… to make life painless
MULTIBONE In Vivo Kit for ‘On the Spot’ Preparation of 153 Sm-EDTMP Injection
Composition of the MULTIBONE Kit (Sm-IK-26)
| Active Ingredient | |
| Ethylenediamine tetramethylene phosphonate (EDTMP) | 25.0 mg |
| Excipients | |
| Stannous chloride dihydrate | 1.0 mg |
| Ascorbic acid | 5.0 mg |
| Glucose anhydrous | 10.0 mg |
Composition of the Radioactive Precursor (Sm-RA-26)
| Active Ingredient | |
| [153Sm] samarium chloride | 2500 MBq |
| Excipients | |
| Sodium chloride | 9.0 mg |
| Water for injection | 1.0 ml |
Composition of the ‘On the Spot’ Prepared Injection
| 153 Sm-MULTIBONE (EDTMP) | 2500 MBq in 3.0 ml volume |
Radiation Properties
| Physical Half Life of 153Sm: | 46.27 hours | |
| Energy and Intensity of the Emitted Gamma Particles |
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| Energy and Intensity of the Emitted Beta Particles |
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| Specific Activity | ≥ 5 GBq/mg | |
| Radionuclidic Purity | 99.9 % | |
| Radiochemical Purity | Limit: ≥95 % | Usual Values Obtained in the Range of 99 ± 1% |
CLINICAL PARTICULARS
Indications
Palliative, analgesic treatment of previously localised bone metastases. Use of Multibone is highly recommended in the case of the bone metastases of breast or prostate cancer.
Posology
The labelling of one Multibone vial should be performed by using 2500 MBq of 153Sm precursor. The individual patient dose is 2500 MBq of 153Sm-Multibone per 70 kg bodyweight.
Method of Administration
153Sm-Multibone should be administered slowly, intravenously to the patient.
Following the administration, the patient should drink 100 ml/10 kg of bodyweight of liquid and/or the blood circulation should be stimulated by administration of 20 ml of saline intravenously. During several hours, medical attention should be provided for the patient’s benefit.
Outpatient’s treatment is possible.
Contraindications
The use of the product is contraindicated at the age under 18 years, except when the necessity and importance of the therapy outweighs the risk coming from the radiation exposure.
Serum Creatinine:> 120 mM / litre
| White Cell Count: | < 3 x 109 |
| Platelet Count: | < 120 x 109 |
| Karnofsky Index: | < 60 % |
The use of the product is contraindicated in case of pregnant or breast-feeding women, or if the patient does not provide an oral or written consent of being treated with the radionuclide.
Special Warnings and Precautions for Use
153Sm-Multibone therapy can be carried out also in case of outpatients. After administration of the preparation, the patient should be kept under medical attendance for several hours because the activity not bound to the bone lesions is excreted during this period.
Interaction with Other Medicinal Products and Other Forms of Interaction
None stated.
Pregnancy and Lactation, Paediatrics
Administration of Multibone to pregnant or lactating women is contraindicated unless the necessity and importance of acquiring the information outweighs the risk coming from the radiation exposure.
The product can be administered to women of childbearing age after the possibility of pregnancy has been precluded. It is recommended to treat these women in the first 10 days after menstruation.
Multibone should not be administered to patients below 18 years of age, unless the necessity and importance of acquiring the information outweighs the risk coming from the radiation exposure.
Effects on Ability to Drive and Use Machines
MULTIBONE has no direct influence on these abilities.
UNDESIRABLE EFFECTS
Early Effects
1 – 2 hours after the intravenous administration nausea may occur.
After 2 – 3 days, temporary increase of the bone pain may occur, lasting for maximum 1 week. This ’flare-up’ usually predicts the chance of the good therapeutic effect.
CLINICAL PARTICULARS
Indications
Palliative, analgesic treatment of previously localised bone metastases. Use of Multibone is highly remommended in the case of the bone metastases of breast or prostate cancer.
Overdose
No case of overdose has been reported. In the unlikely event of overdose the vital functions of the patient should be supported.
Radiation Dosimetry
A single dose of a patient contains 2500 MBq of 153Sm activity.
In case of 70 kg body weight, 1 MBq of the injection causes the following absorbed doses:
| Organ | Absorbed Dose (mGy/MBq) |
| Trabecular Bone | 2.32 |
| Cortical Bone | 0.86 |
| Red Bone Marrow | 1.86 |
| Kidneys | 0.134 |
| Urinary Bladder | 0.120 |
| Stomach | 0.026 |
| Liver | 0.043 |
Palliative Effect
Around 1000 patients have been treated with 153Sm-Multibone injection.
The palliative effect usually lasts for 3 – 6 months. If necessary, the 153Sm-Multibone treatment can be repeated after 3 months.
Pain relief has been quantified in case of 54 patients treated with 153Sm-Multibone, by using a 10 grade pain scale. The lowest and highest score, i.e. 0 and 10 corresponded to the painless state and to the intolerable pain, respectively. Results are presented in the figure below:
PHARMACOLOGY
Pharmacodynamic Properties
ATC code: V10B X 02
47-77% of the administered 2500 MBq of 153Sm-EDTMP is accumulated in the bone and in the bone lesions. The lesion / normal bone activity ratio can be even 16:1. The non-bound activity of 153Sm-Multibone is excreted almost exclusively via the urinary tract. The beta particles of average energy of 710 keV are absorbed in bone metastases around 0.6 mm distance as average, providing the therapeutic effect of 153Sm-Multibone. The upper 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 transfer causes the palliative effect by the destruction of the tissues of the lesions.
Pharmacokinetic Properties
88-90% of the administered 153Sm-Multibone activity is eliminated within half an hour and 98% of it within 4 hours. The excretion can be characterised by two parallel processes described by T1/2 values as follows:
| Quick phase | T1/2 = | 14 | min |
| Slow Phase | T1/2 = | 11.5 | hours |
The activity needed to achieve the therapeutic 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, but in case of several and more extensive lesions the accumulation is greater.
The non-bound activity appears in 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.
Preclinical Safety Data
Intravenous acute toxicity experiments of Multibone on mice showed that no clinical symptoms have been observed up to 50 mg/kg of body weight. One patient dose (25 mg EDTMP in one vial labelled with 2500 MBq 153Sm) corresponds to a value of 0.375 mg/kg body weight (in case of the average body weight of 70 kg ) which is equal to 0.72 % of the dose causing absolutely no symptoms. Thus, MULTIBONE is considered as a safe product.
PHARMACEUTICAL PARTICULARS
List of Excipients
Stannous chloride dihydrate, ascorbic acid, glucose anhydrous, sodium chloride, water for injection.
Shelf Life
Shelf life of Multibone in vivo kit is 12 months from the day of production.
Shelf life of the 153Sm precursor is 5 days from the day of the production.
The ’on the spot’ prepared 153Sm-Multibone injection should be used within 24 hours from labelling.
Packaging
One paper box of Multibone in vivo kit contains 6 vials of the sterile and bacterial endotoxin-free, freeze-dried, non-radioactive components. Vials are closed with rubber stopper and tear-off aluminium cap.
153Sm-chloride precursor of activity of 2500 MBq, for preparation of a single dose of the 153Sm-Multibone injection, is supplied in BEKA type 6 ml injection vials closed with rubber stopper and tear-off aluminium cap. The labelled vial is placed in a lead container, packed in a labelled tear-off metal can, containing plastic insert (Type A packaging for radioactive materials).
One vial from the six of Multibone kit in front of its paper box (left side), as well as the packaging of a single dose of the radioactive 153Sm precursor (right side) are shown in the figure below.
Special Precautions for Storage
Multibone in vivo kit should be stored at 2-8°C in its original paper box.
153Sm-chloride precursor should be stored at room temperature in its original container.
The ’on the spot’ prepared 153Sm-Multibone injection should be stored at room temperature in lead container fulfilling the rules concerning radioactive materials.
Labelling Procedure
Place one vial of the Multibone in vivo kit in a small lead container of 15 mm wall thickness. Under aseptic conditions, inject 2.0 ml of physiological saline into the vial through the rubber stopper. After complete dissolution of the powder, inject the single dose (2500 MBq) of 153Sm-samarium chloride precursor. Shake the vessel thoroughly and allow it to stand at room temperature for 15 minutes. After that, the 153Sm-Multibone injection is ready for intravenous administration.
Control of the Radiochemical Purity
Radiochemical purity of 153Sm-Multibone is tested by using paper chromatography.
Stationary phase: 1.5 x 20 cm stripes of Whatmann ET-31 (catalogue code: 3031915)
Mobile phase: Phosphate buffer, pH=7.5
Distribution of radioactivity: 153Sm-chloride impurity at Rf = 0 – 0.1, 153Sm-EDTMP at Rf = 0.9 – 1.0.
The activity corresponding to 153Sm-EDTMP peak compared to the total activity on the strip as 100% provides the radiochemical purity, which should be not less than 95% at expiry.
Marketing authorization in Hungary: No.OGYI-T- 9192/01, (19.01.2004; first authorization: 07.08.1997)