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Kit for the preparation of Technetium [99mTc] Oxidronate Injection PATIENT INFORMATION LEAFLET
1. IDENTIFICATION OF THE MEDICINAL PRODUCT
Name of the Medicinal Product
OSTEOCIS®
Kit for the preparation of Technetium [99mTc] Oxidronate Injection.
Qualitative Composition Sodium oxidronate.
Quantitative Composition
Each vial contains 3 mg of sodium oxidronate.
Pharmaceutical Form
The product is a powder which, when mixed with a solution of the radioactive substance sodium pertechnetate [99mTc] forms a technetium [99mTc] oxidronate.
Pharmaco-Therapeutic Group
Technetium [99mTc] oxidronate is a diagnostic radiopharmaceutical. When injected the radiopharmaceutical temporarily collects in a particular organ of the body. Because the substance contains a small amount of radioactivity it can be detected from outside the body using special cameras, and a picture, known as a scan, can be taken. This scan will show exactly the distribution of the radioactivity within the organ and the body. This can give the physician valuable information about structure and function of that organ.
Name and Address of the Holder of the Marketing Authorisation
CIS bio international B.P. 32
91192 Gif-sur-Yvette Cedex FRANCE
PL/11876/0006
Name and Address of the Manufacturer
CIS bio international B.P. 32
91192 Gif-sur-Yvette Cedex FRANCE
2. WHEN IS THE PRODUCT USED ?
When injected, technetium [99mTc] oxidronate circulates in the blood and collects in the bones. A scan will then help your physician to determine if there is any bone abnormality.
3. WARNINGS
When should this Product not be used ?
There are no special circumstances in which this product must not be used.
IN CASE OF DOUBT IT IS ESSENTIAL TO CONSULT YOUR PHYSICIAN Special Warnings
The use of technetium [99mTc] oxidronate does involve administration of small amounts of radioactivity. The risk this involves is very small and your physician will not consider carrying out the investigation unless he believes that the risk is outweighed by the potential benefit of the study.
Precautions for Use
In order to ensure the most efficient use of the product, you are recommended to avoid strenuous exercise after injection until satisfactory scans have been taken.
Because technetium [99mTc] oxidronate is administered as a single dose by trained personnel there are no precautions which are your responsibility.
Your physician will inform you if you need to take any special precautions after use of this product.
IN CASE OF DOUBT DO NOT HESITATE TO CONSULT YOUR PHYSICIAN
Interactions with other Medicinal Products and other Forms of Interaction
Some medicines may affect the quality of the scans obtained from technetium [99mTc] oxidronate examinations.
IN ORDER TO AVOID POSSIBLE INTERACTIONS WITH OTHER MEDICINAL PRODUCTS, ANY OTHER CURRENT MEDICATION MUST BE NOTIFIED TO YOUR PHYSICIAN.
Pregnancy-Lactation
It is important to tell your physician if there is any possibility that you are pregnant. Special consideration is given to the use of radiopharmaceuticals during pregnancy. Your physician will only use this product if he considers that the potential benefit outweighs the risk.
Tell your physician if you are breast-feeding as he may delay the investigation until breast-feeding is completed or ask you to stop breast-feeding for a short while until the radioactivity is no longer in your body.
Effects on Ability to Drive or to Operate Machinery
Technetium [99mTc] oxidronate has no effect on your fitness to drive or to operate machinery.
Sportsmen and Sportswomen
There are no particular precautions for the use of technetium [99mTc] oxidronate by people engaged in active sport.
List of those Excipients, Knowledge of which is important for the Safe Use of the Medicinal Product in certain Patients
This product contains no ingredients which might necessitate special consideration being given to it's use for particular types of patients.
4. HOW IS THIS PRODUCT USED ?
Dosage
Your physician will decide on the amount of radioactive technetium [99mTc] oxidronate to be used. This will be the minimum amount necessary to give a scan clear enough to supply the required information. Doses may be from 40 MBq for small children, up to a maximum of 700 MBq (Megabecquerel - the unit in which radioactivity is measured).
Method and Route of Administration
Technetium [99mTc] oxidronate is administered by injection into a vein.
Frequency of Administration and appropriate Time of Administration
One injection is sufficient to provide your physician with the information needed. Before the scan you will be told to urinate. This will increase the quality of the scan.
Duration of the treatment
Scans may be taken during a few minutes after the injection in some cases or at 2 or 3 hours after the injection.
Action to be taken in the case of an Overdose
Since technetium [99mTc] oxidronate is administered by a physician under strictly controlled conditions there is a little chance of possible overdose.
Action to be taken when one or more doses have not been taken
Not applicable in the case of this medicinal product.
Risk of withdrawal effects No such risks occur with this product.
5. UNDESIRABLE EFFECTS
Technetium [99mTc] oxidronate does not normally produce any side effects.
Some allergic type reaction have been notified (rash, itching and skin irritation several hours after injection). On rare occasions, fall in blood pressure, hypotensive symptoms, nausea, vomiting, flushing, headache, malaise, swelling of the extremities and pain in joints have been reported.
INFORM YOUR PHYSICIAN IF YOU EXPERIENCE ANY ILL-EFFECTS
6. STORAGE
The product label includes the appropriate storage conditions and the expiry date for the batch of product. Hospital personnel will ensure that the product is stored correctly and not administered to you after the stated expiry date.
7. DATE OF LAST REVISION OF THE PACKAGE LEAFLET
04/2006
OSTEOCIS®
Kit for the preparation of Technetium [99mTc] Oxidronate Injection
USER PACKAGE LEAFLET
IDENTIFICATION OF THE MEDICINAL PRODUCT
Trade name of the medicinal product
OSTEOCIS®
Kit for the preparation of Technetium [99mTc] Oxidronate Injection
Qualitative and quantitative composition
OSTEOCIS®, kit for the preparation of Technetium [99mTc] Oxidronate Injection, consists of 5 multidose vials, each containing the following sterile, pyrogen-free, freeze-dried product under nitrogen :
|
Sodium oxidronate (I.N.N.) |
3.0 |
mg |
|
Stannous chloride dihydrate |
0.45 |
mg |
|
Ascorbic acid |
0.75 |
mg |
|
Sodium chloride |
10.0 |
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] Oxidronate Injection (technetium [99mTc] hydroxymethylene diphosphonate, i.e. technetium [99mTc] HMDP).
Nature and contents of container
15 ml, colourless, European Pharmacopoeia type I, drawn glass vials, closed with rubber stoppers and aluminium capsules.
Pharmaceutical form
Powder for injection.
Pharmaco-therapeutic group
Radiopharmaceutical product for diagnostic use.
Name and address of the marketing authorisation holder
CIS bio international B.P. 32
91192 Gif-sur-Yvette Cedex FRANCE
Tel. : +33-(0)1.69.85.70.70 Fax : +33-(0)1.69.85.70.71
Marketing authorisation n° : PL/11876/0006
Name and address of the manufacturer
CIS bio international B.P. 32
91192 Gif-sur-Yvette Cedex FRANCE
Tel. : +33-(0)1.69.85.70.70 Fax : +33-(0)1.69.85.70.71
PHARMACODYNAMIC PROPERTIES
At the chemical concentrations of radiopharmaceutical and excipients used for diagnostic procedures technetium [99mTc] oxidronate does not appear to exert any pharmacodynamic effect.
PHARMACOKINETIC PROPERTIES
Intravenously administered technetium [99mTc] oxidronate is rapidly distributed throughout the extracellular space. Skeletal uptake begins almost immediately and proceeds rapidly. 30 minutes post injection 10 % of the initial dose is still present in whole blood. At 1 hour, 2 hours, 3 hours and 4 hours after injection these values are resp. 5 %, 3 %, 1.5 % and 1 %. Clearance from the body takes place via the kidneys. Of the administered activity about 30 % is cleared within the first hour, 48 % within two hours and 60 % within 6 hours.
PRECLINICAL SAFETY DATA
This agent is not intended for regular or continuous administration. Reproduction, mutagenicity studies and long-term carcinogenicity studies have not been carried out.
Minimal liver abnormalities are seen at the level of 30 mg/kg in rats. In subacute toxicity studies rats do not react to the administration of 10 mg/kg/day for 14 days, dogs show histological changes in the liver (microgranuloma) after 3 and 10 mg/kg/day for 14 days. In dogs, treated for 14 consecutive days, long-lasting indurations at the site of injection were observed.
RADIATION DOSIMETRY
For this product the effective dose equivalent resulting from an administered activity of 700 MBq (18.9 mCi) is typically 5.6 mSv (per 70 kg individual).
For an administered activity of 700 MBq (18.9 mCi) the typical radiation dose to the target organ (bone) is 44.1 mGy and the typical radiation dose to the critical organ (bladder wall) is 35 mGy.
In cases of high bone uptake and/or severely impaired kidney function, the effective dose equivalent resulting from an administered activity of 700 MBq (18.9 mCi) of technetium [99mTc] oxidronate is 5.7 mSv. The typical radiation dose to the target organ is 84 mGy and the typical radiation dose to the critical organ (red marrow) is 12.6 mGy.
[99mTc] technetium disintegrates with the emission of gamma radiation with an energy of 140 keV and a half life of 6 hours to [99Tc] technetium which can be regarded as quasi stable.
The dosimetry data were quoted from ICRP publication 53 for phosphonates.
Radiation exposure (normal bone uptake) as absorbed dose / injected activity (mGy/MBq)
|
Organ |
Adult |
Children (age in years) | |||
|
15 |
10 |
5 |
1 | ||
|
Adrenals |
0.0019 |
0.0027 |
0.0039 |
0.0060 |
0.011 |
|
Bladder wall |
0.050 |
0.062 |
0.090 |
0.13 |
0.24 |
|
Bone surface |
0.063 |
0.082 |
0.13 |
0.22 |
0.53 |
|
Breast |
0.00088 |
0.00088 |
0.0014 |
0.0022 |
0.0042 |
|
Stomach wall |
0.0012 |
0.0015 |
0.0025 |
0.0037 |
0.0070 |
|
Small intestine |
0.0023 |
0.0028 |
0.0044 |
0.0066 |
0.012 |
|
Upper large intestine |
0.0020 |
0.0025 |
0.0038 |
0.0062 |
0.011 |
|
Lower large intestine |
0.0038 |
0.0047 |
0.0072 |
0.010 |
0.017 |
|
Kidneys |
0.0073 |
0.0089 |
0.013 |
0.018 |
0.033 |
|
Liver |
0.0013 |
0.0016 |
0.0024 |
0.0038 |
0.0070 |
|
Lungs |
0.0013 |
0.0016 |
0.0024 |
0.0036 |
0.0069 |
|
Ovaries |
0.0035 |
0.0046 |
0.0066 |
0.0097 |
0.016 |
|
Pancreas |
0.0016 |
0.0020 |
0.0030 |
0.0046 |
0.0085 |
|
Red marrow |
0.0096 |
0.013 |
0.020 |
0.038 |
0.075 |
|
Spleen |
0.0014 |
0.0018 |
0.0028 |
0.0043 |
0.0081 |
|
T estes |
0.0024 |
0.0033 |
0.0055 |
0.0084 |
0.016 |
|
Thyroid |
0.0010 |
0.0016 |
0.0022 |
0.0035 |
0.0056 |
|
Uterus |
0.0061 |
0.0076 |
0.012 |
0.017 |
0.028 |
|
Other tissue |
0.0019 |
0.0023 |
0.0033 |
0.0050 |
0.0089 |
|
Effective dose equivalent (mSv/MBq) |
0.0080 |
0.010 |
0.015 |
0.025 |
0.050 |
Radiation exposure
(high bone uptake and/or severely impaired kidney function) as absorbed dose / injected activity (mGy/MBq)
|
Organ |
Adult |
Children (age in years) | |||
|
15 |
10 |
5 |
1 | ||
|
Adrenals |
0.0035 |
0.0050 |
0.0072 |
0.011 |
0.021 |
|
Bladder wall |
0.0025 |
0.0035 |
0.0054 |
0.0074 |
0.015 |
|
Bone surface |
0.12 |
0.16 |
0.26 |
0.43 |
1.0 |
|
Breast |
0.0021 |
0.0021 |
0.0032 |
0.0051 |
0.0096 |
|
Stomach wall |
0.0026 |
0.0032 |
0.0051 |
0.0073 |
0.014 |
|
Small intestine |
0.0031 |
0.0038 |
0.0057 |
0.0085 |
0.016 |
|
Upper large intestine |
0.0029 |
0.0036 |
0.0053 |
0.0086 |
0.015 |
|
Lower large intestine |
0.0034 |
0.0042 |
0.0065 |
0.0096 |
0.018 |
|
Kidneys |
0.0030 |
0.0037 |
0.0056 |
0.0087 |
0.016 |
|
Liver |
0.0027 |
0.0033 |
0.0049 |
0.0075 |
0.014 |
|
Lungs |
0.0030 |
0.0037 |
0.0053 |
0.0081 |
0.015 |
|
Ovaries |
0.0029 |
0.0041 |
0.0059 |
0.0089 |
0.016 |
|
Pancreas |
0.0032 |
0.0040 |
0.0059 |
0.0089 |
0.016 |
|
Red marrow |
0.018 |
0.023 |
0.037 |
0.072 |
0.14 |
|
Spleen |
0.0026 |
0.0034 |
0.0051 |
0.0078 |
0.015 |
|
T estes |
0.0023 |
0.0027 |
0.0039 |
0.0060 |
0.011 |
|
Thyroid |
0.0024 |
0.0037 |
0.0054 |
0.0083 |
0.014 |
|
Uterus |
0.0029 |
0.0037 |
0.0054 |
0.0082 |
0.015 |
|
Other tissue |
0.0030 |
0.0036 |
0.0053 |
0.0081 |
0.015 |
|
Effective dose equivalent (mSv/MBq) |
0.0082 |
0.011 |
0.017 |
0.028 |
0.061 |
DIAGNOSTIC INDICATIONS
After reconstitution with sodium pertechnetate [99mTc] solution the agent may be used for bone scintigraphy, where it delineates areas of altered osteogenesis.
NECESSARY INFORMATION BEFORE TAKING THE MEDICINAL PRODUCT
Contra-indications
There are no specific contra-indications.
Special warnings and special precautions for use.
In infants and children particular attention should be paid to the relatively higher radiation exposure of the epiphyses in growing bone.
Appropriate precautions should be taken concerning the activity which is eliminated by the patients, to avoid any contamination. To reduce the radiation exposure to the bladder wall, sufficient hydration of the patient and frequent voiding is recommended.
To avoid accumulation of tracer in the musculature it is advised that strenuous exercise be discouraged immediately after injection until satisfactory bone imaging has been effected.
Inadvertent or accidental subcutaneous administration of technetium [99mTc] oxidronate should be avoided as perivascular inflammation has been described.
This radiopharmaceutical may be received, used and administered only by authorised persons in hospitals. Its receipt, storage, use, transfer and disposal are subject to the regulations and the appropriate licenses of the local competent official organisations.
Radiopharmaceuticals intended for administration to patients 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 Pharmaceutical Manufacturing Practice for pharmaceuticals.
Interaction with other medicaments and other forms of interaction
The accumulation of technetium [99mTc] oxidronate in the skeleton, and thus the quality of the scintigraphic procedure, may be decreased after medication with chelates, with diphosphonates, after tetracycline or after iron containing drugs.
Regular medication with aluminium containing drugs (notably antacids) may lead to abnormal high accumulation of technetium [99mTc] in the liver, presumably caused by formation of labelled colloids.
Pregnancy and lactation
When it is necessary to administer radioactive medicinal products to women 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 likely benefit exceeds the risk incurred by mother and foetus. Administration of 700 MBq technetium [99mTc] oxidronate to a patient with normal bone uptake results in an absorbed dose to the uterus of 4.27 mGy. The dose decreases to 2.03 mGy in patients with high bone uptake and/or severely impaired kidney function. Doses above 0.5 mGy would be regarded as a potential risk for the 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, one breast feed should be banked prior to injection and the subsequent one discarded after injection. Breast feeding can be restarted 4 hours post injection.
Effects on ability to drive and use machines
Effects on the ability to drive or to operate machines have not been described.
List of excipients
Stannous chloride dihydrate Ascorbic acid Sodium chloride
Incompatibilities
None known.
NECESSARY AND USUAL INSTRUCTIONS FOR PROPER USE
Posology and method of administration
The average activity administered by single intravenous injection is 500 MBq i.e. 300 - 700 MBq (13.5 mCi, i.e. 8.1 - 18.9 mCi) in a 50 to 70 kg adult. Other activities may be justifiable. There is no special dosage regimen for the elderly patient. The dose to be administered to a child should be a fraction of the adult dose calculated from the body weight according to the following table.
|
3 |
kg |
= |
0.10 |
22 kg |
= |
0.50 |
42 kg |
= |
0.78 |
|
4 |
kg |
= |
0.14 |
24 kg |
= |
0.53 |
44 kg |
= |
0.80 |
|
6 |
kg |
= |
0.19 |
26 kg |
= |
0.56 |
46 kg |
= |
0.82 |
|
8 |
kg |
= |
0.23 |
28 kg |
= |
0.58 |
48 kg |
= |
0.85 |
|
10 |
kg |
= |
0.27 |
30 kg |
= |
0.62 |
50 kg |
= |
0.88 |
|
12 |
kg |
= |
0.32 |
32 kg |
= |
0.65 |
52 - 54 kg |
= |
0.90 |
|
14 |
kg |
= |
0.36 |
34 kg |
= |
0.68 |
56 - 58 kg |
= |
0.92 |
|
16 |
kg |
= |
0.40 |
36 kg |
= |
0.71 |
60 - 62 kg |
= |
0.96 |
|
18 |
kg |
= |
0.44 |
38 kg |
= |
0.73 |
64 - 66 kg |
= |
0.98 |
|
20 |
kg |
= |
0.46 |
40 kg |
= |
0.76 |
68 kg |
= |
0.99 |
In very young children (up to 1 year) a minimum dose of 40 MBq (1.1 mCi) is necessary in order to obtain images of sufficient quality.
Images obtained shortly after injection (e.g. in the so-called "3-phase bone scan" procedure) will only partly reflect metabolic bone activity. Late phase static scintigraphy should be performed not earlier than 2 hours after injection. The patient should void before scanning.
Instructions for use/handling
- 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 2 to 10 ml of sterile and pyrogen-free sodium pertechnetate [99mTc] injection, radioactivity varying as a function of the volume from 0.74 to maximum 11.1 GBq (from 20 to maximum 300 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, withdraw an equivalent volume of nitrogen in order to avoid excess pressure in the vial.
Shake for about 2 minutes.
The obtained preparation is a clear and colourless solution, with a pH ranging between 5.0 and 7.0.
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 .
- Quality control
The quality of labelling (radiochemical purity) could be checked according to the following procedure.
Method
Thin-layer chromatography Materials and reagents
1. Adsorbent
2 ITLC-SG GELMAN strips (A and B) for thin-layer chromatography (2.5 x 20 cm) coated with silica gel. Trace a starting line 2.5 cm from one of the ends of each strip.
2. Nitrogen
3. Solvents
Solvent A : 0.9 % sodium chloride solution Solvent B : methanol-acetone (1/1)
4. Containers
Appropriate containers, such as 1000 ml Erlenmeyer flasks. Keep the containers stoppered and flush with a nitrogen stream before use.
5. Miscellaneous
Forceps, scissors, syringes, needles, appropriate counting assembly.
Procedure
Do not let air enter the vial to be tested and store all vials containing radioactive solution in lead shieldings.
1. Apply a spot of the preparation to the starting line of strip A using a syringe and needle. Apply another spot of the preparation to the starting line of strip B. Note the time. Dry under nitrogen.
2. Using forceps, introduce each strip vertically into the corresponding container for development (i.e. container with solvent A for strip A and container with solvent B for strip B), with the starting line downward. Stopper the containers.
3. When the solvent has reached the top of the strips, use the forceps to remove each strip and dry in the air.
4. After identifying the strips, cut strip A at Rf = 0.1 and strip B at Rf = 0.9.
5. Separately count each section of the strips and record the obtained values (use an appropriate detection apparatus with a constant counting time, and known geometry and background noise).
6. Calculations
Correct the counting data for background noise.
Calculate the percentage of hydrolysed technetium [99mTc] from counting data for the A strip :
% hydrolysed 99mTc = Error! X 100
Calculate the percentage of free technetium [99mTc] from counting data for the B strip :
% free 99mTc
= Error! X 100
Calculate the percentage of bound technetium [99mTc] (radiochemical purity) :
% bound 99mTc = 100 % - (% hydrolysed 99mTc + % free 99mTc)
7. The percentage of bound 99mTc (radiochemical purity) should be more than 95 % and the percentage of total hydrolysed 99mTc and free 99mTc should be less than 5 %.
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.
Radioactive waste must be disposed of in conformity with the relevant national and international regulations.
Overdose
In the event of the administration of a radiation overdose with technetium [99mTc] oxidronate 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 bladder voiding.
UNDESIRABLE EFFECTS
Adverse drug effects are extremely rare following administration of technetium [99mTc] oxidronate injection. Reports suggest an incidence of not more than one in 200 000 administrations. Symptoms of anaphylactoid reactions are rash, nausea, hypotension and sometimes arthralgia. Onset of symptoms may be delayed 4 to 24 hours after administration.
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 doses 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.
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 expiry date for the labelled product is 8 hours after labelling.
Special precautions for storage
This kit must be stored at a temperature ranging between +2°C and +8°C.
The labelled product must be stored at a temperature ranging between +2°C and +8°C.
DATE OF REVISION OF THE TEXT
04/2006
T2009nD
03.04.06