EDTMP is a solution containing a radioactive isotope. When preparing and using it both the pharmaceutical regulations and the rules concerning radioactive materials should be kept. Radioactive labelling is to be carried out as follows:

Place the glass vial containing the freeze-dried material in a small lead pot of 15 mm wall thickness (e.g. type KT-3). In aseptic conditions 2.0 ml physiological saline solution is injected into the vial through the rubber cap with a sterile syringe. After the content of the ampoule dissolved completely pump up the ¹⁵³Sm-chloride labelling product ordered for one patient (activity: 1500-2500 MBq, volume: 1 ml) with a sterile syringe equipped with lead shielding. It is injected to the ampoule containing the previously prepared EDTMP solution through the rubber plug. Shake the vessel thoroughly and let it stand at room temperature for 15 minutes. Thereafter the labelled compound can be administered intravenously. pH of the labelled preparative is 5.0-8.0 .

The labelled preparative must be used within 24 hours from labelling. The quantity of the radiochemical impurities must not exceed 5% during that time.

Radiochemical purity of ¹⁵³Sm-Multibone should be determined with a Paper Chromatography test.

Drop 5 µl of ¹⁵³Sm-Multibone solution on each of three Whatman 31 ET (cat. no.: 3031915) paper strips of 1.5×20 cm size 1.5 cm from the end. With using phosphate buffer (pH=7.5) as eluent let the front run approximately up to 12-15 cm. Then dry the chromatograms, coat them with approx. 5% polystyrene solution and after drying them again the distribution of the radioactivity is determined by a gamma scanner with moving table.

Approximate Rf values:

Free ¹⁵³Sm-chloride:    0.0-0.1
¹⁵³Sm-EDTMP:    0.9-1.0

Radiochemical purity is calculated with considering the peak areas. The activity corresponding to the ¹⁵³Sm-EDTMP peak compared to the total activity on the strip as 100% provides the radiochemical purity, which should be minimum 95% at expiry.

7. MARKETING AUTHORISATION HOLDER

Institute of Isotopes Co., Ltd..
1121 Budapest, Konkoly Thege Miklós út 29-33.
1535 Budapest, P.O.B. 851.

8. NUMBER OF THE MARKETING AUTHORISATION

5538/46/97

9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION

Original Marketing Authorisation:    Aug 7^th, 1997

10. DATE OF REVISION OF THE TEXT

February 18^th, 2003