Indio (111-In) ossina Curium Netherlands

PACKAGE LEAFLET

NAME OF THE MEDICINAL PRODUCT
Indio (¹¹¹In) Ossina Curium Netherlands 37 MBq/mL radiopharmaceutical precursor, solution
PHARMACOTHERAPEUTIC CATEGORY
Pharmacotherapeutic category: Diagnostic radiopharmaceuticals, detection of inflammation and infection,
Indium compounds (¹¹¹In).
ATC Code: V09HB01.
THERAPEUTIC INDICATIONS
Medicinal product for diagnostic use only.
Indio (¹¹¹In) oxine is used as a component for the in vitro radiolabelling of specific blood cells that have been appropriately separated, which are subsequently administered intravenously for various investigative purposes using appropriate imaging/cell counting procedures.
Investigative procedures using blood cells labelled with indium (¹¹¹In) include:

• Leukocytes or granulocytes labelled with ¹¹¹In: Investigations in inflammatory processes and abscesses, complementary to other imaging techniques; for example, localisation of focal infection sites such as abdominal abscesses, confirmation of bone infections following prosthetic implantation, investigations in fever of unknown origin, and evaluation of inflammatory conditions not associated with infection, such as inflammatory bowel disease. In skeletal areas containing red marrow, reduced uptake of ¹¹¹In-labelled leukocytes may be associated with osteomyelitis. Diffuse or local pulmonary uptake of ¹¹¹In-labelled leukocytes should be interpreted with caution, as it may result from physiological margination.
• Platelets (thrombocytes) labelled with ¹¹¹In: Determination of platelet survival and biodistribution; in particular, splenic and hepatic uptake in cases of thrombocytopenia, arterial or vascular thrombosis, aneurysms, and inflammatory sites in organ transplant rejection, such as renal and pancreatic sites.
• Erythrocytes labelled with ¹¹¹In: Investigations for sites of gastrointestinal bleeding.

CONTRAINDICATIONS
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
PRECAUTIONS FOR USE
Potential occurrence of hypersensitivity or anaphylactic reactions
If hypersensitivity or anaphylactic reactions occur, administration of the medicinal product must be immediately discontinued and, if necessary, intravenous treatment initiated. Medicinal products and equipment necessary for immediate emergency intervention, such as endotracheal tubes and ventilators, must be readily available.
Justification of individual benefit/risk ratio
For each patient, exposure to ionizing radiation must be justified based on potential benefits. The administered activity should be such that the resulting radiation dose is as low as reasonably achievable while still obtaining the desired diagnostic outcome.
Paediatric population
For information on use in the paediatric population, see section Dosage, Method and Time of Administration.
Extreme caution is required when evaluating the indication for use in the paediatric population, as the dose efficacy per MBq is higher than that used in adults (see section Dosimetry).
Specific warnings
The contents of the indium (¹¹¹In) oxine vial must be used only for the in vitro labelling of appropriately separated blood cells, avoiding direct administration to the patient.
Materials used for cell separation may cause hypersensitivity reactions. It is essential to remove sedimenting agents from the cells before re-injecting them into the patient.
Literature references regarding clinical uses of blood cells labelled with indium-111 mainly refer to the use of autologous blood cells; obviously, administration of donor cells may involve certain risks.
INTERACTIONS
No interaction studies have been conducted.
It has been reported that corticosteroids and antibiotics may reduce the uptake of ¹¹¹In-labelled leukocytes in abscesses, although clear evidence is still lacking. Antibiotics that are effective in treatment may impair leukocyte migration by reducing chemotactic stimuli.
SPECIAL WARNINGS
Women of childbearing potential
When administering radioactive medicinal products to women of childbearing age, it is always necessary to obtain information regarding possible pregnancy. Any woman who has missed a menstrual period should be considered pregnant until proven otherwise. In case of doubt, radiation exposure should be kept to the minimum compatible with obtaining the required clinical information. Alternative techniques not involving ionizing radiation should be considered. Women of childbearing age should be advised to take measures to avoid pregnancy until the calculated uterine dose falls below 0.5 mGy.
Pregnancy
There are no available data on the use of indium-111-labelled blood cells prepared with indium-111 oxine during human pregnancy. There is some evidence of teratogenicity of indium from animal studies.
Radionuclide procedures performed in pregnant women expose the fetus to radiation doses. Such investigations should only be carried out during pregnancy if absolutely necessary, when the probable benefit outweighs the risk to both mother and fetus.
Breast-feeding
Before administering a radioactive medicinal product to a breast-feeding woman, it is essential to evaluate whether the investigation can reasonably be delayed until the end of breast-feeding and whether the most appropriate radiopharmaceutical has been selected, considering the excretion of radioactivity into breast milk.
If administration of ¹¹¹In-labelled blood cells is considered necessary, interruption of breast-feeding is not required.
Fertility
The effect of administration of Indio (¹¹¹In) Ossina Curium Netherlands on fertility is unknown.
Effects on ability to drive and use machines
No studies have been performed on the effects on the ability to drive vehicles and use machines.
Important information on certain excipients
This medicinal product contains less than 1 mmol of sodium (23 mg) per dose, i.e. it is practically “sodium-free”.
DOSAGE, METHOD AND TIME OF ADMINISTRATION
Posology
The vial contains a sterile isotonic solution for the in vitro radiolabelling of blood cells, which are subsequently administered intravenously.
Leukocytes or granulocytes labelled with ¹¹¹In
The recommended activity for adults and elderly patients is 7.4–30 MBq administered intravenously. Scintigraphic studies to detect focal accumulations of ¹¹¹In-labelled leukocytes can be successfully initiated 3–6 hours after administration. However, relative accumulation in inflammatory lesions is significantly more pronounced if imaging is performed 24 hours after injection.
Platelets labelled with ¹¹¹In
The recommended activity for adults and elderly patients for platelet survival studies is 1.85–3.7 MBq, while for platelet distribution studies it is 3.7–18.5 MBq. In both cases, labelled platelets are administered intravenously.
In platelet survival studies, the timing and number of blood samples depend on the study objective and the presumed average platelet survival. Sampling is recommended at least 20 minutes, 2 hours, 3 hours, and 4 hours after injection, followed by daily sampling for up to 10 days.
Scintigraphic studies to detect deposition of labelled platelets can be successfully initiated 2–6 hours after administration. Imaging is recommended at multiple time points up to 48 or 72 hours after injection.
Erythrocytes labelled with ¹¹¹In
The recommended activity for adults and elderly patients is 3.7–30 MBq administered intravenously.
Use in children
The dosage to be administered to children can be approximately calculated by appropriately adjusting the adult activity based on weight, body surface area, or age. For neonates and children under one year of age, the size of the target organ relative to the whole body must also be considered.
In very young children (up to one year), a minimum dose of 10% of the recommended adult dose is required to obtain images of sufficient quality.
Method of administration
Intravenous use after in vitro labelling of blood cells.
Image acquisition
To evaluate hydrocephalus or obstruction of cerebrospinal fluid flow, the first imaging of the cranial region should preferably be performed 1–1.5 hours after injection. Further imaging investigations are performed at 3, 6, and 24 hours, or, if necessary, even at 48 or 72 hours after administration, depending on the required diagnostic information.
After suboccipital injection, scintigraphy should begin, if possible, as early as 15 minutes after injection. For subsequent imaging, the previously indicated times should be advanced by 1 or more hours.
In cases of otorrhoea or rhinorrhoea, the leakage may be so minimal that it is not detectable on scintigraphic images. Leaks through the nose or ear can be detected by placing hydrophilic cotton swabs in the external ear or nasal cavity and measuring their radioactivity.
OVERDOSE
In case of accidental administration of an excessive dose of indium-111-labelled blood cells, there are few possibilities for supportive treatment, as elimination of the radionuclide depends entirely on normal physiological cellular degradation.
UNDESIRABLE EFFECTS
Adverse reactions are listed below according to system organ class and frequency group. Frequencies are classified as: Very common (≥ 1/10); Common (≥ 1/100 to < 1/10); Uncommon (≥ 1/1,000 to < 1/100); Rare (≥ 1/10,000 to < 1/1,000); Very rare (< 1/10,000); Not known (frequency cannot be estimated from the available data).
For indium-111-labelled blood cells (i.e. the suspension for re-injection of labelled blood cells), the following adverse effects are known:

Very limited cases of hypersensitivity, manifested as cutaneous and generalized reactions, possibly of anaphylactic nature, have been reported following administration of blood cells labelled with indium-111. It should be noted that materials used for cell separation might also cause hypersensitivity reactions. It is essential to purify cells from sedimenting agents before re-injecting them into the patient (see also section 4.4).

Exposure to ionizing radiation is associated with the induction of cancer and, potentially, with the development of hereditary defects. Given that the effective dose is 10.8 mSv for labelled leukocytes (7.2 mSv for labelled platelets) when the maximum recommended activity of 30 MBq for labelling leukocytes (18.5 MBq for platelets) is administered, the risk of such adverse reactions is expected to be low.

Reporting of adverse reactions
If you experience any adverse reaction, including those not listed in this leaflet, please inform your doctor or pharmacist. You may also report adverse reactions directly via the national reporting system at the following address:
https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse .
By reporting adverse reactions, you can help provide more information on the safety of this medicinal product.

EXPIRY AND STORAGE
The expiry date is set at a maximum of 8 days after production (reference date of activity and time plus one day).
The Tris buffer expires 3 years after the date of manufacture.
Store below +25 °C.
This product does not contain antimicrobial preservatives.
Storage must comply with national regulations for radioactive materials.

COMPOSITION

• Indium (In) chloride 37 MBq
• Oxine 0.025 mg

Physical characteristics of the radioactive isotope (In) in the active substance:
Physical half-life: 2.8 days
Main radiation emitted:

Excipients:
Glacial acetic acid, Sodium acetate trihydrate, Sodium chloride, Ferric chloride hexahydrate,
Hydrochloric acid, Water for injections
Tris buffer (pH = 7.9 – 8.1): trometamol, hydrochloric acid, water for injections

PHARMACEUTICAL FORM AND CONTENT
Radiopharmaceutical precursor, solution (pH = 2.5 – 3.5).
10 mL glass vial (Type I Ph. Eur.) closed with a bromobutyl rubber stopper coated with
polytetrafluoroethylene (PTFE), sealed with a colorless aluminum crimp cap and provided with a
lead shielding container.
Tris buffer: 10 mL glass vial (Type I Ph. Eur.) closed with a bromobutyl rubber stopper and sealed
with a yellow aluminum crimp cap.

MARKETING AUTHORISATION HOLDER
Curium Netherlands B.V.
Westerduinweg 3
1755 LE Petten
The Netherlands

MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
Curium Netherlands B.V.
Westerduinweg 3
1755 LE Petten
The Netherlands

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

REVISION OF THE PACKAGE LEAFLET BY THE ITALIAN MEDICINES AGENCY

THE FOLLOWING INFORMATION IS INTENDED EXCLUSIVELY FOR HEALTHCARE PROFESSIONALS

Instructions for use
Withdrawals must be performed under aseptic conditions. The vial must not be opened before
disinfecting the stopper. The solution should be withdrawn through the stopper using a single-dose
syringe equipped with an appropriate lead shield and a sterile disposable needle.

Incompatibilities
Indium (In) oxine is a non-specific blood cell labelling agent which, in the presence of whole blood,
rapidly forms indium-111 labelled transferrin. Therefore, care must be taken during the preparation of
separated blood cells for labelling, to ensure removal of unwanted blood cells and other blood
proteins. It is essential that all glassware used in reagent preparation be thoroughly cleaned to ensure
absence of impurities such as traces of metal ions.

SPECIAL PRECAUTIONS FOR DISPOSAL AND HANDLING

General warnings
Radiopharmaceuticals must be received, used and administered only by authorized personnel in
specially designated healthcare facilities. Receipt, storage, use, transfer and disposal must comply with
local regulatory requirements and/or appropriate authorizations from competent authorities.

Radiopharmaceuticals must be prepared in accordance with both radiation protection standards and
pharmaceutical quality requirements. Adequate aseptic precautions must be taken.

If at any time during product preparation the integrity of the vial is compromised, the product must not
be used.

Administration procedures must be carried out in such a way as to minimize the risk of medicinal
product contamination and operator irradiation. Appropriate shielding is mandatory.

The administration of radiopharmaceuticals poses risks to other individuals due to external radiation
or contamination from excretion of urine, vomit, etc. Therefore, radiation protection measures must be
implemented in accordance with national regulations.

Waste disposal instructions:
Unused indium (In) oxine should be allowed to decay until its activity level is so low that, according to
local regulations, it is no longer considered radioactive. At that point, it may be disposed of as non-
hazardous waste. Unused vials containing lyophilized Tris buffer may be disposed of as non-
hazardous waste.

Any unused medicinal product and waste materials derived from such medicinal product must be
disposed of in accordance with local applicable regulations.

DOSIMETRY
Data are taken from ICRP Publication 53, International Commission on Radiological Protection,
"Radiation dose to Patients from Radiopharmaceuticals", Pergamon Press, 1988 (Annals of the ICRP,
Vol. 18 (1-4), 1987).

Indium (In)-labelled leukocytes:

Absorbed dose per unit of administered activity (mGy/MBq)

| Organ | Adult | 15 years | 10 years | 5 years | 1 year |
|-----------------------------|-------------|--------------|--------------|-------------|------------|
| Adrenal glands | 3.1E-01 | 4.0E-01 | 5.9E-01 | 8.2E-01 | 1.4E+00 |
| Bladder wall | 7.2E-02 | 1.0E-01 | 1.6E-01 | 2.4E-01 | 4.1E-01 |
| Bone surfaces | 3.5E-01 | 5.0E-01 | 8.0E-01 | 1.4E+00 | 2.9E+00 |
| Breast | 9.0E-02 | 9.0E-02 | 1.5E-01 | 2.3E-01 | 3.9E-01 |
| Gastrointestinal tract: | | | | | |
| Gastric wall | 2.8E-01 | 3.3E-01 | 4.9E-01 | 6.8E-01 | 1.1E+00 |
| Small intestine | 1.6E-01 | 1.9E-01 | 2.9E-01 | 4.3E-01 | 7.1E-01 |
| Upper large intestine wall | 1.6E-01 | 1.9E-01 | 3.0E-01 | 4.7E-01 | 7.8E-01 |
| Lower large intestine wall | 1.3E-01 | 1.6E-01 | 2.4E-01 | 3.3E-01 | 5.4E-01 |
| Heart | 1.7E-01 | 2.1E-01 | 3.0E-01 | 4.3E-01 | 7.3E-01 |
| Kidneys | 3.3E-01 | 3.9E-01 | 6.0E-01 | 8.7E-01 | 1.4E+00 |
| Liver | 7.1E-01 | 8.8E-01 | 1.3E+00 | 1.8E+00 | 3.2E+00 |
| Lungs | 1.6E-01 | 2.1E-01 | 3.1E-01 | 4.6E-01 | 8.1E-01 |
| Ovaries | 1.2E-01 | 1.7E-01 | 2.4E-01 | 3.5E-01 | 5.6E-01 |
| Pancreas | 5.2E-01 | 6.1E-01 | 9.1E-01 | 1.3E+00 | 2.1E+00 |
| Red bone marrow | 6.9E-01 | 8.8E-01 | 1.3E+00 | 2.3E+00 | 4.5E+00 |
| Spleen | 5.5E+00 | 7.6E+00 | 1.1E+01 | 1.7E+01 | 3.0E+01 |
| Testes | 4.5E-02 | 6.4E-02 | 9.9E-02 | 1.5E-01 | 2.8E-01 |
| Thyroid | 6.1E-02 | 9.0E-02 | 1.3E-01 | 2.1E-01 | 3.8E-01 |
| Uterus | 1.2E-01 | 1.4E-01 | 2.1E-01 | 3.0E-01 | 5.0E-01 |
| Other tissues | 1.1E-01 | 1.4E-01 | 2.0E-01 | 3.0E-01 | 5.3E-01 |
| Effective dose equivalent (mSv/MBq) | 5.9E-01 | 7.9E-01 | 1.2E+00 | 1.8E+00 | 3.2E+00 |

Indium (In)-labelled platelets:

Absorbed dose per unit of administered activity (mGy/MBq)

| Organ | Adult | 15 years | 10 years | 5 years | 1 year |
|-----------------------------|-------------|--------------|--------------|-------------|------------|
| Adrenal glands | 3.7E-01 | 4.7E-01 | 7.2E-01 | 1.0E+00 | 1.8E+00 |
| Bladder wall | 6.6E-02 | 9.2E-02 | 1.4E-01 | 2.2E-01 | 3.9E-01 |
| Bone surfaces | 2.3E-01 | 3.2E-01 | 5.1E-01 | 8.7E-01 | 1.8E+00 |
| Breast | 1.0E-01 | 1.1E-01 | 1.8E-01 | 2.9E-01 | 4.9E-01 |
| Gastrointestinal tract: | | | | | |
| Gastric wall | 3.5E-01 | 4.1E-01 | 6.0E-01 | 8.3E-01 | 1.4E+00 |
| Small intestine | 1.4E-01 | 1.7E-01 | 2.7E-01 | 4.2E-01 | 7.4E-01 |
| Upper large intestine wall | 1.4E-01 | 1.8E-01 | 2.9E-01 | 4.7E-01 | 8.0E-01 |
| Lower large intestine wall | 9.7E-02 | 1.3E-01 | 2.0E-01 | 2.9E-01 | 5.0E-01 |
| Heart | 3.9E-01 | 4.8E-01 | 7.1E-01 | 1.0E+00 | 1.8E+00 |
| Kidneys | 4.1E-01 | 5.0E-01 | 7.6E-01 | 1.1E+00 | 1.8E+00 |
| Liver | 7.3E-01 | 9.1E-01 | 1.3E+00 | 1.9E+00 | 3.4E+00 |
| Lungs | 2.8E-01 | 3.6E-01 | 5.5E-01 | 8.5E-01 | 1.5E+00 |
| Ovaries | 9.8E-02 | 1.3E-01 | 2.0E-01 | 3.1E-01 | 5.3E-01 |
| Pancreas | 6.6E-01 | 7.5E-01 | 1.1E+00 | 1.6E+00 | 2.6E+00 |
| Red bone marrow | 3.6E-01 | 4.6E-01 | 6.8E-01 | 1.1E+00 | 2.1E+00 |
| Spleen | 7.5E+00 | 1.0E+01 | 1.5E+01 | 2.3E+01 | 4.1E+01 |
| Testes | 4.3E-02 | 6.0E-02 | 9.1E-02 | 1.4E-01 | 2.7E-01 |
| Thyroid | 8.1E-02 | 1.1E-01 | 1.8E-01 | 2.9E-01 | 5.4E-01 |
| Uterus | 9.5E-02 | 1.2E-01 | 1.8E-01 | 2.8E-01 | 4.9E-01 |
| Other tissues | 1.2E-01 | 1.4E-01 | 2.1E-01 | 3.1E-01 | 5.6E-01 |
| Effective dose equivalent (mSv/MBq) | 7.0E-01 | 9.3E-01 | 1.4E+00 | 2.1E+00 | 3.7E+00 |

ICRP 80 provides a value of 3.6E-01 mSv/MBq as the effective dose for adults regarding indium (In)-labelled leukocytes. The effective dose resulting from an administered activity of 30 MBq of indium (In)-labelled leukocytes is therefore 10.8 mSv.

Furthermore, ICRP 80 provides a value of 3.9E-01 mSv/MBq as the effective dose for adults regarding indium (In)-labelled platelets. The effective dose resulting from an administered activity of 18.5 MBq of indium (In)-labelled platelets is therefore 7.2 mSv. These effective doses are within the same range as those resulting from commonly performed radiographic examinations.

Administration of 3 MBq of indium (In)-labelled leukocytes in very young children (up to 1 year of age) results in a spleen absorbed dose of 90 mGy and an effective dose equivalent of 9.6 mSv. Administration of 1.85 MBq of indium (In)-labelled platelets similarly results in a spleen absorbed dose of 76 mGy and an effective dose equivalent of 6.8 mSv.

ICRP 53 does not include dosimetry data for indium (In)-labelled erythrocytes. However, using the same methodology, the following effective dose equivalent has been calculated:

| Effective dose equivalent (mSv/MBq) | Adult | 15 years | 10 years | 5 years | 1 year |
|-----------------------------------------|-----------|--------------|--------------|-------------|------------|
| | 4.0E-01 | 4.0E-01 | 7.0E-01 | 1.1E+00 | 2.0E+00 |

The effective dose equivalent resulting from an administered activity of 18.5 MBq of indium (In)-labelled erythrocytes is 7.4 mSv.