2. november 2015
SUMMARY OF PRODUCT CHARACTERISTICS
for
Hippuran (I-123) Injection
Kit for radiopharmaceutical preparation
1
NAME OF THE MEDICINAL PRODUCT
Hippuran (I-123) Injection
Kit for radiopharmaceutical preparation
2
QUALITATIVE AND QUANTITATIVE COMPOSITION
123
I as sodium iodohippurate, 37 MBq
o-iodo hippuric acid, 5 mg
For a full list of excipients, see section 6.1.
3
PHARMACEUTICAL FORM
Kit for radiopharmaceutical preparation.
Solution for injection.
4
CLINICAL PARTICULARS
4.1
Therapeutic indications
This medicinal product is for diagnostic use only.
Investigation of renal function:
 Measurement of effective renal plasma flow
 split and regional renal function (i.e. duplicated kidneys)
 localisation of intact renal parenchyma
Dynamic renal scintigraphy for perfusion, function and urinary tract studies.
4.2
Posology and method of administration
Sodium Iodohippurate (123I) is administered intravenously. Paravasal deposition of radioactivity may cause local damaging effect and must therefore be avoided.
Adults
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For adults following activities are recommended:
Investigation of renal function:
 Blood sampling: 2 - 4 MBq
 Partially shielded whole body counter
(According to Oberhausen): 10 - 20 MBq
Dynamic renal scintigraphy for perfusion, function and urinary tract studies: 10 - 40 MBq
Children
The activities to be administered to children should be a fraction of the adult dose. Body
surface area is the more usual pro rata factor on which to base the adjustment of the administered activity according to the following formula:
Paediatric dose (MBq) =
Adult dose (MBq) x child surface (m2)
1.73
In some cases relative body weight may be considered more appropriate:
Paediatric dose (MBq) =
3 kg = 0.1
12 kg = 0.32
22 kg = 0.50
32 kg = 0.65
42 kg = 0.78
52-54 kg = 0.90
Adult dose (MBq) x child weight (kg)
70 kg
4 kg = 0.14
14 kg = 0.36
24 kg = 0.53
34 kg = 0.68
44 kg = 0.80
56-58 kg = 0.92
6 kg = 0.19
16 kg = 0.40
26 kg = 0.56
36 kg = 0.71
46 kg = 0.82
60-62 kg = 0.96
8 kg = 0.23
18 kg = 0.44
28 kg = 0.58
38 kg = 0.73
48 kg = 0.85
64-66 kg = 0.98
10 kg = 0.27
20 kg = 0.46
30 kg = 0.62
40 kg = 0.76
50 kg = 0.88
68 kg = 0.99
In very young children (up to 1 year) a minimum activity of 5 - 10 MBq is necessary for
scintigraphic studies in order to obtain images of sufficient quality.
4.3
Contraindications
Hypersensitivity to the active substance or to any of the excipients.
4.4
Special warnings and special precautions for use
This radiopharmaceutical may be used only by qualified personnel with the government
authorization for the use and manipulation of radionuclides.
The patient should hydrate before and drink and urinate frequently after scintigraphic studies in order to limit the radiation dose to the bladder.
The product administration to patients sensitive to iodine derivatives should be carefully
evaluated.
This medicinal product contains less than 1 mmol sodium (23 mg) per ml (1 maximal
dose), i.e. essentially “sodium – free”.
4.5
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Interaction with other medicinal products and other forms of interaction
Drugs, such as probenecid, interacting directly by decreasing the renal extraction fraction
of sodium iodohippurate (123I) may decrease the effective renal plasma flow (ERPF) with-
Page 2 of 10
out any variation in the true renal plasma flow.
Drugs which modify the renal hemodynamics (dopamine, frusemide, cyclosporine, ACEinhibitors in the presence of renovascular hypertension) may also alter the basal extraction
fraction of sodium iodohippurate (123I) by redistributing a variable fraction of the renal
plasma flow from the cortical to the medullary vasculature.
Drugs which induce transient (iodinated contrast agents) or long-standing (cyclosporine,
cisplatin) tubulopathies may reduce the extraction fraction (unrelated to a proportional decrease in glomerular rate).
4.6
Pregnancy and lactation
Sodium iodohippurate (123I) crosses the placenta and is secreted in breast milk. Any free
iodine released will have a longer retention half-life.
Pregnancy
Only imperative investigations should be carried out during pregnancy, when the likely
benefit exceeds the risk incurred by mother and foetus.
Radionuclide procedures carried out on pregnant women also involve radiation doses to the
foetus.
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.
Lactation
If the administration is considered necessary, breast-feeding should be interrupted for 12
hours and the expressed milk discarded. It is usual to advice that 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.
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.
4.7
Effects on the ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been performed.
4.8
Undesirable effects
Mild reactions e.g. transitory hypotension, sweating and nausea and in some cases severe
anaphylactic reactions have been reported
Congenital and familial/genetic disorders
Not known (cannot be estimated from the
available data)
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Hereditary defects1.
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Gastro-intestinal disorders
Not known (cannot be estimated from the
available data)
Nausea.
Skin and subcutaneous tissue disorders
Not known (cannot be estimated from the
available data)
Sweating.
Neoplasms benign and malignant (including cysts and polyps)
Not known (cannot be estimated from the
Cancer induction1.
available data)
Vascular disorders
Not known (cannot be estimated from the
available data)
Hypotension2.
Immune system disorders
Not known (cannot be estimated from the
available data)
Severe anaphylactic reactions.
1
2
Linked with ionising radiation.
Transitory
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 reasonable achievable bearing in mind the need to obtain the intended diagnostic or
therapeutic 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 (effective dose/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
Lægemiddelstyrelsen
Axel Heides Gade 1
DK-2300 København S
Websted: www.meldenbivirkning.dk
E-mail: dkma@dkma.dk
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4.9
Overdose
In the event of inadvertent administration of excess radioactivity the absorbed dose to the
patient may be limited by promoting a diuresis and frequent voiding of urine.
5
PHARMACOLOGICAL PROPERTIES
5.1
Pharmacodynamic properties
V 09 CX 01 - Diagnostic radiopharmaceuticals, other renal system.
At the chemical concentrations and activities used for diagnostic procedure sodium iodohippurate (123I) does not appear to exert any pharmacodynamic effects.
5.2.
Pharmacokinetic properties
After intravenous injection, sodium iodohippurate is rapidly distributed in the extracellular
fluid and excreted by the renal system, predominantly in the unmetabolised form.
Protein binding complexes are labile and dissociate rapidly.
About 30 % of sodium iodohippurate is loosely bound to red blood cells.
Sodium iodohippurate is excreted by both glomerular filtration (20 %) and tubular secretion (80 %) and is not reabsorbed.
Maximum renal uptake occurs normally within 2 - 5 minutes of intravenous injection, depending on the patient's state of hydration, degree of renal impairment, the nature of the
kidney disease and medication.
With normal renal function and hydration, 70 % of a single dose is excreted in the urine
within 30 minutes and hepatobiliary excretion is less than 0.4%. In cases of severe renal
failure, hepatobiliary excretion may increase to 5%.
Total body retention is described by a monoexponential function with a half-life of 25
minutes and renal transit time of 2.5 - 5.0 minutes.
With abnormal renal function renal transit time may increase to several hours or possibly
days.
Sodium iodohippurate (123I) crosses the placenta and is secreted in breast milk. Any free
iodine released will have a longer retention half-life.
5.3
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Preclinical data
Studies on acute toxicity were performed in mice, rats and rabbits. After single intravenous
injection of 50 mg/kg body weight (rats 25 mg/kg) sodium iodohippurate no adverse reactions or growth disturbances were noted over 3 weeks of observation. Rabbits also showed
no changes during 4 months of observation after intravenous doses of 2 - 2.5 mg/kg body
weight. Furthermore, no effects were seen in histological studies involving the heart, liver
and kidneys.
The LD50 of iodohippurate for mice was 3.8 g/kg body weight and 4.0 g/kg body weight
for rats.
Sodium iodohippurate (123I) is not intended for regular or continuous administration.
No studies on reproductive toxicity, mutagenic or cancerogenic potential were performed.
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6
PHARMACEUTICAL PARTICULARS
6.1
List of excipients
Water for injections
Citric acid
Sodium citrate
Sodium hydroxide.
The pH of the product is 3.5 - 4.5
6.2
Incompatibilities
In order to safeguard its stability, Hippuran (I-123) Injection should not be administered
together with other substances.
6.3
Shelf life
Hippuran (I-123) Injection expires 20 hours after the activity reference date and time.
Activity reference date and time and expiry date and time are stated on the label of the container and of the lead shielding and in the shipping papers accompanying each shipment.
6.4
Storage precaution
When the product is not to be used immediately upon arrival it may be stored for later use
in the intact packaging.
Do not store above 25° C.
However, if multi-dose use is intended, each aliquot should be removed under aseptic conditions and then the vial should be stored at 2 - 8 °C after removal of the first aliquot and
for no longer than 24 hours or up to end of shelf life, whichever comes first.
Storage should be in accordance with national regulations for radioactive material.
6.5
Nature and contents of the container
10 ml glass vial (Type 1 Ph.Eur) closed with a bromobutyl rubber stopper sealed with an
aluminium crimp cap.
Hippuran (I-123) Injection is supplied in the following activity amounts at activity reference time:

18.5 MBq (0.5 mCi) in 0.5 ml

37 MBq ( 1 mCi)
in 1 ml

74 MBq ( 2 mCi) in 2 ml
 185 MBq ( 5 mCi)
in 5 ml
 370 MBq (10 mCi) in 10 ml
Not all pack sizes may be marketed
6.6
Special precautions for disposal and other handling
Ready to use product.
The administration of radiopharmaceuticals creates risks for other persons from external
radiation or contamination from spills of urine, vomiting, etc. Radiation protection precau-
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tions in accordance with national regulations must therefore be taken.
Any unused product or waste material should be disposed of in accordance with local requirements for radioactive material.
7
8
MARKETING AUTHORISATION HOLDER
Mallinckrodt Medical B.V.
Westerduinweg 3
1755 LE Petten
The Netherlands
MARKETING AUTHORISATION NUMBER
DK R 1123
9
DATE OF FIRST AUTHORISATION
19. January 1996
10
DATE OF REVISION OF THE TEXT
2. november 2015
11.
DOSIMETRY
Physical characteristics of the nuclide
(123I) Iodine is a cyclotron product and decays to stable (123Te) Tellurium emitting of pure
gamma radiation with energies of 159 keV (83.4 %), 440 keV (0.4 %), and 529 keV (1.4
%) and a half-life of 13.2 hours.
The dosimetry data were quoted from ICRP publication 53.
Normal renal function
Absorbed dose per unit activity administered (mGy/MBq)
Organ
Adrenals
*Bladder wall
Bone surface
Breast
GI-tract
Stomach wall
*Small intestine
*ULI wall
*LLI wall
*Kidneys
Liver
Lungs
Ovaries
Pancreas
Red marrow
Spleen
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Adult
9.2E-04
2.0E-01
1.3E-03
4.4E-04
15 years
1.1E-03
2.5E-01
1.6E-03
4.4E-04
10 years
1.8E-03
3.7E-01
2.5E-03
7.0E-04
5 years
2.9E-03
5.5E-01
3.9E-03
1.2E-03
1 year
5.8E-03
1.0E+00
8.0E-03
2.5E-03
7.9E-04
3.2E-03
2.5E-03
7.5E-03
6.4E-03
7.2E-04
4.8E-04
7.3E-03
8.9E-04
2.5E-03
8.2E-04
9.7E-04
3.9E-03
3.2E-03
9.8E-03
7.9E-03
9.0E-04
6.2E-04
9.0E-03
1.0E-03
3.0E-03
1.0E-03
1.8E-03
6.5E-03
5.3E-03
1.5E-02
1.1E-02
1.6E-03
9.8E-04
1.4E-02
1.9E-03
4.3E-03
1.7E-03
3.0E-03
1.1E-02
8.9E-03
2.2E-02
1.6E-02
2.7E-03
1.6E-03
2.1E-02
3.1E-03
5.8E-03
2.8E-03
5.7E-03
1.9E-02
1.6E-02
3.9E-02
2.9E-02
5.2E-03
3.2E-03
3.6E-02
6.1E-03
8.7E-03
5.5E-03
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Testes
Thyroid
Uterus
Other tissues
Effective dose
equivalent
(mSv/MBq)
4.6E-03
3.7E-04
1.7E-02
2.2E-03
7.1E-03
5.6E-04
2.1E-02
2.6E-03
1.4E-02
9.1E-04
3.5E-02
4.0E-03
2.2E-02
1.5E-03
5.3E-02
6.3E-03
4.4E-02
2.9E-03
9.2E-02
1.1E-02
1.5E-02
1.9E-02
2.8E-02
4.3E-02
7.8E-02
The effective dose equivalent resulting from an administered activity of 40 MBq is typically 0.6 mSv.
The bladder wall contributes to 80 % of the effective dose equivalent.
Impurities:
Undesirable impurities of radionuclide ((124I) Iodine), (125I) Iodine can occur in some
methods of preparation of (123I) Iodine resulting in an increase of radiation exposure.
This has to be taken into account when estimating the absorbed dose. (According to the
monograph of the European Pharmacopoeia for sodium Iodohippurate (123I) not more than
0.3 % of the total radioactivity is due to radionuclides other than (123I) Iodine).
Effective dose equivalent (mSv/MBq of the impurity)
124
I
125
I
(4.18 d.)
(60.14 d.)
Adult
9.4E-02
1.0E-02
15 year
1.2E-01
1.3E-02
10 year
1.7E-01
2.0E-02
5 year
2.7E-01
3.1E-02
1 year
4.9E-01
6.0E-02
Abnormal renal function
Absorbed dose per unit activity administered (mGy/MBq)
Organ
Adrenals
*Bladder wall
Bone surface
Breast
GI-tract
Stomach wall
*Small intestine
ULI wall
*LLI wall
*Kidneys
*Liver
Lungs
Ovaries
Pancreas
Red marrow
Spleen
Testes
Thyroid
Uterus
Other tissues
Effective dose
equivalent
(mSv/MBq)
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Adult
5.3E-03
1.1E-01
5.1E-03
3.4E-03
15 years
6.5E-03
1.4E-01
6.2E-03
3.4E-03
10 years
1.0E-02
2.0E-01
9.7E-03
5.0E-03
5 years
1.6E-02
3.0E-01
1.5E-02
8.1E-03
1 year
2.9E-02
5.5E-01
3.0E-02
1.6E-02
4.4E-03
6.0E-03
5.6E-03
7.8E-03
2.7E-02
5.9E-03
3.8E-03
7.9E-03
5.1E-03
6.4E-03
4.9E-03
5.3E-03
3.0E-03
1.3E-02
4.5E-03
5.5E-03
7.3E-03
6.9E-03
1.0E-02
3.2E-02
7.6E-03
4.8E-03
9.8E-03
6.3E-03
7.8E-03
5.9E-03
7.4E-03
4.5E-03
1.6E-02
5.3E-03
8.8E-03
1.2E-02
1.1E-02
1.6E-02
4.5E-02
1.1E-02
7.3E-03
1.5E-02
9.9E-03
1.2E-02
9.3E-03
1.3E-02
7.4E-03
2.7E-02
8.3E-03
1.3E-02
1.8E-02
1.7E-02
2.3E-02
6.5E-02
1.6E-02
1.2E-02
2.4E-02
1.5E-02
1.7E-02
1.5E-02
2.1E-02
1.2E-02
4.1E-02
1.3E-02
2.4E-02
3.3E-02
3.1E-02
4.2E-02
1.1E-01
3.0E-02
2.2E-02
4.2E-02
2.8E-02
3.0E-02
2.6E-02
4.0E-02
2.2E-02
7.2E-02
2.4E-02
1.3E-02
1.6E-02
2.4E-02
3.7E-02
6.7E-02
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The effective dose equivalent resulting from an administered activity of 40 MBq is typically 0.52 mSv.
The bladder wall contributes to 50.8 % of effective dose equivalent.
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Unilateral renal blockage
Absorbed dose per unit activity administered (mGy/MBq)
Organ
Adrenals
*Bladder wall
Bone surface
Breast
GI-tract
Stomach wall
*Small intestine
ULI wall
*LLI wall
*Kidneys
*Liver
Lungs
Ovaries
Pancreas
Red marrow
Spleen
Testes
Thyroid
Uterus
Other tissues
Effective dose
equivalent
(mSv/MBq)
Adult
4.0E-02
1.1E-01
5.0E-03
1.2E-03
15 years
4.4E-02
1.3E-01
6.7E-03
1.2E-03
10 years
7.0E-02
2.0E-01
1.1E-02
2.7E-03
5 years
1.1E-01
3.0E-01
1.8E-02
4.2E-03
1 year
2.0E-01
5.4E-01
3.9E-02
7.7E-03
1.1E-02
1.0E-02
9.7E-03
6.2E-03
7.8E-01
1.2E-02
2.7E-03
7.1E-03
2.0E-02
1.3E-02
3.1E-02
2.8E-03
3.6E-04
1.2E-02
5.8E-03
1.1E-02
1.3E-02
1.2E-02
8.0E-03
9.4E-01
1.5E-02
4.1E-03
8.5E-03
2.4E-02
1.5E-02
3.9E-02
4.0E-03
5.4E-04
1.4E-02
6.9E-03
1.9E-02
2.1E-02
1.8E-02
1.3E-02
1.3E+00
2.4E-02
6.5E-03
1.4E-02
3.8E-02
2.2E-02
6.1E-02
7.8E-03
1.0E-03
2.4E-02
1.0E-02
2.5E-02
3.1E-02
2.8E-02
2.1E-02
1.9E+00
3.4E-02
1.1E-02
2.3E-02
5.5E-02
3.0E-02
9.1E-02
1.3E-02
2.1E-03
3.8E-02
1.6E-02
3.5E-02
5.4E-02
4.5E-02
3.4E-02
3.3E+00
5.3E-02
2.1E-02
4.1E-02
8.9E-02
4.3E-02
1.4E-01
2.7E-02
3.8E-03
6.5E-02
2.8E-02
6.2E-02
7.5E-02
1.1E-01
1.6E-01
2.7E-01
The effective dose equivalent resulting from an administered activity of 40 MBq is typically 2.48 mSv.
12.
INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS
This is a ready-to-use medicinal product for intravenous injection. Use under aseptic conditions.
Any unused product or waste material should be disposed of in accordance with local requirements.
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