PUBLIC ASSESSMENT REPORT

Decentralised Procedure

TEKTROTYD 16 Mikrogramm, Kit für ein radioaktives Arzneimittel Procedure Number: DE/H/3726/01/DC

Active Substance: HYNIC-Tyr3-octreotide.TFA; ethylenediamine-N,N'- diacetic acid

Dosage Form: Kit for preparation

Marketing Authorisation Holder in the RMS, Germany: Rotop Pharmaka AG

Publication: 06.05.2020

This module reflects the scientific discussion for the approval of TEKTROTYD 16 Mikrogramm, Kit für ein radioaktives Arzneimittel. The procedure was finalised on 02.12.2015. TABLE OF CONTENTS

I. INTRODUCTION ...... 4 II. EXECUTIVE SUMMARY ...... 4 II.1 Problem statement ...... 4 II.2 About the product ...... 5 II.3 General comments on the submitted dossier ...... 5 II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles 6 III. SCIENTIFIC OVERVIEW AND DISCUSSION ...... 6 III.1 Quality aspects ...... 6 III.2 Non-clinical aspects ...... 8 III.3 Clinical aspects ...... 9 IV. BENEFIT RISK ASSESSMENT ...... 17

TEKTROTYD 16 Mikrogramm Kit für ein radioaktives Arzneimittel DE/H/3726/01/DC Public Assessment Report Page 2/18 ADMINISTRATIVE INFORMATION

Proposed name of the medicinal TEKTROTYD 16 Mikrogramm, Kit für ein radioaktives product in the RMS Arzneimittel INN (or common name) of the active 1. HYNIC-Tyr3-octreotide.TFA, substance(s): 2. ethylenediamine-N,N'-diacetic acid Pharmaco-therapeutic group V09IA07 (ATC Code): Pharmaceutical form(s) and Kit for radiopharmaceutical preparation strength(s): 16 µg HYNIC-Tyr3-octreotide.TFA per kit. Reference Number(s) for the DE/H/3726/01/DC Decentralised Procedure Reference Member State: DE Member States concerned: AT; ES; FR; IT; PT; UK Marketing Authorisation Holder Rotop Pharmaka AG (name and address) Bautzner Landstr. 400 01328 Dresden Germany Names and addresses of National Centre for Nuclear Research manufacturer(s) responsible for Andrzej Soltan 7 batch release in the EEA 05-400 Otwock-`Swierk POLAND

TEKTROTYD 16 Mikrogramm Kit für ein radioaktives Arzneimittel DE/H/3726/01/DC Public Assessment Report Page 3/18 I. INTRODUCTION

Based on the review of the data and the Applicant’s response to the questions raised by RMS and CMSs on quality, safety and efficacy, the RMS considers that the application for TEKTROYTD 16 µg in the treatment of scintigraphic imaging of pathological lesions in which somatostatin receptors (particularly subtype 2 and, to a lesser extent, subtypes 3 and 5) are overexpressed (neuroendocrine tumours) is approved

II. EXECUTIVE SUMMARY

Type of application: Abridged application, according to article 10 (a) so called well established use

This decentralised application concerns the somatostatin analogue radiopharmaceutical 99mTc- Tektrotyd (or 99mTc-HYNIC-TOC) under the trade name Tektrotyd 16 µg. In this Assessment Report, the names 99mTc-EDDA-HYNIC-TOC as well as Tektrotyd are used.

With DE as the Reference Member State in this Decentralised Procedure Rotop Pharmaka AG applied for the marketing authorisations for Tektrotyd 16 µg in AT, ES, FR, IT, PT, and UK.

II.1 Problem statement

Somatostatin receptors are overexpressed in different such as neuroendocrine tumours, meningiomas, lymphomas, breast, , and prostate , and also in small cell pulmonary . Somatostatin receptor subtype sst2a is the most frequently overexpressed somatostatin receptor subtype in primary lesions and their metastases (80-100%). A high incidence and density of somatostatin receptors particularly in neuroendocrine tumours (NET) is the rationale for the somatostatin analogues application in the diagnosis of these tumours. NET are rare and potentially malignant neoplasms in endocrine glands, digestive tract and , usually slow- growing, well-differentiated, and characterised mostly by their ability to secrete hormones. Due to their small size, often atypical location, and the absence of characteristic clinical symptoms NET are difficult to detect. Surgical treatment of NET to radically remove the tumour mass depends on the successful pre- and intra-operative tumour location.

Neuroendocrine gastropancreatic (NE-GEP) tumors constitute a heterogeneous group of tumors with location of the primary tumors in the gastric mucosa, pancreas, small and large intestine. The incidence is approx 2.5 – 5 cases /100 000/year1 whereas the largest group is small intestinal neuroendocrine tumors (midgut carcinoids) with an incidence rate of 2.4/ 100 000/year. The incidence and prevalence of carcinoid tumors has increased substantially over the last decades, which may partly reflect better diagnosis of incidentally identified lesions due to increased availability of advanced endoscopic techniques and radiological imaging.

Tektrotyd is proposed for use in adult patients with somatostatin receptor bearing gastro-entero- pancreatic neuroendocrine tumours (GEP-NET) for localizing primary tumours and their metastases.

The first substance to be broadly used for visualisation of neuroendocrine tumours of the expressing somatostatin receptors was [¹¹¹In]-octreotide but its relatively high energy, which results in suboptimum resolution of the image and its relatively high patients exposure

1 Modlin IM, Oberg K, Chung DC, et al. Gastroenteropancreatic neuroendocrine tumours. Lancet Oncol 2008;9:61-72. TEKTROTYD 16 Mikrogramm Kit für ein radioaktives Arzneimittel DE/H/3726/01/DC Public Assessment Report Page 4/18 to ionising radiation including the release of Auger are drawbacks of this method and therefore somatostatin analogues radiolabelled with sodium pertechnetate (99mTc) solution like 99mTc- HYNIC-TOC were developed. 99mTc-HYNIC-TOC has better image resolution and lower radiation exposure than [¹¹¹In]-octreotide which is the authorised product currently used in the indication. 99mTc-HYNIC-TOC is, according to the applicant, under the name 99mTc-Tektrotyd the most frequently used tracer in scintigraphic visualisation of neuroendocrine tumours authorised in Poland with about 1800 examinations in 2014 and the applicant has shown remarkable use on a single patient description basis in the EU, particularly in Germany (4800 examinations in 2014). The use of 99mTc-Tektrotyd is also mentioned in current guidelines (Portuguese guidelines as well as S1 Guideline of the German Society of ).

II.2 About the product

The active ingredients of Tektrotyd 16 µg after radiolabelling with sodium pertechnetate (99mTc) solution is 99mTc-Tektrotyd, a [99mTc]technetium complex with two ligands consisting of [99mTc]- HYNIC-Tyr3-octreotide with the co-ligand ethylenediamine-N,N'-diacetic acid (EDDA).1

99mTc-Tektrotyd binds with high affinity to somatostatin receptor subtypes 2 and 5 and with lesser affinity also to subtype 3.

The pharmacotherapeutic group is Diagnostic , Tumour Detection, Technetium (99mTc) compounds with the ATC code V09IA07.

99mTc-HYNIC-TOC solution is indicated in adults for scintigraphic imaging and assessment of pathological lesions in which somatostatin receptors (particularly subtype 2 and, to a lesser extent, subtypes 3 and 5) are overexpressed, particularly neuroendocrine tumours, among them gastro- entero-pancreatic neuroendocrine tumours (GEP-NET). The used for radiolabelling is technetium-(99mTc) which decays by gamma emission (energy 141 keV) with a physical half-life of 6.02 hours to technetium-99 which is regarded as quasi stable.

The method of administration is intravenously, the suggested dose is 370 to 740 MBq for an average (70 kg) patient. Image acquisition should be carried out between 2 – 4 hours after intravenous administration.

As no clinical data are available for patients under 18 years of age concerning the safety and diagnostic efficacy of this product it is not recommended for use in patients under 18 years of age.

II.3 General comments on the submitted dossier

Non-clinical The non-clinical overview is dated August 2012. The report refers 29 publications and 3 study reports up to year 2012. Clinical The originally provided clinical overview is dated 10 July 2012. The report refers to 59 publications up to year 2012. During the procedure it was updated according to the requirements discussed by RMS and CMSs and is now considered acceptable. The revised report refers to 126 publications up to the year 2015.

TEKTROTYD 16 Mikrogramm Kit für ein radioaktives Arzneimittel DE/H/3726/01/DC Public Assessment Report Page 5/18 II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles

GMP The RMS has been assured that acceptable standards of GMP are in place for these product types at all sites responsible for the manufacture and assembly of this product. For the relevant finished product manufacturer National Centre of Nuclear Research, 05-400 Otwocck-Swierk, Poland, an effective manufacturing authorisation issued by the competent authority, the Polish Chief Pharmaceutical Inspector under the number GIF-IW-N-4001/WTC348/297 – 1/11, dated 20th October 2011 is presented. GCP The quality of the clinical trials corresponds to those of other drugs evaluated in the same time period. Additional studies conducted according to GCP would not provide further information and are not planned by the applicant.

III. SCIENTIFIC OVERVIEW AND DISCUSSION

III.1 Quality aspects

Introduction [99mTc]Technetium Kits for radiochemical preparation enables local hospitals around the clock to prepare radiopharmaceuticals for diagnostic use because of the availability of [99mTc]pertechnetate solution supplied by the 99Mo / 99mTc radionuclide generators. By this [99mTc]Technetium Kits have been the premise for daily routine diagnostics in nuclear medicine. The only drawback is, that technetium as a metal does not chemically bind directly to carbon atoms and therefore all technetium radiopharmaceuticals are metal complex molecules with ligands coordinating the [99mTc]Technetium radionuclide. Because of the bulky metal complexes technetium radiolabelled substances are sometimes not suitable for the radiolabelling of dedicated molecules as for example receptor ligands. However in this case a derivative of the well known octreotide peptide the HYNIC-Tyr3-octreotide is radiolabelled by the assistance of a co-ligand, ethylenediamine-N,N`-diacetic acid (EDDA) with [99mTc]technetium. The actual (radiolabelled) active substance for patient use consists of [99mTc]technetium, which is as a metal ion coordinated by the two ligands HYNIC-Tyr3-octreotide and ethylenediamine-N,N'- diacetic acid (EDDA). They build together a metal – organic – complex which is the actual radiolabelled active substance for patient use. The biodistribution of the active substance is determined by the peptide HYNIC-Tyr3-octreotid (HYNIC-TOC). HYNIC-TOC is a peptide with 8 amino acids and with a covalently bound chelator (HYNIC). Because of the fact that the radiolabelled complex is formed by two ligands each of these ligands has in the cold kit formulation the status of an active substance according the definitions given by the quality guideline on radiopharmaceuticals. The applicant has submitted a part describing the manufacture of the octreotide derivative HYNIC-Tyr3-octreotide and additionally lately during the clock-stop period an active substance master file describing the manufacture of HYNIC-Tyr3-octreotide. HYNIC-Tyr3- octreotide with its peptide chain will determine the pharmacokinetic of the radiolabelled complex and by this the diagnostic efficacy of the radiolabelled active substance. However it is not to deny that also the co-ligand EDDA plays an important role in the formation and stabilisation of the [99mTc]Technetium-core-organic-metal complex which carries the technetium-99m radiolabel of the actual active substance for patient use. The applicant submits during the clock-stop period for the first time a part describing EDDA also as an active substance.

TEKTROTYD 16 Mikrogramm Kit für ein radioaktives Arzneimittel DE/H/3726/01/DC Public Assessment Report Page 6/18 For EDDA manufactured by National Centre for Nuclear Research (Polatom) a potential serious risk to public health was seen in an unsufficient control of the toxic starting material cyanide in the finished active substance EDDA. This major concern was solved by the applicant with the day 160 response new introducing in the release specification of the precursor EDDA a test on cyanide. For the peptide HYNIC-TOC it is demonstrated by their quality documentation and the submitted responses on concerns during the procedure that both manufacturers of HYNIC-TOC are able to produce the peptide HYNIC-TOC in an appropriate quality. The structure of the peptide is clear after a consequent analysis of the cold peptide precursor. The manufacture of the drug substance has been adequately described and satisfactory specifications have been provided for starting materials, reagents and solvents. However the biodistribution determining entity is the peptide and not the technetium-core complex. The peptide HYNIC-TOC is intensively characterized. In view to the technetium-core complex it is assured that the technetium-99m is bounded stable and reproducible to the biodistribution determining peptide. The structure of the drug substance has been adequately proven and its physico- chemical properties are sufficiently described. Drug Product The drug product, the kit for radiopharmaceutical preparation consists of two components, vial I and vial II, and is by this a little bit more complicate than the usual kits with only one vial which needs to be only filled up with pertechnetate (99mTc) solution. In a first step the ingredients of vial II containing the co-ligand EDDA are solved with water for injection. A part of this solution is transferred to vial I which contains the HYNIC-Tyr3-octreotide followed by the addition of the [99mTc]pertechnetate solution for radiolabelling. For the forming of the desired technetium complex vial I is heated to 100°C for 10 minutes. The medicinal product is formulated using excipients listed in section 6.1 in the Summary of Product Characteristics. Using physiological saline in the ready to use formulation good patient compatibility is assured. The development of the product has been described, the choice of excipients is justified and their functions are explained. The primary packaging material uses the typical material for packaging of sterile aqueous solutions as sterile glass vials with glass pharmacopeia grade type I and chloro butyl rubber stoppers which is acceptable. From its concept Tektrotyd is a typical diagnostic [99mTc]Technetium Kit for radiopharmaceutical preparation which offers the possibility to radiolabel an octreotide-derivative with the diagnostic standard radionuclide technetium-99m which is because of its radionuclide generator origin everywhere available.

Conclusion on quality aspects Coming to the end of the procedure in view to pharmaceutical quality a recommendation to issue a marketing authorisation can be given.

Demand note to the applicant ROTOP Pharmaka GmbH to commit himself for the following items: 1. To assure the conformity between the given responses on deficiency questions made during the marketing authorisation procedure and the currently valid quality documentation the applicant made the commitment, that ROTOP Pharmaka GmbH will up-date the quality dossier in the cases where an up-date is necessary as a result of the given responses within the next 3 months after the end of the marketing authorisation procedure.

TEKTROTYD 16 Mikrogramm Kit für ein radioaktives Arzneimittel DE/H/3726/01/DC Public Assessment Report Page 7/18 2. Because of the fact that the shelf-life of the active substance HYNIC-TOC-TFA is not proved by stability data according the applicable guidelines, a use of HYNIC-TOC-TFA supplied by active substance manufacturer in the manufacturing of Tektrotyd is only possible, if the quality of the active substance is repeatedly tested directly before the manufacturing process of Tektrotyd starts. ROTOP Pharmaka GmbH should commit himself to assure that HYNIC-TOC-TFA is tested before the manufacturing process of Tektrotyd starts, at least up till the moment, when a shelf life of HYNIC-TOC-TFA based on relevant stability data is established by a variation. 3. The applicant ROTOP Pharmaka GmbH should commit himself to ensure that the supplier of the active substance submits within a deadline of 6 months up to the time point of the issue of the marketing authorisation for Tektrotyd an up-dated ASMF for the active substance HYNIC- TOC-TFA to assure the conformity between the given responses on deficiency questions made during the marketing authorisation procedure and the currently valid ASMF. If within the given deadline of 6 months no up-dated ASMF is submitted, the applicant ROTOP Pharmaka GmbH commit himself to ensure that the use of HYNIC-TOC-TFA derived from this active substance manufacturer will be stopped.

III.2 Non-clinical aspects The active ingredient 99mTc-HYNIC-TOC is well established in medical practice. 99mTc-HYNIC-TOC is intended for single use in scintigraphic applications for detection of somatostatin receptors (SSTR) in tissues in which this receptor is overexpressed on particular tumour cell membranes. 99mTc- HYNIC-TOC is a peptide [D-Phe1, Tyr3-octreotide] radiolabelled with gamma rays emitting metastable technetium-99m [99mTc] via HYNIC (hydrazinonicotinamide) stabilized by EDDA (ethylenediamine-N,N`-diacetic acid). For the intended diagnostic purposes pharmacodynamic effects are not desired. The small amount of octreotide peptide (16 µg compared to up to 500 µg three times daily in therapeutic use) appears to be sufficient to get the required diagnostic information. As expected pharmacodynamic effects have not been observed at this very low dosage level of the peptide. The non-clinical overview is dated April 2014. The report refers 29 publications and 3 study reports up to year 2012. The non-clinical overview on the pre-clinical pharmacology, pharmacokinetics and toxicology is adequate. The references chosen exhibit an adequate scientific standard for this type of application, though these references mainly refer to publications dealing with the outcome of clinical use. Further studies are not required for this kind of application. Therefore an overview mainly based on literature review is appropriate. The Applicant has provided three non-clinical studies. The results of acute toxicity studies performed in Wistar rats and albino mice with 99mTc-HYNIC-TOC and results of a reverse mutation assay using bacteria with 99mTc-HYNIC-TOC for testing for a genotoxic potential were submitted. In the acute toxicity studies with a high dose level of up to 40 µg/kg body weight in mice and rats followed by a 14 day observation period showed no effects. In the bacterial reverse mutation assay no 99mTC- HYNIC-TOC induced gene mutations were observed. As stated by the Applicant from clinical routine with the use of 99mTc-HYNIC-TOC in scintigraphic imaging and as well from the therapeutic use of octreotide as an already marketed somatostatin receptor agonist the safety of the product from a non-clinical point of view is given. A slight rewording for SmPC sections "4.3 Contraindications" and “5.3 Preclinical safety data” to reflect the information gathered in line with the wording recommended by the “Core SmPC for Radiopharmaceuticals” was recommended and implemented by the Applicant. As stated above, all Non-Clinical issues raised during the procedure were clarified by the Applicant. Therefore, there are no objections against granting of marketing authorisation from a Non-Clinical point of view.

TEKTROTYD 16 Mikrogramm Kit für ein radioaktives Arzneimittel DE/H/3726/01/DC Public Assessment Report Page 8/18 III.3 Clinical aspects

Pharmacokinetics 99mTc-EDDA-HYNIC-TOC will be administered intravenously. Distribution of the drug is similar in rats and in mice. Four hours after administration, residual activity of the drug was found mainly in the tumor and in the kidney. Urinary excretion is the main elimination pathway. Most of 99mTc- EDDA-HYNIC-TOC, eliminated by urine, is excreted within the first two hours.

Pharmacodynamics The most important part of the 99mTc–HYNIC-TOC molecule is a peptide sequence of Tyr3- octreotide (the sequence of octreotide with Tyr in the 3rd position in amino acid chain replacing D- Phe). It binds with high affinity to somatostatin receptor subtypes 2 and 5, also to subtype 3 but with lesser affinity. Due to a fast time of reaching the target a few minutes after the injection of the compound visualisation of organs and pathological foci is observed. Positive with 99mTc-HYNIC-TOC reflects the presence of an increased density of tissue somatostatin receptors rather than a malignant disease. Tumours which do not bear receptors will not be visualised. In a number of patients suffering from GEP-NET or carcinoid tumours the receptor density is insufficient to allow visualisation with 99mTc-HYNIC-TOC. This uncertainty is reflected in the SmPC of Tektrotyd. 99mTc-HYNIC-TOC is indicated in adults for scintigraphic imaging and assessment of pathological GEP-NET tumour lesions in which somatostatin receptors are overexpressed. However, there are some limitations to be considered: Positive uptake is not specific for GEP-NET and carcinoid- tumours; positive scintigraphic results require evaluation whether another disease characterised by high local somatostatin receptor concentrations may be present. An increase in somatostatin receptor density can also occur in various pathological conditions; tumours arising from tissue embryologically derived from the neural crest (paragangliomas, medullary carcinomas, , ), tumours of the pituitary gland, endocrine neoplasms of the lungs (small-cell carcinoma), meningiomas, mammary carcinomas, lympho-proliferative disease (Hodgkin's disease, non-Hodgkin lymphomas), and the possibility of uptake in areas of lymphocyte concentrations (subacute ) must be considered. This uncertainty is adequately reflected in the SmPC. Radiation Radation dosimetry was performed and published by Grimes et al., 2011 and the average absorbed doses and effective dose of 99mTc-HYNIC-TOC are as follows:

Organ Dose absorbed per unit activity administered (mGy/MBq) Adult 15 years 10 year 5 years 1 years Adrenals 0.0053 0.0067 0.0099 0.014 0.024 Brain 0.0020 0.0024 0.0040 0.0064 0.011 Breasts 0.0019 0.0024 0.0035 0.0056 0.010 Gallbladder Wall 0.0056 0.0070 0.011 0.016 0.022 LLI Wall 0.0034 0.0043 0.0068 0.010 0.018 Small Intestine 0.0037 0.0047 0.0072 0.011 0.019 Stomach Wall 0.0044 0.0055 0.0086 0.012 0.020 ULI Wall 0.0037 0.0048 0.0073 0.012 0.019 Heart Wall 0.0035 0.0044 0.0065 0.0095 0.017 Kidneys 0.020 0.024 0.033 0.048 0.082 0.010 0.013 0.019 0.027 0.048 TEKTROTYD 16 Mikrogramm Kit für ein radioaktives Arzneimittel DE/H/3726/01/DC Public Assessment Report Page 9/18 Lungs 0.0031 0.0040 0.0058 0.0087 0.0155 Muscle 0.0027 0.0033 0.0049 0.0074 0.014 Ovaries 0.0036 0.0045 0.0067 0.010 0.018 Pancreas 0.0063 0.0078 0.011 0.017 0.028 Red Marrow 0.0027 0.0033 0.0050 0.0074 0.015 Osteogenic Cells 0.0070 0.0088 0.013 0.019 0.038 Skin 0.0017 0.0020 0.0032 0.0051 0.0095 Spleen 0.037 0.052 0.079 0.120 0.213 Testes 0.0024 0.0030 0.0046 0.0072 0.013 Thymus 0.0025 0.0032 0.0047 0.0073 0.013 Thyroid 0.0071 0.011 0.017 0.035 0.065 Urinary Bladder Wall 0.012 0.015 0.022 0.032 0.059 Uterus 0.0041 0.0050 0.0078 0.012 0.020 Total Body 0.0031 0.0039 0.0059 0.0091 0.016

Effective Dose (mSv/MBq) 0.0050 0.0066 0.0099 0.015 0.027 The effective dose resulting from the administration of a maximal recommended activity of 740 MBq for an adult weighing 70 kg is about 3.7 mSv. For an administered activity of 740 MBq the typical radiation dose to the critical organ, i.e. kidneys, is 15.5 mSv.

Clinical efficacy

The evidence for efficacy of 99mTc-HYNIC-TOC to visualise gastroentero-pancreatic neuroendocrine (GEP-NET) tumours2 is entirely based on literature sources of studies with 99mTc-HYNIC-TOC partly in comparison to and 111In-octreotide [Octreoscan]. However, the indium-111 containing Octreoscan cannot be considered as gold standard as its image resolution is worse than the one of the Technetium-99m containing 99mTc-HYNIC-TOC discussed here. As this diagnostic modality aims at a rare disease all papers concerning studies in which GEP-NET patients should be analysed for efficacy data. NET tumours should be considered as supportive data for the claimed indication GEP- NET tumours. The choice of the applicant to use histopathological characterization as the SOT and 111In-Octreoscan as the comparator is acceptable and direct head-to-head comparison with 111In- Octreoscan has been shown in some papers. The overall number of documented patients is N=685. Technical performance Concerning technical performance, a head-to-head comparison of imaging of 99mTc-EDDA/HYNIC- TOC with 111In-Octroscan in patients with pancreatic tumour or carcinoid syndrome showed very similar pattern of distribution, particularly high uptake of the tracer in tumour tissue and elimination pathways. Semi-quantitative analysis showed even considerably higher tumour/organ ratios for the 99mTc study than for the 111In study. Diagnostic Performance (Sensitivity and Specificity) Studies with the 99mTc labelled somatostatin analogue 99mTc-HYNIC-TOC in detection of tumours overexpressing somatostatin receptors showed in most studies high sensitivities as well as the specificities (see Table below).

2 As the CMS FR has stated in his d70 commentary that FR is not ready to extend the indication beyond digestive neuroendocrine tumours of the pancreas or the duodenum, the applicant has amended the indication to GEP-NET of the pancreas or the duodenum only. Therefore in this summary reference is made only to GEP-NET of the pancreas or the duodenum and evidence for efficacay of 99mTc- HYNIC-TOC in the diagnosis of other tumor entities is not further pursued. TEKTROTYD 16 Mikrogramm Kit für ein radioaktives Arzneimittel DE/H/3726/01/DC Public Assessment Report Page 10/18

Source Malignancy Patient Sensitivity Specificity NPV PPV Accura s cy Gabriel M, 20053 GEP-NET 88 80.9% 94.4% ------(SPECT) Gomez M, 20104 GEP-NET 32 87% 100% ------Pavlovic S, 20105 NET 34 88% ------Pusuwan P, 20106 Pancreatic 5 87% 100% ------NET Parisella MG, 20127 NET and 50 70.3% 76.9% ------72% GEP-NET

Sepúlveda-Méndez J, GEP-NET 56 88.4% 92.3% 70.6 97.4 89.3% 20128 % % Artiko V, 20129 Net (GEP- 30 (18) 87%(91%) 86%(86%) 67% 95% 87% NET)

The sensitivity and specificity outcomes, however, can be hampered by results that are erroneously positive due to nonspecific accumulation of the tracer (physiological jejunal uptake) or due to accumulation of the radiolabelled somatostatin analogue in inflammatory infiltrations. This has been adequately labelled in SmPC section 4.4 (subtitle Image interpretation). All reported / discussed clinical studies on the 99mTc-radiopharmaceutical exclusively refer to the same EDDA/HYNIC-TOC complex of technetium. As the indication according to current standards should reflect the properties of the compound for localizing the primary tumour site, evaluating disease extension (staging and restaging), monitoring the effect of treatment (follow-up) and for selecting patients before starting therapy if shown by the cited studies. Concerning diagnostic performance the applicant has therefore re-analysed the data for detection and tumour localization (Sensitivity 87 – 100%), Staging (Sensitivity 73-97%) which was comparable to values found for 111In-Octreoscan (see following Table).

3 Gabriel M, Muehllechner P, Decristoforo C, von Guggenberg E, Kendler D, Prommegger R, Profanter C, Moncayo R, Virgolini I. 99mTc- HYNIC-Tyr(3)-octreotide for staging and follow-up of patients with neuroendocrine gastro-entero-pancreatic tumours. Q J Nucl Med Mol Imaging 2005; 49:237-244. 4 Gómez M, Ferrando R, Vilar J, Hitateguy R, López B, Moreira E, Kapitán M, De Lima F, Agüero B, Gabriela Villegas M, Urdaneta N, Gutiérrez E, Battegazzore A, Bayardo K, Silveira A, Lago G, Páez A. 99mTc-octreotide in patients with neuroendocrine tumours from the GI tract. Acta Gastroenterol Latinoam. 2010; 40:332-8. 5 Pavlovic S, Artiko V, Sobic-Saranovic D, Damjanovic S, Popovic B, Jakovic R, Petrasinovic Z, Jaksic E, Todorovic-Tirnanic M, Saranovic D, Micev M, Novosel S, Nikolic N, Obradovic V. The utility of 99mTc-HYNIC-TOC scintigraphy for assessment of lung lesions in patients with neuroendocrine tumours. Neoplasma. 2010; 57:68-73 6 Pusuwan P, Tocharoenchai C, Sriussadaporn S, Muangsomboon K, Poromatikul N, Tiparoj R. Somatostatin Receptor Scintigraphy in Localization of Pancreatic Neuroendocrine tumours: A preliminary Study. Siriraj Med J. 2010; 63:53-56. 7 Parisella MG, Chianelli M, D'Alessandria C, Todino V, Mikolajczak R, Papini E, Dierckx RA, Scopinaro F, Signore A. Clinical indications to the use of 99mTc-HYNIC-TOC to detect somatostatin receptor-positive neuroendocrine tumours. Q J Nucl Med Mol Imaging 2012; 54:1-9. 8 Sepúlveda-Méndez J, de Murphy CA, Pedraza-López M, Murphy-Stack E, Rojas-Bautista JC, González-Treviño O. Specificity and sensitivity of 99mTc-HYNIC-Tyr3-octreotide (99mTc-TOC) for imaging neuroendocrine tumours. Nucl Med Commun. 2012; 33:69-79. 9 Artiko V, Sobic-Saranovic D, Pavlovic S, Petrovic M, Zuvela M, Antic A, Matic S, Odalovic S, Petrovic N, Milovanovic A, Obradovic V. The clinical value of scintigraphy of neuroendocrine tumors using (99m)Tc-HYNIC-TOC. J BUON. 2012; 17:537-42. TEKTROTYD 16 Mikrogramm Kit für ein radioaktives Arzneimittel DE/H/3726/01/DC Public Assessment Report Page 11/18 Diagnostic performance of 99mTc-EDDA/HYNIC-TOC vs. 111In-Octreoscan Diagnostic Sensitivity [%] Specificity [%] Objective 99mTc- 111In-Octreoscan 99mTc- 111In-Octreoscan in GEP-NETs EDDA/HYNIC-TOC EDDA/HYNIC-TOC Detection and 87 - 100 62-90 86-100 71-98 Tumour localization Staging 73-97 87-94 50*-100 94-96 * due to low patient number (n=2)

There were no sufficient study data on monitoring the effect of treatment (follow-up) and patient selection for peptide receptor radionuclide therapy and therefore the efficacy in this respect has not been established.

Impact on diagnostic thinking and patient management The technetium compound offers a series of advantages over 111In. Generator availability, reduced patient`s and staff`s exposure to radiation and improved image quality of 99mTc over 111In prompted to replace the 111In tracer in daily routine. The advantage of a single 1-d protocol with early imaging at 4 h after injection as compared with the standard dual-time acquisition 2-d protocol has encouraged practical implementation rather than scientific studies. The inherent advantages of 99mTc 111 vs. In are resulting from short physical half-life (T1/2=6 h) and optimum radiation energy for detection by gamma camera (140 keV). 111In has a much longer physical half-life and two energy ranges (173keV with abundance 89% and 247keV with abundance 94%), which makes it necessary to use a medium-energy collimator that results in worse spatial resolution of images. Concerning impact on diagnostic thinking and patient management the applicant has shown changes in clinical management after 99mTc-Tectrotyd which are comparable to 111In-Octreoscan which are important for treatment planning and monitoring the effects of therapy (follow-up). The impact of Tektrotyd on diagnostic thinking and patient management is also acknowledged in guidelines of scientific societies. Gabriel et al. in a study comparing 99mTc-EDDA/HYNIC-TOC with 111In -octreotide in 41 patients with various neuroendocrine and endocrine tumours reported change of patient management based solely on 99mTc-EDDA/HYNIC-TOC scintigraphy results in two patients (treatment with unlabelled or labelled somatostatin analogues started (Gabriel M, 2003). Findings in 99mTc-EDDA/HYNIC- TOC scintigraphy prompted changes in clinical management in 11 of the 88 patients reported by Gabriel et al. (Gabriel M, 2005). In 5 patients chemotherapy was administered instead of surgery when either multiple metastases or recurrence in surgically inaccessible sites were detected by SRS. In another 5 patients surgery was performed or its strategy was modified following positive scan results. Chrapko et al. reported the results of 99mTc-Tektrotyd SRS in 117 patients with NETs (of various origin) and SPNs. Although detailed analysis was not presented, the authors concluded from their study that 99mTc-Tektrotyd SRS is useful in staging of SSRT-overexpressing tumours of known and unknown primary origin, as well as in restaging after primary tumour surgery. This method is less effective in detecting suspected NETs and assessing SPNs (Chrapko B, 2010). (Parisella MG, 2012) In 3 patients (1 MTC, 2 NETs of unknown origin) SRS with 99mTc-Tektrotyd revealed greater number of pathological sites than other imaging modalities, what modified the clinical management and prevented unnecessary surgery. The authors conclude that 99mTc-Tektrotyd SRS is highly indicated for in vivo histological characterisation of known NET lesions to plan appropriate therapy especially for patients with inoperable disease. However, in the authors’ opinion in patients with only biochemical suspicion of NET and in those with negative markers, this scintigraphy does not significantly modify the clinical management and should be not performed as a first line examination. Impact of 99mTc-EDDA/HYNIC-TOC scintigraphy on clinical management compares favourably

TEKTROTYD 16 Mikrogramm Kit für ein radioaktives Arzneimittel DE/H/3726/01/DC Public Assessment Report Page 12/18 with data on 111In-octreoscan, where the scintigraphic data modified patient classification in 24% and changed surgical therapeutic strategy in 25% (Lebtahi R, 1997). In patients with GEP-NETs SRS with 111In-octreotide changed the clinical management overall in 11.7% of the patients; CT or MRI altered the management in 13.3% of patients (Gotthardt M, 2003). 111In-octreotide scintigraphy the SRS identified disease foci not seen on CT/MRI in just 8 of 74 of the cohort with evidence of disease and altered the surgical management in only 3 of 74 cases. (Shaveridian N, 2013). The impact of 99mTc-EDDA/HYNIC-TOC scintigraphy on clinical management is presented in the table below.

Source Patients Outcome of 99mTc-EDDA/HYNIC-TOC scintigraphy Gabriel 200010 88 Changes in clinical management in 9.6% of patients Chrapko 201011 117 Useful in staging of sst-positive tumors and tumors of unknown primary origin as well as in restaging after primary tumor surgery, less effective in detecting suspected NETs and assessing SPNs. Parisella 201212 50 Impact on clinical management (conservative treatment, surgery, PRRT) in 7 patients Posology The applicant has outlined that the proposed posology in the SmPC is in relation to the posology found in literature (see Table below). The majority13 of the posology found in the literature is in the range of 370 to 740 MBq in one single intravenous injection and is therefore the suggested activity range to be given to an adult. As in other diagnostic radiopharmaceuticals the injected dose depends on the equipment used and is a subject of adjustment by the physician performing the investigation.

Reference Activity Comment Effective dose (mSv) Decristoforo et al. 200014 200 - 300 MBq SPECT 1.0-1.5 Gabriel et al. 200315 350 - 400 MBq SPECT 1.8-2.1 Gabriel et al. 200516 400 MBq (average) SPECT 2.1 Płachcińska 200617 740 - 925 MBq SPECT 3.8-4.8 Płachcińska 200618

10 Gabriel M, Muehllechner P, Decristoforo C, von Guggenberg E, Kendler D, Prommegger R, Profanter C, Moncayo R, Virgolini I. 99mTc- HYNIC-Tyr(3)-octreotide for staging and follow-up of patients with neuroendocrine gastro-entero-pancreatic tumours. Q J Nucl Med Mol Imaging 2005; 49:237-244. 11 Chrapko BE, Nocuń A, Gołebiewska R, Stefaniak B, Korobowicz E, Czekajska-Chehab E, Sawicki M, Polkowski WP. 99mTc-HYNIC-TOC somatostatin receptor scintigraphy in daily clinical practice. Med Sci Monit 2010;16:MT35-44 12 Parisella MG, Chianelli M, D'Alessandria C, Todino V, Mikolajczak R, Papini E, Dierckx RA, Scopinaro F, Signore A. Clinical indications to the use of 99mTc-HYNIC-TOC to detect somatostatin receptor-positive neuroendocrine tumours. Q J Nucl Med Mol Imaging 2012; 54:1-9. 13 only in one study (Gomez 2010) a higher activity of 925 MBq was applied. 14 Decristoforo C, Mather SJ, Cholewinski W, Donnemiller E, Riccabona G, Moncayo R. 99mTc-HYNIC-TOC: a new 99mTc-labelled radiopharmaceutical for imaging somatostatin receptor- positive tumours; first clinical results and intra-patient comparison with 111In- labelled octreotide derivatives. Eur J Nucl Med. 2000; 27:1318-1325 15 Gabriel M, Decristoforo C, Donnemiller E, Ulmer H, Watfah Rychlinski C, Mather SJ, Moncayo R. An intrapatient comparison of 99mTc- EDDA/HYNIC-TOC with 111In-DTPA-octreotide for diagnosis of somatostatin receptor-expressing tumors. J Nucl Med. 2003; 44:708–716. 16 Gabriel M, Muehllechner P, Decristoforo C, von Guggenberg E, Kendler D, Prommegger R, Profanter C, Moncayo R, Virgolini I. 99mTc- HYNIC-Tyr(3)-octreotide for staging and follow-up of patients with neuroendocrine gastro-entero-pancreatic tumours. Q J Nucl Med Mol Imaging 2005; 49:237-244. 17 Płachcińska A, Mikołajczak R, Kozak J, Rzeszutek K, Kuśmierek J. Comparative analysis of 99mTc-depreotide and 99mTc-HYNIC-TOC thorax scintigrams acquired for the purpose of differential diagnosis of solitary pulmonary nodules. Nucl Med Rev Cent East Eur 2006; 9:24-29. 18 Płachcińska A., Mikołajczak R., Kozak J., Rzeszutek K., Kuśmierek J. Differential diagnosis of solitary pulmonary nodules based on 99mTc- HYNIC-TOC scintigraphy: the effect of tumour size on the optimal method of image assessment. Eur J Nucl Med Mol Imaging 2006; 33: 1041-1047. TEKTROTYD 16 Mikrogramm Kit für ein radioaktives Arzneimittel DE/H/3726/01/DC Public Assessment Report Page 13/18 Reference Activity Comment Effective dose (mSv) Płachcińska 200419 Płachcińska 200320 Gonzales-Vazquez et al. 740 MBq --- 3.8 200621 Cwikla 200822 480-560 MBq SPECT (images of high 2.4-2.9 quality and good resolution) Chrapko 201023 740 MBq SPECT 3.8 Pusuwan 201024 370 MBq SPECT 1.9 Grimes 201125 750-1020 MBq SPECT 3.9-5.2 Parisella 201226 370 MBq SPECT 1.9 Sepulveda-Mendez 201227 500 MBq +/-100 MBq Images of high quality and 2.1-3.1 good resolution Artiko et al. 201228 740 MBq SPECT 3.8

The effective dose resulting from the administration of reported diagnostic activities from 200 MBq to 1020 MBq 99mTc-Tektrotyd ranged from 1.0 to 5.2 mSv which does not differ from other nuclear medicine diagnostic studies as shown in the table below (adapted from Mettler FA, 2008).

Examination (radiopharmaceutical) Effective dose Administered (mSv) activity (MBq) Brain (99mTc-HMPAO–exametazime) 6.9 740 Brain (99mT -ECD–Neurolite) 5.7 740 Thyroid scan (99mT -pertechnetate) 4.8 370 Parathyroid scan (99mT -sestamibi) 6.7 740 Cardiac rest-stress test (99mT -sestamibi 2-day protocol) 12.8 1500 Cardiac rest-stress test (99mT c-tetrofosmin) 11.4 1500 Cardiac ventriculography (99mT -labeled red blood cells) 7.8 1110 Lung perfusion (99mT -MAA) 2.0 185 Liver-spleen (99mT –sulfur colloid) 2.1 222

19 Płachcińska A, Mikołajczak R, Maecke HR, Michalski A, Rzeszutek K, Kozak J, Kuśmierek J. 99mTc-HYNIC-TOC scintigraphy in the differential diagnosis of solitary pulmonary nodules. (short communication). Eur J Nucl Med Mol Imaging 2004; 31:1005 –1010. 20 Płachcińska A, Mikołajczak R, Maecke HR, Młodkowska E, Kunert-Radek J, Michalski A, Rzeszutek K, Kozak J, Kuśmierek J. Clinical usefulness of 99mTc-HYNIC-TOC scintigraphy in oncological diagnostics – a preliminary communication.(short communication) Eur J Nucl Med Mol Imaging 2003; 30(10): 1402 –1406. 21 González-Vázquez A, Ferro-Flores G, Arteaga de Murphy C, Gutiérrez-García Z. Biokinetics and dosimetry in patients of 99mTc-HYNIC- Tyr3-octreotide prepared from lyophilized kits. Appl Rad Isot. 2006; 64:792-797. 22 Cwikla JB, Mikolajczak R, Pawlak D, Buscombe JR, Nasierowska-Guttmejer A, Bator A, Maecke HR, Walecki J. Initial direct comparison of 99mTc-TOC and 99mTc-TATE in identifying sites of disease in patients with proven GEP NETs. J Nucl Med. 2008; 49:1060-5. 23 Chrapko BE, Nocuń A, Gołebiewska R, Stefaniak B, Korobowicz E, Czekajska-Chehab E, Sawicki M, Polkowski WP. 99mTc-HYNIC-TOC somatostatin receptor scintigraphy in daily clinical practice. Med Sci Monit 2010;16:MT35-44 24 Pusuwan P, Tocharoenchai C, Sriussadaporn S, Muangsomboon K, Poromatikul N, Tiparoj R. Somatostatin Receptor Scintigraphy in Localization of Pancreatic Neuroendocrine tumours: A preliminary Study. Siriraj Med J. 2010; 63:53-56. 25 Grimes J, Celler A, Birkenfeld B, Shcherbinin S, Listewnik MH, Piwowarska-Bilska H, Mikolajczak R, Zorga P. Patient-Specific Radiation Dosimetry of 99mTc-HYNIC-Tyr3-Octreotide in Neuroendocrine Tumours. J Nucl Med 2011; 52:1474-1481 26 Parisella MG, Chianelli M, D'Alessandria C, Todino V, Mikolajczak R, Papini E, Dierckx RA, Scopinaro F, Signore A. Clinical indications to the use of 99mTc-HYNIC-TOC to detect somatostatin receptor-positive neuroendocrine tumours. Q J Nucl Med Mol Imaging 2012; 54:1-9. 27 Sepúlveda-Méndez J, de Murphy CA, Pedraza-López M, Murphy-Stack E, Rojas-Bautista JC, González-Treviño O. Specificity and sensitivity of 99mTc-HYNIC-Tyr3-octreotide (99mTc-TOC) for imaging neuroendocrine tumours. Nucl Med Commun. 2012; 33:69-79. 28 Artiko V, Sobic-Saranovic D, Pavlovic S, Petrovic M, Zuvela M, Antic A, Matic S, Odalovic S, Petrovic N, Milovanovic A, Obradovic V. The clinical value of scintigraphy of neuroendocrine tumors using (99m)Tc-HYNIC-TOC. J BUON. 2012; 17:537-42. TEKTROTYD 16 Mikrogramm Kit für ein radioaktives Arzneimittel DE/H/3726/01/DC Public Assessment Report Page 14/18 Examination (radiopharmaceutical) Effective dose Administered (mSv) activity (MBq) Biliary tract (99mT -disofenin) 3.1 185 Gastrointestinal bleeding (99mT -labeled red blood cells) 7.8 1110 Renal (99mT -DTPA) 1.8 370 Renal (99mT -DMSA) 3.3 370 Bone (99mT -MDP) 6.3 1110 Pentreotide (111In) 12 222 Tumor (18F-FDG) 14.1 740 The activity to be administered for single SPECT depends on the sensitivity of the available equipment. High quality SPECT images were obtained with 370 to 1020 MBq (in most cases 370 to 740 MBq) 99mTc-EDDA/HYNIC-TOC; therefore injection of 370 to 740 MBq 99mTc-Tektrotyd is considered sufficient. The administered doses are not different whether for SPECT or planar (Whole Body) imaging. As the effective dose is about 3.7 mSv when 740 MBq 99mTc-Tektrotyd are administered the adverse events related to ionising radiation are expected to occur with a low probability. The dose used should in every case be as low as possible to obtain the required diagnostic information. Renal impairment As 99mTc-Tektrotyd is excreted predominantly via kidneys in patients with renal impairment exposure to ionising radiation can be increased due to prolonged retention of the radiopharmaceutical in the body. This must be taken into account when calculating the activity to be administered. Administration should be considered only when the possible damage from radiation is outweighed by the potential diagnostic information. Interpretable scintigrams may be obtained after haemodialysis during which the high background activity can at least partially be removed. After dialysis a higher than usual uptake in liver, spleen and intestinal tract, and higher than usual activity in circulation can be observed. Paediatric patients There are no data on safety and efficacy of 99mTc-Tektrotyd in paediatric patients, therefore use in children and adolescents is not recommended. The applicant, however, has also shown that in single cases the use of Tektrotyd in children is favourable over Octreoscan (discussion on EAMN homepage). The radiation exposure of 99mTc Tektrotyd in children is remarkably lower than of 111In Octreoscan which also releases Auger electrons. The same approach with respect to use in children should be claimed for Tektrotyd as already required for Octreoscan (i.e. no absolute contraindication in children). The decision to administer 99mTc-Tektrotyd to a child must be taken by a nuclear medicine specialist familiar with somatostatin receptor scintigraphy, after considering the use of alternative techniques.

Clinical safety Referring to the available reports concerning the use of 99mTc-HYNIC-TOC in scintigraphic examination, no adverse effects have been published. The administered radioactivity should be adjusted in order to achieve the desired diagnostic effect and possibly lower the radiation dose to the patient. The exposure to ionising radiation is potentially related to induction of and potential risk for hereditary defects. In case of radiodiagnostic examinations the risk is negligible because of the low doses of radiation. No unfavourable side effects were observed. The other proposals are standard requirements for radiopharmaceuticals and fully acceptable. It should be noted however that the withdrawal of therapy with somatostatin analogues as a preparatory step to 99mTc-HYNIC-TOC scintigraphy might provoke severe adverse effects, generally of the nature of a return of the symptoms seen before this therapy was started. This is reflected in the SmPC.

TEKTROTYD 16 Mikrogramm Kit für ein radioaktives Arzneimittel DE/H/3726/01/DC Public Assessment Report Page 15/18 Summary Pharmacovigilance system The Applicant has submitted a signed Summary of the Applicant's Pharmacovigilance System. Provided that the Pharmacovigilance System Master File fully complies with the new legal requirements as set out in the Commission Implementing Regulation and as detailed in the GVP module, the RMS considers the Summary acceptable.

Risk Management Plan The Applicant submitted an updated RMP version 01.5 with data lock point 13.11.2015 and date of final sign off 01.12.2015. The updated RMP partly addresses the outstanding points for clarification. The RMP was submitted in the “new” RMP format.

The following safety concerns have been identified by the applicant:

No additional risk minimisation measures have been proposed.

Periodic Safety Update Report (PSUR) With regard to PSUR submission, the MAH should take into account the following: - In accordance with the revised legislation on pharmacovigilance (Directive 2010/84/EU), the list of European Union Reference Dates (the EURD list) of PSURs has been established and published by EMA. Marketing authorisation holders shall continuously check the EMA web- portal for the DLP and frequency of submission of the next PSUR. - For medicinal products authorised under the legal basis of Article 10(1) or Article 10a of Directive 2001/83/EC, no routine PSURs need to be submitted, unless otherwise specified in the EURD list. - For medicinal products that do not fall within the categories waived of the obligation to submit routine PSURs by the revised pharmacovigilance legislation, the MAH should follow the DLP according to the EURD list.

Common renewal date A common renewal date of 5 years after finalisation of the procedure was accepted.

Legal status Subject to medical prescription, product on restricted prescription

User Test The applicant has provided a full readability test for Tektrotyd according to Directive EC 92/27IEEC dated 08 April 2014. The test shows that essential information of the package leaflet of Tektrotyd can be identified and the user can act upon it. In the readability user testing of the package leaflet of

TEKTROTYD 16 Mikrogramm Kit für ein radioaktives Arzneimittel DE/H/3726/01/DC Public Assessment Report Page 16/18 Tektrotyd with 20 subjects every subject answered at least 80% of the total questions correctly showing an acceptable level of readability of the package leaflet.

IV. BENEFIT RISK ASSESSMENT

99mTc-HYNIC-TOC (Tektrotyd)is a somatostatin analogue radiolabelled with sodium pertechnetate (99mTc) solution. It has a peptide sequence which binds with high affinity to somatostatin receptor subtypes 2 and 5, and with lesser affinity to subtype 3. 99mTc-HYNIC-TOC is indicated in adults for scintigraphic imaging and assessment of pathological lesions in GEP-NET tumours in which somatostatin receptors are overexpressed. Positive scintigraphy with 99mTc-HYNIC-TOC reflects the presence of an increased density of tissue somatostatin receptors. Tumours which do not bear receptors will not be visualised. In a number of patients suffering from GEP-NET or carcinoid tumours the receptor density is insufficient to allow visualisation with 99mTc-HYNIC-TOC. Positive uptake, however, is not specific for GEP-NET and carcinoid-tumours and therefore positive scintigraphic results require evaluation of the possibility that another disease characterised by high local somatostatin receptor concentrations may be present. This uncertainty is reflected in the SmPC. The evidence for efficacy of 99mTc-HYNIC-TOC to visualise GEP-NET is based on literature sources of studies with 99mTc-HYNIC-TOC in comparison to 111In-octreotide. All clinical studies on 99mTc- HYNIC-TOC reported / discussed by the applicant refer to the same EDDA/HYNIC-TOC complex of technetium. The overall number of documented patients is N=685. Concerning technical performance, a head-to-head comparison of imaging of 99mTc-EDDA/HYNIC- TOC with 111In-Octroscan in patients with pancreatic tumour or carcinoid syndrome showed very similar pattern of distribution, particularly high uptake of the tracer in tumour tissue and elimination pathways. Semi-quantitative analysis showed even considerably higher tumour/organ ratios for the 99mTc study than for the 111In study. 99mTc-HYNIC-TOC offers clear technical advantages (better image resolution resulting in images of higher quality and lower radiation exposure) over [¹¹¹In]- octreotide which is the authorised product currently used in the indication and can replace the 111In tracer in daily routine. Sodium pertechnetate (99mTc) solution is ubiquitary available for labelling. The advantage of a single 1-day protocol with early imaging at 4 hours after injection as compared with the standard dual-time acquisition 2-days protocol has encouraged practical implementation. Concerning diagnostic performance the applicant has shown the data for detection and tumour localization (Sensitivity 87 – 100%), Staging (Sensitivity 73-97%) which was comparable to values found for 111In-Octreoscan. The efficacy for monitoring the effect of treatment (follow-up) and patient selection for peptide receptor radionuclide therapy has, however, not been established The sensitivity and specificity outcomes, however, can be hampered by results that are erroneously positive due to nonspecific accumulation of tracer (physiological jejunal uptake) or due to accumulation of the radiolabelled somatostatin analogue in inflammatory infiltrations; this is adequately reflected in the SmPC. Concerning impact on diagnostic thinking and patient management the applicant has shown changes in clinical management after 99mTc-Tectrotyd which are comparable to 111In-Octreoscan which are important for treatment planning and monitoring the effects of therapy (follow-up). The impact of Tektrotyd on diagnostic thinking and patient management is also acknowledged in guidelines of scientific societies. Impact of 99mTc-EDDA/HYNIC-TOC scintigraphy on clinical management compares favourably with data on 111In-octreoscan. The benefit of somatostatin receptor scintigraphy with 99mTc-HYNIC-TOC in NET visualisation has been shown in a relatively large group of patients

TEKTROTYD 16 Mikrogramm Kit für ein radioaktives Arzneimittel DE/H/3726/01/DC Public Assessment Report Page 17/18 in different studies with several different neoplasms. Reviewing the available literature it is considered to be a good method in localising primary foci of GEP-NETs, initial staging, treatment planning, and follow up. It seems to be helpful in detecting small tumours or tumours expressing somatostatin receptors only with low density. Moreover a positive somatostatin receptor scintigraphy result has a significant impact on further patient management and changes in the therapeutic procedure. The activity to be administered for single SPECT depends on the available equipment. The suggested activity range to be given to an adult patient is 370 to 740 MBq in one single intravenous injection. The administered doses are not different whether for SPECT or planar (Whole Body) imaging. As the effective dose is about 3.7 mSv when 740 MBq 99mTc-Tektrotyd are administered the adverse events related to ionising radiation are expected to occur with a low probability. For elderly people (> 60 years of age) the probability seems to be about 5 to 10-times lower, whereas for children up to the age of 10 years the probability of fatal cancer induction is about 2 to 3-times higher. For pregnant women the risk is the same as for the average population; however, the unborn child is assumed to have the same risk as young children to develop a fatal cancer, about 15% per Sv. In patients with renal impairment administration should be considered only when the possible damage from radiation is outweighed by the potential diagnostic information as 99mTc-Tektrotyd is excreted predominantly via kidneys. There are no data on safety and efficacy of 99mTc-Tektrotyd in paediatric patients, therefore use in children and adolescents is not recommended. The applicant, however, has shown that in single cases the use of Tektrotyd in children is favourable over Octreoscan (discussion on EAMN homepage). The radiation exposure of 99mTc Tektrotyd in children is remarkably lower than of 111In Octreoscan. 99mTc-Tektrotyd should only be administered to a child when alternative techniques not using ionising radiation are not available or they do not yield a satisfactory performance in the clinical setting of the child. No unfavourable side effects of 99mTc-HYNIC-TOC were observed. However, the withdrawal of therapy with somatostatin analogues as a preparatory step to 99mTc-HYNIC-TOC scintigraphy might provoke severe adverse effects although this has no causal relationship to 99mTc-HYNIC-TOC administration. It can be concluded that 99mTc-HYNIC-TOC improves the diagnostic efficacy in visualisation of GEP-NET neoplasms overexpressing somatostatin receptors and contributes to the selection of an optimal therapeutic procedure. The benefit risk ratio is from a clinical point of view clearly positive. The application is approved. For intermediate amendments see current product information.

TEKTROTYD 16 Mikrogramm Kit für ein radioaktives Arzneimittel DE/H/3726/01/DC Public Assessment Report Page 18/18