SomaKit TOC 40 micrograms kit for radiopharmaceutical preparation

This medicinal product is for diagnostic use only.

After radiolabelling with gallium (⁶⁸Ga) chloride solution, the solution of gallium (⁶⁸Ga) edotreotide obtained is indicated for positron emission tomography (PET) imaging of somatostatin receptor overexpression in adult patients with confirmed or suspected well-differentiated gastro-enteropancreatic neuroendocrine tumours (GEP-NET) for localising primary tumours and their metastases.

The medicinal product should only be administered by trained healthcare professionals with technical expertise in using and handling nuclear medicine diagnostic agents and only in a designated nuclear medicine facility.

Posology

The recommended activity for an adult weighing 70 kg is 100 to 200 MBq, administered by direct slow intravenous injection.

The activity will be adapted to patient characteristics, the type of PET camera used and acquisition mode.

Elderly

No special dose regimen for elderly patients is required.

Renal/Hepatic impairment

The safety and efficacy of gallium (⁶⁸Ga) edotreotide have not been studied in patients with renal or hepatic impairment.

Paediatric population

The safety and efficacy of gallium (⁶⁸Ga) edotreotide have not been established in paediatric populations, where the effective dose might be different than in adults. There is no recommendation for use of SomaKit TOC in paediatric patients.

Method of administration

SomaKit TOC is for intravenous use and for single use only.

This medicinal product should be radiolabelled before administration to the patient.

The activity of gallium (⁶⁸Ga) edotreotide must be measured with an activimeter immediately prior to injection.

The injection of gallium (⁶⁸Ga) edotreotide must be administered intravenously in order to avoid local extravasation resulting in inadvertent radiation to the patient and imaging artefacts.

For instructions on extemporaneous preparation of the medicinal product before administration, see sections 6.6 and 12.

For patient preparation, see section 4.4.

Image acquisition

Radiolabelled SomaKit TOC is suitable for PET medical imaging. The acquisition must include a whole body acquisition from skull to mid-thigh. The recommended time for imaging is 40 to 90 minutes post injection. Imaging acquisition start time and duration should be adapted according to the equipment used, the patient and the tumour characteristics in order to obtain the best image quality possible.

Hypersensitivity to the active substance, to any of the excipients listed in section 6.1 or to any of the components of the labelled radiopharmaceutical.

Potential for hypersensitivity or anaphylactic reactions

If hypersensitivity or anaphylactic reactions occur, the administration of the medicinal product must be discontinued immediately and intravenous treatment initiated, if necessary. To enable immediate action in emergencies, the necessary medicinal products and equipment such as endotracheal tube must be immediately available.

Individual benefit/risk justification

For each patient, the radiation exposure must be justifiable by the likely benefit. The activity administered should in every case be as low as reasonably achievable to obtain the required diagnostic information.

Renal/Hepatic impairment

Careful consideration of the benefit/risk ratio in these patients is required since an increased radiation exposure is possible.

Paediatric population

For information on use in the paediatric population, see section 4.2.

Patient preparation

The patient should be well hydrated before the start of the examination and urged to void as often as possible during the first hours after examination in order to reduce radiation.

Errors of interpretation of gallium (⁶⁸Ga) edotreotide images

PET images with gallium (⁶⁸Ga) edotreotide reflect the presence of somatostatin receptors in the tissues.

The organs with high physiological uptake of gallium (⁶⁸Ga) edotreotide include spleen, kidneys, liver, pituitary gland, thyroid gland and adrenals. High physiological uptake of gallium (⁶⁸Ga) edotreotide by the pancreas uncinate process can also be observed.

An increased uptake of gallium (⁶⁸Ga) edotreotide is not specific for GEP-NET. Healthcare professionals should be aware that further imaging or histological and/or other relevant investigations may be required to establish the diagnosis. Due to physiological uptake of gallium (⁶⁸Ga) edotreotide, splenosis and accessory intrapancreatic spleen may be incidentally detected with somatostatin receptor targeted diagnostics. Cases in which such uptake has been misdiagnosed as neuroendocrine tumours, leading to unnecessary intervention, have been reported. Spleen disorders (e.g. splenectomy, splenosis and accessory intrapancreatic spleen) should therefore be considered as a relevant factor when reporting the outcome of somatostatin receptor targeted diagnostics.

Positive results also require evaluating the possibility that another disease, characterised by high local somatostatin receptor concentrations, may be present. As an example, an increase in somatostatin receptor density can also occur in the following pathological conditions: subacute inflammations (areas of lymphocyte concentrations, including reactive lymph nodes, for example following vaccination), thyroid diseases (e.g. thyroid autonomy and Hashimoto's disease), tumours of the pituitary gland, neoplasms of the lungs (small-cell carcinoma), meningiomas, mammary carcinomas, lymphoproliferative disease (e.g. Hodgkin's disease and non-Hodgkin lymphomas) and tumours arising from tissue embryologically derived from the neural crest (e.g. paragangliomas, medullary thyroid carcinomas, neuroblastomas, pheochromocytomas).

In case of Cushing syndrome, a long-term exposure to endogenous hypercortisolism may down regulate somatostatin receptor expression and negatively influence the results of somatostatin receptor imaging with gallium (⁶⁸Ga) edotreotide. Thus, in patients with GEP-NET and Cushing syndrome, normalisation of hypercortisolism should be suggested before performing PET with gallium (⁶⁸Ga) edotreotide.

Limitations of gallium (⁶⁸Ga) edotreotide imaging

In GEP-NET, a more intense gallium (⁶⁸Ga) edotreotide uptake than normal background is a consistent finding. However, lesions of GEP-NET not expressing sufficient density of somatostatin receptors cannot be visualised with gallium (⁶⁸Ga) edotreotide. PET images with gallium (⁶⁸Ga) edotreotide should be interpreted visually, and semiquantitative measurement of gallium (⁶⁸Ga) edotreotide uptake should not be used for clinical interpretation of images.

Data supporting efficacy of gallium (⁶⁸Ga) edotreotide for predicting and monitoring of therapeutic response to peptide receptor radionuclide therapy (PRRT) in histologically confirmed metastatic NET are limited (see section 5.1).

Concomitant use of somatostatin analogues

It is preferable to perform imaging with gallium (⁶⁸Ga) edotreotide the day(s) before the next administration of a somatostatin analogue. See section 4.5.

After the procedure

Close contact with infants and pregnant women should be restricted during the first 12 hours after administration.

Specific warnings

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially 'sodium-free'.

Due to the acidic pH of the radiolabelled gallium (⁶⁸Ga) edotreotide solution, accidental extravasation may cause local irritation. In case of extravasation, the injection must be stopped, the site of injection must be changed and the affected area should be irrigated with sodium chloride solution.

Precautions with respect to environmental hazard are in section 6.6.

Somatostatin and its analogues are probably competing to bind to the same somatostatin receptors. Therefore, when treating patients with somatostatin analogues, it is preferable to perform imaging with gallium (⁶⁸Ga) edotreotide the day(s) preceding the next administration of a somatostatin analogue.

A long-term exposure to endogenous hypercortisolism may down-regulate somatostatin receptor expression and negatively influence the results of somatostatin receptor imaging with gallium (⁶⁸Ga) edotreotide. In patients with Cushing syndrome, the normalisation of hypercortisolism should be considered before performing PET with SomaKit TOC.

Some evidence exists that corticosteroids can induce down-regulation of somatostatin subtype 2 receptors (SSTR2). Repeated administration of high-doses of glucocorticosteroids prior to gallium (⁶⁸Ga) edotreotide administration may cause insufficient SSTR2 expression for adequate visualisation of somatostatin receptor-positive NETs.

Women of childbearing potential

When an administration of radiopharmaceuticals to a woman of childbearing potential is intended, it is important to determine whether or not she is pregnant. Any woman who has missed a period should be assumed to be pregnant until proven otherwise. If in doubt about her potential pregnancy (if the woman has missed a period, if her periods are very irregular, etc.), alternative techniques not using ionising radiation (if there are any) should be offered to the patient.

Pregnancy

No data are available regarding the use of this medicinal product during pregnancy. Radionuclide procedures carried out on pregnant women also involve radiation doses to the fœ tus. Only essential investigations should therefore be carried out during pregnancy, when the likely benefit far exceeds the risk incurred by the mother and fœ tus.

Breast-feeding

Before administering radiopharmaceuticals to a mother who is breast-feeding, consideration should be given to the possibility of delaying the administration of radionuclide until the mother has ceased breast-feeding, and to what is the most appropriate choice of radiopharmaceuticals, bearing in mind the secretion of activity in breast milk. If the administration is considered necessary, breast-feeding should be interrupted for 12 hours and the expressed feeds discarded.

Close contact with infants should be restricted during the initial 12 hours following injection.

Fertility

No studies were conducted to assess the impact on fertility.

Gallium (⁶⁸Ga) edotreotide has no or negligible influence on the ability to drive and use machines.

Exposure to ionising radiation is linked with cancer induction and a potential for development of hereditary defects. As the effective dose is about 4.5 mSv when the maximal recommended activity of 200 MBq is administered, these adverse reactions are expected to occur with a low probability.

Adverse reactions are divided into groups according to the MedDRA convention frequencies: 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 (cannot be estimated from the available data).

General disorders and administration site conditions

Not known: injection site pain

Description of selected adverse reactions

Cases in which physiological uptake of gallium (⁶⁸Ga) edotreotide by splenic tissue has been misdiagnosed as neuroendocrine tumour, leading to unnecessary intervention, have been reported (see section 4.4).

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 the national reporting system:

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

In the event of administration of a radiation overdose, the absorbed dose to the patient should be reduced where possible by increasing the elimination of the radionuclide from the body by reinforced hydration and by frequent micturition. It might be helpful to estimate the effective dose that was applied.

Pharmacotherapeutic group: Diagnostic radiopharmaceuticals; other diagnostic radiopharmaceuticals for tumour detection. ATC code: V09IX09.

Mechanism of action

Gallium (⁶⁸Ga) edotreotide binds to somatostatin receptors. In vitro, this radiopharmaceutical binds with high affinity mainly to SSTR2 but also, to a lesser extent, to SSTR5.

In vivo, semiquantitative correlation was not assessed between gallium (⁶⁸Ga) edotreotide uptake in tumours and the density of SSTR in histopathological samples either in GEP-NET patients or in normal organs. Moreover, the in vivo binding of gallium (⁶⁸Ga) edotreotide to structures or receptors other than SSTR remains unknown.

Pharmacodynamic effects

At the chemical concentrations used for diagnostic examinations, gallium (⁶⁸Ga) edotreotide does not appear to have any clinically relevant pharmacodynamic effect.

Edotreotide is a somatostatin analogue. Somatostatin is a neurotransmitter in the central nervous system, but also a hormone which binds to cells of neuroendocrine origin and inhibits the release of growth hormone, insulin, glucagon and gastrin. There are no data on whether the intravenous administration of edotreotide produces variation of serum gastrin and serum glucagon levels.

Clinical efficacy and safety

For the detection of the primary GEP-NET site in case of rising levels of a relevant biochemical tumour marker or in case of proven NET metastasis, patient-based sensitivity and specificity of gallium (⁶⁸Ga) edotreotide PET were 100% (4/4) and 89% (8/9), respectively, in the prospective study of Gabriel et al. 2007. Lesion-detection rate was 75% (3/4) in the subgroup of patients with unknown primary tumour site in the prospective study of Frilling et al. 2010. In the retrospective paper of Schreiter et al. 2014, the intra-individual comparison in a subgroup of 20 patients showed that gallium (⁶⁸Ga) edotreotide permitted to localise the primary tumour in 9/20 (45%) patients while indium (¹¹¹In) pentetreotide did in 2/20 (10%).

A prospective intra-individual comparison showed that gallium (⁶⁸Ga) edotreotide is able to detect lesions better than indium (¹¹¹In) pentetreotide. A lesion detection rate of 100% (40/40) versus 85% (34/40) was observed in the study of Hofmann et al. 2001 recruiting patients with histologically proven bronchial (n=2) or midgut (n=6) NETs. In the study of Buchmann et al. 2007, conducted in 27 patients mostly with GEP-NET (59%) or NETs of unknown primary (30%), gallium (⁶⁸Ga) edotreotide identified 279 lesions versus 157 lesions seen with indium (¹¹¹In) pentetreotide. In the study of Van Binnebeek et al. 2015 in 53 patients with metastatic GEP-NET [mostly GEP-NET (n=39) or NET of unknown origin (n=6)], the lesion-based detection rate of gallium (⁶⁸Ga) edotreotide was 99.9% (1098/1099) versus 60% (660/1099) for indium (¹¹¹In) pentetreotide based on the follow-up scans. In the study of Lee et al. 2015 in 13 GEP-NET patients, a total of 35 positive lesions were detected in 10 patients on either gallium (⁶⁸Ga) edotreotide PET/CT or indium (¹¹¹In) pentetreotide SPECT/CT while 3 patients did not exhibit any positive lesions on either imaging method. Gallium (⁶⁸Ga) edotreotide detected 35/35 (100%) lesions vs 19/35=54% for indium (¹¹¹In) pentetreotide SPECT/CT. In the study of Kowalski et al. 2003 in 4 patients with GEP-NET, gallium (⁶⁸Ga) edotreotide showed a better patient-based detection rate (100%) than indium (¹¹¹In) pentetreotide (50%).

Data available on clinical efficacy of gallium (⁶⁸Ga) edotreotide for the indication of predicting and monitoring of therapeutic response to peptide receptor radionuclide therapy (PRRT) in histologically confirmed metastatic NET are limited. Five studies have been submitted, one of them prospective (Gabriel et al. 2009) and four retrospective (Kroiss et al. 2013, Ezziddin et al. 2012, Kratochwil et al. 2015 and Luboldt et al. 2010a). In the study by Gabriel et al. 2009 pre-PRRT gallium (⁶⁸Ga) edotreotide was compared with CT or MRI using the Response Evaluation Criteria in Solid Tumors (RECIST). Gallium (⁶⁸Ga) edotreotide PET and CT showed a concordant result in 32 patients (70%) and discrepancies in 14 patients (30%) presenting 9 with progressive disease and 5 with remission.

The retrospective study of Kroiss et al. 2013 in 249 NET patients showed that PRRT does not significantly influence semiquantitative uptake of gallium (⁶⁸Ga) edotreotide PET, except in liver metastases of patients with NET, but the study lacked histological confirmation. The three remaining retrospective studies recruited small samples (ranging from 20 to 28 GEP-NET patients or those with cancer of unknown origin) and found that semiquantitative uptake in the pre-PRRT gallium (⁶⁸Ga) edotreotide PET scan correlated with the tumour-absorbed doses per injected activity of the subsequent first treatment cycle, differed between those lesions classified as responding and non-responding after three PRRT cycles, and helped to separate hepatic metastases from normal liver tissue.

Distribution

After intravenous injection, gallium (⁶⁸Ga) edotreotide is rapidly cleared from the blood following bi-exponential elimination of activity with half-lives of 2.0 ± 0.3 min and 48 ± 7 min, respectively.

Organ uptake

The organ with the highest physiological uptake of gallium (⁶⁸Ga) edotreotide is the spleen, followed by the kidneys. The uptake in the liver and in the pituitary, thyroid and adrenal glands is lower. High physiological uptake of gallium (⁶⁸Ga) edotreotide by the pancreas uncinate process can also be observed. About 50 minutes after intravenous administration, gallium (⁶⁸Ga) edotreotide accumulation shows plateauing in all organs.

The organ uptake has been shown to be age-independent in normal adult human tissues and also predominantly gender-independent (except for the thyroid and head of pancreas).

Elimination

No radioactive metabolites were detected in serum within 4 hours after intravenous injection of gallium (⁶⁸Ga) edotreotide.

Approximately 16% of gallium (⁶⁸Ga) edotreotide activity is removed from the body in the urine within 2 to 4 hours. The peptide is excreted via the kidneys as intact compound.

Half-life

Given that the elimination rate is substantially slower than the physical half-life of gallium (⁶⁸Ga) (68 min), the biological half-life will have little impact on the effective half-life of the medicinal product, which then would be expected to be somewhat less than 68 minutes.

Renal/Hepatic impairment

The pharmacokinetics in patients with renal or hepatic impairment have not been characterised.

Non-clinical data did not reveal any special hazard for gallium (⁶⁸Ga) edotreotide in humans.

Local tolerance assessment resulted in mild to moderate inflammation signs in the perivascular region of some animals which can be attributed to the acidic pH of the solution.

No studies on fertility, embryology, mutagenicity or long-term carcinogenicity have been conducted.

Regarding the novel excipient (1,10-phenanthroline), during the toxicity study conducted with the kit formulation of SomaKit TOC including 1,10-phenanthroline at a dose 400 fold higher than the human dose, no toxicity signs were observed.

Genotoxicity studies on 1,10-phenanthroline available in the literature show negative results in bacterial mutation assay (Ames test), while in a mouse lymphoma assay an indication of possible genotoxicity was obtained at concentrations 750 times higher than the maximum 1,10-phenanthroline blood concentration achievable in patients. However, even taking as worst case reference the limits for genotoxic and carcinogenic impurities, the risk related to the trace amounts of 1,10-phenanthroline in SomaKit TOC formulation is considered negligible at the dose to be administered in patients: the exposure to 1,10-phenanthroline (5 µ g/dose) is 24 fold lower than the acceptable daily intake for a genotoxic impurity (120 µ g/day for exposures <1 month).

Powder

1,10-phenanthroline

Gentisic acid

Mannitol (E421)

Buffer

Formic acid

Sodium hydroxide (E524)

Water for injections

After radiolabelling, the solution obtained also contains, as excipient, hydrochloric acid from the generator eluate.

Radiolabelling of carrier molecules with gallium (⁶⁸Ga) chloride is very sensitive to the presence of trace metal impurities. Only syringe and syringe needles able to minimise trace metal impurity levels (for example, non-metallic or coated with silicone needles) should be used.

This medicinal product must not be mixed with other products except those mentioned in section 12.

Kit as packaged for sale

2 years.

After radiolabelling

4 hours.

Do not store above 25° C after radiolabelling.

From a microbiological point of view, the medicinal product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.

Store in a refrigerator (2° C to 8° C).

Store in the original package in order to protect from light.

For storage conditions after radiolabelling of the medicinal product, see section 6.3.

Storage of radiopharmaceuticals should be in accordance with national regulation on radioactive materials.

Each pack contains:

• One vial of powder for solution for injection: 10 ml Type I glass vial closed with a bromobutyl rubber stopper and sealed with a flip-off cap. Each vial contains 40 micrograms of edotreotide.

• One vial of reaction buffer: 10 ml cyclic olefin polymer vial closed with a teflon stopper and sealed with a flip-off cap. Each vial contains 1 ml of reaction buffer.

General warnings

Radiopharmaceuticals should be received, used and administered only by authorised persons in designated clinical settings. Their receipt, storage, use, transfer and disposal are subject to the regulations and/or appropriate licenses of the competent official organisation.

Radiopharmaceuticals should be prepared in a manner which satisfies both radiation safety and pharmaceutical quality requirements. Appropriate aseptic precautions should be taken.

Contents of the vials are intended only for use in the preparation of gallium (⁶⁸Ga) edotreotide solution for injection and are not to be administered directly to the patient without first undergoing the preparative procedure.

Each 40 microgram vial contains an excess of medicinal product. However, it is recommended that the vial be prepared as instructed and used for a single patient dose, based on the activity to be injected; any remaining material should be discarded after radiolabelling and use.

Precautions to be taken before handling or administration of the medicinal product

For instructions on radiolabelling of the medicinal product before administration, see section 12.

If at any time in the preparation of this medicinal product the integrity of the vials is compromised it should not be used.

Administration procedures should be carried out in a way to minimise risk of contamination of the medicinal product and irradiation of the operators. Adequate shielding is mandatory.

The content of the kit before radiolabelling is not radioactive. However, after gallium (⁶⁸Ga) chloride solution is added, adequate shielding of the final preparation must be maintained.

The administration of radiopharmaceuticals creates risks for other persons from external radiation or contamination from spills of urine, vomiting, blood, etc. Radiation protection precautions in accordance with national regulations must therefore be taken.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.