Leaflet PYLCLARI 1 000 MBQ/ml solution for injection

Pylclari 1 000 MBq/mL solution for injection

Pylclari 1 500 MBq/mL solution for injection

Pylclari 1 000 MBq/mL solution for injection

Each mL of solution contains 1 000 MBq of piflufolastat (18F) at the date and time of calibration.

The total activity per vial ranges from 500 MBq to 10 000 MBq at the date and time of calibration.

Pylclari 1 500 MBq/mL solution for injection

Each mL of solution contains 1 500 MBq of piflufolastat (18F) at the date and time of calibration.

The total activity per vial ranges from 750 MBq to 15 000 MBq at the date and time of calibration.

Fluorine (18F) decays to stable oxygen (18O) with a half-life of 110 minutes by emitting a positronicradiation of maximum energy of 634 keV, followed by photonic annihilation radiations of 511 keV.

Each mL of solution contains a maximum of 3.5 mg of sodium and 90 mg of ethanol.

For the full list of excipients, see section 6.1.

Solution for injection.

Clear, colourless solution with a pH ranging from 4.5 to 7.5.

This medicinal product is for diagnostic use only.

Pylclari is indicated for the detection of prostate-specific membrane antigen (PSMA) positive lesionswith positron emission tomography (PET) in adults with prostate cancer (PCa) in the followingclinical settings:

* Primary staging of patients with high-risk PCa prior to initial curative therapy,

* To localize recurrence of PCa in patients with a suspected recurrence based on increasing serumprostate-specific antigen (PSA) levels after primary treatment with curative intent.

This medicinal product is for use in designated nuclear medicine facilities only and should only behandled by authorised personnel.

The mean recommended activity of (18F) piflufolastat is 4 MBq/kg of body weight and can vary from3 to 5 MBq/kg of body weight depending on the PET equipment and acquisition mode used. Theminimum activity should not fall below 190 MBq and the maximum activity should not exceed360 MBq.

Renal impairment/Hepatic impairment

Piflufolastat (18F) has only been studied in patients with mild renal impairment. Careful considerationof the activity to be administered is required since an increased radiation exposure is possible inpatients with severe impaired renal function.

Piflufolastat (18F) has not been studied in patients with hepatic impairment.

There is no relevant use of piflufolastat (18F) in the paediatric population.

It is administered by a single intravenous injection.

Pylclari is presented in multidose vial. The minimal volume is 0.5 mL of solution per vial.

The volume of solution to be administered can range from 0.2 mL to 10 mL.

For instruction before administration, see section 6.6.

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

Image acquisition

It is recommended to position the patient supine with arms above the head. A non contrast-enhancedlow-dose CT scan is performed from the vertex of the skull through mid-thigh for attenuationcorrection and anatomic correlation. The PET acquisition is performed from mid-thigh through thevertex of the skull, starting 90 to 120 minutes after tracer injection. It must include lower extremities ifthere is known or suspected disease. Image acquisition duration is 12 to 40 minutes depending on thetype of PET cameras, number of bed positions (typically 6 to 8) and acquisition time per bed position(typically 2 minutes to 5 minutes). If the acquisition leads to indeterminate findings, and provided asufficient activity remains for adequate counting statistics, late acquisitions can also be performed,thus reducing background activity.

For patient preparation, see section 4.4.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Potential for hypersensitivity or anaphylactic reactions

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

Individual benefit/risk justification

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

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

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

Patient preparation

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

A diuretic expected to act within the uptake time period may be administered to improve interpretationof piflufolastat (18F) PET/CT as it results in less activity depositions in ureters and the bladder.

After the procedure

Close contact with infants and pregnant women should be restricted during the initial 12 hoursfollowing the injection.

Interpretation of piflufolastat (18F) images

The recommended method for PET images interpretation with piflufolastat (18F) PET/CT is the visualinterpretation.

Lesions should be considered suspicious if uptake is greater than physiologic uptake in that tissue orgreater than adjacent background if no physiologic uptake is expected.

Piflufolastat (18F) accumulates in normal tissue where the density of PSMA is high including thelacrimal glands, salivary glands, liver, spleen, and kidneys. Normal organs demonstrate significantvariability in the uptake of piflufolastat (18F); however, the impact of tumor burden on normal uptakeis minimal and unlikely to be clinically significant. The expression of PSMA can predominantly befound in prostate cancer, but can also be observed in other neoplasms (e.g. renal cell carcinoma,hepatocarcinoma, breast cancer, lung cancer and other malignancies) or non-malignant conditions (e.ghemangioma, ganglia, since they can mimic lymph nodes, benign bone disease as Paget’s disease, orpulmonary sarcoidosis/granulomatosis).

Images should be interpreted only by readers trained in the interpretation of PET images withpiflufolastat (18F).

Clinical correlation, which may include histopathological evaluation of the suspected prostate cancersite, is recommended. A negative image does not rule out the presence of prostate cancer and apositive image does not confirm the presence of prostate cancer.

Piflufolastat (18F) was not studied for detection of distant metastases in primary staging.

The performance of piflufolastat (18F) for imaging of patients with biochemical evidence of recurrenceof prostate cancer seems to be affected by serum PSA levels (see section 5.1). The performance ofpiflufolastat (18F) for imaging of metastatic pelvic lymph nodes prior to initial definitive therapy seemsto be affected by risk factors such as Gleason score.

Small lymph nodes metastases, or any lesion under spatial resolution of PET (= 5 mm) may be missedby piflufolastat (18F) PET/CT.

To date no outcome data exist to support subsequent management of patients based on PSMA-PET inthe primary staging. Therefore, treatment should not be changed based on piflufolastat (18F) PET/CTfindings only.

Specific warnings

This medicinal product contains up to 3.5 mg sodium per mL equivalent to 0.2 % to the WHOrecommended maximum daily intake of 2 g sodium for an adult.

This medicinal product contains up to 900 mg of alcohol (ethanol) in each administration which isequivalent to 90 mg per mL. The amount in 10 mL of this medicinal product is equivalent to less than23 mL of beer or 11 mL of wine.

The small amount of alcohol in this medicinal product will not have any noticeable effects.

No interaction studies have been performed.

Androgen deprivation therapy (ADT) and other therapies targeting the androgen pathway, such asandrogen receptor antagonists, may result in changes in uptake of piflufolastat (18F) in prostate cancer.

The effect of these therapies on performance of piflufolastat (18F) PET has not been established.

Chronic treatment with diuretics does not seem to have any interference with piflufolastat (18F) forinterpretation of images.

Piflufolastat (18F) is not intended for use in women.

Piflufolastat (18F) is not intended for use in women.

No studies on fertility have been performed.

Pylclari has no or negligible influence on the ability to drive and use machines.

The overall safety profile is based on data from its administration to 797 patients from three clinicalstudies and spontaneous reporting. In the clinical studies, each patient received a single administrationwith a median administered activity of 330 MBq.

Adverse reactions have been reported during clinical development and are listed below by MedDRAbody system organ class.

The frequencies of adverse reactions are defined as follows: Very common (≥1/10), common (≥1/100to <1/10), Uncommon (≥1/1 000 to <1/100), Rare (≥1/10 000 to <1/1 000), Very rare (<1/10 000), notknown (cannot be estimated from the available data). Within each frequency grouping, adversereactions are presented in order of decreasing seriousness.

Table 1: Adverse reactions observed with piflufolastat (18F)

MedDRA body system organ class Adverse reactions Frequency

Immune system disorders Hypersensitivity Uncommon

Metabolism and nutrition disorders Dehydration Uncommon

Psychiatric disorders Disorientation Uncommon

Nervous system disorders Syncope Not known*

Dysgeusia Common

Dizziness Uncommon

Hyperaesthesia

Migraine

Eye disorders Visual field defect Uncommon

Ear and labyrinth disorders Vertigo Uncommon

Gastrointestinal disorders Nausea Not known*

Skin and subcutaneous tissue Dry skin Uncommondisorders Rash

Musculoskeletal and connective Arthralgia Uncommontissue disorders Muscular weakness

Pain in extremity

Renal and urinary disorders Dysuria Uncommon

General disorders and administration Fatigue Uncommonsite conditions Chest discomfort Uncommon

Application site rash

Feeling abnormal

Injection site pain

*Adverse reactions derived from spontaneous reporting with a not known frequency.

A total of 108 treatment emergent adverse events (TEAEs) were reported in 69 (8.6 %) patients, withheadache (1.4 %), dysgeusia (1.0 %), and fatigue (0.5 %) being the most frequent. Three serious drug-related adverse events (hypersensitivity, headache, and paresthesia) were reported, all experienced byone patient and only hypersensitivity was assessed as drug-related in this patient who had a significanthistory of allergic reactions. All three serious drug-related adverse events were resolved.

Exposure to ionising radiation is linked with cancer induction and a potential for development ofhereditary defects.

As the effective dose is 4.4 mSv when the maximal recommended activity of 360 MBq is administeredin a 70 kg-weighted patient, these adverse reactions are expected to occur with a low probability.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

The maximum amount of piflufolastat (18F) injection that can be safely administered to humans hasnot been determined.

In the event of administration of a radiation overdose, the absorbed dose to the patient should bereduced where possible by increasing the elimination of the radionuclide from the body by forceddiuresis and frequent bladder voiding. It might be helpful to estimate the effective dose that wasapplied.

Pharmacotherapeutic group: Diagnostic radiopharmaceuticals, other diagnostic radiopharmaceuticalsfor tumour detection, ATC code: V09IX16.

Prostate-Specific Membrane Antigen (PSMA), is a trans-membrane glycoprotein primarily expressedin normal human prostate epithelium at low levels, but may be overexpressed by malignant tissues,particularly by prostate cancer cells, including metastatic disease. Fluorine (18F) is a β+ emittingradionuclide that enables positron emission tomography. Piflufolastat (18F) is a selective second-generation fluorine-18-labeled small-molecule PSMA inhibitor. Based on the intensity of the signals,

PET images obtained using piflufolastat (18F) indicate the presence of PSMA expressing tissues.

At the chemical concentrations used for diagnostic examinations, this medicinal product does notappear to have any pharmacodynamic activity.

The safety and efficacy of piflufolastat (18F) were evaluated in three prospective, open-label, multi-center clinical studies in men with prostate cancer: OSPREY (NCT02981368), CONDOR(NCT03739684), and PYTHON (EudraCT number 2020-000121-37).

OSPREY cohort A enrolled a cohort of 268 men with high-risk biopsy-proven prostate cancer whowere considered candidates for radical prostatectomy and pelvic lymph node dissection. Each patientreceived a single piflufolastat (18F) PET/CT from mid-thigh to skull vertex. Three central independentreaders blinded to all clinical information interpreted each PET scan for the presence of abnormaluptake in pelvic lymph nodes in multiple subregions, including the common iliac lymph nodes. Co-primary endpoints were specificity and sensitivity of piflufolastat (18F) PET/CT against histopathologywithin the pelvic lymph nodes. Secondary endpoints were Positive Predictive Value (PPV) and

Negative Predictive Value (NPV) of piflufolastat (18F) PET/CT to predict the presence or absencerespectively of prostate cancer within the prostate gland and lymph nodes in Cohort A.

A total of 252 patients (94 %) underwent prostatectomy and pelvic lymph node dissection and hadsufficient histopathology data for evaluation of the pelvic lymph nodes. Surgical specimens wereseparated into three regions: left hemipelvis, right hemipelvis, and other. For each patient,piflufolastat (18F) PET/CT results and histopathology results obtained from dissected pelvic lymphnodes were compared by surgical region. PET/CT results in locations that were not dissected wereexcluded from analysis. For the 252 evaluable patients, the mean age was 64 years (range 46 to84 years). The median serum PSA was 9.3 ng/mL. The total Gleason score was 7 for 19 %, 8 for 46 %,and 9 for 34 % of the patients, with the remainder of the patients having Gleason scores of 6 or 10.

The pre-defined thresholds for the co-primary endpoints were 40 % for sensitivity and 80 % forspecificity. Sensitivity did not reach statistical significance for at least 2 of the 3 independent imagingreviewers, therefore, it was considered a failed study.

Table 2 shows piflufolastat (18F) PET/CT performance by reader using pelvic lymph nodehistopathology as standard of truth, at the patient-level with region matching (one true positive regiondefines a true positive patient). Approximately 24% of the evaluable patients had pelvic lymph nodemetastases based on histopathology ( 95% confidence interval: 19 %, 29 %).

Table 2: Performance evaluation of piflufolastat (18F) PET/CT for pelvic lymph node metastasisdetection in OSPREY cohort A (n=252) using Patient-Level and Region-Matched analysis.

Reader 1 Reader 2 Reader 3

True positive 23 17 23

False Positive 7 4 9

False Negative 36 43 37

True Negative 186 188 183

Sensitivity, % (95% CI) 39 (27;51) 28 (17;40) 38 (26;51)

Specificity, % (95% CI) 96 (94;99) 98 (95;99) 95 (92;98)

PPV, % (95% CI) 77 (62;92) 81 (59;93) 72 (56;87)

NPV, % (95% CI) 84 (79;89) 81 (76;86) 83 (78;88)

Abbreviations: CI = confidence interval, PPV = positive predictive value, NPV = negative predictive value

For primary staging (OSPREY Cohort A), high level reader agreement for pelvic lymph nodesmetastases (92.5 %) was achieved with Fleiss’ kappa statistic of 0.78 (95 %CI: 0.71; 0.85).

In exploratory analyses, there were numerical trends towards more true positive results among patientswith total Gleason score of 8 or higher and among patients with tumor stage of T2c or higher relativeto those patients with lower Gleason score or tumor stage.

A comparison on diagnostic performance of piflufolastat (18F) PET/CT with baseline conventionalimaging (CI) in patients with high risk prostate cancer from Osprey Cohort A was performed as a post-hoc study. Piflufolastat (18F) PET/CT demonstrated a 3-fold higher PPV than conventional imaging(median 86.7 % vs. 28.3 %, respectively) despite similar sensitivity (median 40.3 % for piflufolastat(18F) PET/CT and 42.6 % for conventional imaging). Mean specificiy of piflufolastat (18F) PET/CT was97.9 % and 65.1 % for CI and mean NPV 83.2 % vs. 78.8 % respectively.

CONDOR enrolled 208 patients with biochemical evidence of suspected recurrent prostate cancerafter initial treatment (radical prostatectomy in 85 % of the patients). The median serum PSA was0.82 ng/mL. All enrolled patients had negative or equivocal for prostate cancer conventional imagingevaluation (for most patients, CT or MRI) within 60 days prior to receiving piflufolastat (18F). Allpatients received a single PET/CT from mid-thigh to skull vertex with optional imaging of the lowerextremities. Three independent central readers, blinded to all clinical information, evaluated each

PET/CT scan for the presence and location of positive lesions. Location of each lesion wascategorized into 5 regions (prostate/prostate bed, pelvic lymph nodes, other lymph nodes, soft tissue,bone). The primary endpoint was the correct localisation rate (CLR) at the patient level, defined as thepercentage of patients for whom there was a one-to-one correspondence between localisation of atleast one lesion identified on piflufolastat (18F) PET/CT imaging and the composite truth standard. Ifthe lower bound of the 95 % CI was >0.2 (CLR of 20 %) for at least 2 of the 3 independent imagingreviewers, then the primary endpoint analysis was considered a success. The secondary endpoint wasthe impact on patient management (IMP) defined as the percentage of patients with a change inintended prostate cancer treatment plans due to piflufolastat (18F) PET/CT as measured by comparisonof intended management questionnaires completed pre- and post- piflufolastat (18F) PET/CT imagingresults.

Depending on the reader, a total of 123 to 137 patients (59 % to 66 %) had at least one lesion that wasidentified as piflufolastat (18F) PET-positive (Table 3). The region most commonly observed to have a

PET-positive finding was pelvic lymph nodes (40 % to 42 % of all PET-positive regions) and the leastcommon region was soft tissue (6 % to 7 %).

Depending on the reader, 99 to 104 patients with a piflufolastat (18F) PET-positive region hadlocation-matched composite reference standard information that consisted of histopathology, imaging(CT, MRI, ultrasound, fluciclovine (18F) PET, choline PET, or bone scan) obtained within 60 days ofthe PET/CT scan, or response of serum PSA level to targeted radiotherapy. Table 3 shows patient-level performance results of piflufolastat (18F) PET/CT by reader, including location-matched positivepredictive value, also known as Correct Localization Rate (CLR). A patient was considered truepositive if they had at least one matching location positive on both piflufolastat (18F) PET/CT and thecomposite reference standard.

Table 3. Patient-Level Performance of piflufolastat (18F) PET/CT in CONDOR (n=208)

Reader 1 Reader 2 Reader 3

PET-negative 71 84 85

PET-positive 137 124 123

True positive 89 87 84

False positive 15 13 15

Unevaluable (PET- 33 24 24positive Without

Reference Standard)

CLR % (95% CI) 86 (79,92) 87 (80,94) 85 (78,92)

Abbreviations: CLR = location-matched positive predictive value, CI = confidence interval

Table 4 shows patient-level piflufolastat (18F) PET/CT results from the majority read stratified byserum PSA level. Percent PET positivity was calculated as the proportion of patients with a positive

PET/CT out of all patients scanned. The likelihood of a patient having at least one piflufolastat (18F)

PET-positive lesion generally increased with higher serum PSA level.

Table 4: Patient-Level piflufolastat (18F) PET results and percent PET positivity* stratified byserum PSA level in the CONDOR study using majority result among three readers (n=199)**

PSA (ng/mL) PET positive patients PET Percentnegative PETpatients positivity(95% CI) *

Total TP FP Unevaluable(Withoutreferencestandard)< 0.5 24 11 4 9 45 35 (24;46)≥0.5 and <1 18 12 3 3 18 50 (34;66)≥1 and <2 21 15 3 3 10 68 (51;84)≥2 57 50 3 4 6 90 (83;98)

Total 120 88 13 19 79 60 (54;67)

* Percent PET positivity = PET positive patients/total patients scanned. PET positive patients include truepositive and false positive patients as well as those who did not have reference standard information.

** Six patients were excluded from this table due to lack of baseline PSA level, and three patients were excludedfrom this table due to lack of majority result among three readers.

Abbreviations: TP = true positive, FP = false positive, CI = confidence interval

For the 207 patients with medical management questionnaires completed by treating physicians at pre-and post-PSMA imaging, 64 % (131/207) of patients had a change in intended management afterpiflufolastat (18F) PET/CT. Of the patients with changed clinical plans, 79 % (103/131) were due topositive PSMA PET/CT findings, and 21 % (28/131) were due to negative scans. The most frequentchanges were from salvage local therapy to systemic therapy (58 patients), from observation toinitiating any therapy (49 patients), from noncurative systemic therapy to salvage local therapy(43 patients), and from planned treatment to observation (no treatment) (9 patients).

PYTHON was a randomised, open-label, two-treatment cross-over study. It enrolled 217 male patientswith first biochemical recurrence of prostate cancer, who underwent definitive therapy (radicalprostatectomy (RP) ± extented lymph node dissection (eLND) in 73.2 % patients, EBRT orbrachytherapy in 26.8 % patients). The primary endpoint was detection rate (DR) defined as numberof patients defined as positive at patient level by the independent readers among the total number ofpatients assessed (for piflufolastat (18F) PET/CT and fluorocholine (18F) PET/CT). A significantdifference of 12 % detection rate in favour of piflufolastat (18F) against Fluorocholine (18F) was pre-defined. Secondary endpoints were sensitivity (ratio between the number of patients defined aspositive for a given region by the independent readers and the total number of patients assessed aspositive for a given region by the truth panel), concordance (ratio between the number of regionsdefined as positive by both piflufolastat (18F) PET/CT and Fluorocholine (18F) PET/CT + the numberof regions defined as negative by both piflufolastat (18F) PET/CT and Fluorocholine (18F) PET/CT andthe total number of assessed regions) and impact on patient management.

Two-hundred one patients performed one piflufolastat (18F) PET/CT and one fluorocholine (18F)

PET/CT from mid-thigh to skull vertex in a randomised order. Three independent central readers,blinded to all clinical information, evaluated each piflufolastat (18F) and each fluorocholine (18F)

PET/CT for the presence and location of positive lesions. Location of each lesion was categorized into5 regions (prostate/prostate bed, pelvic lymph nodes, other lymph nodes, bone, soft tissue). Recurrencewas detected by the blind read experts in 119 (60.4%) and 82 (41.0%) of the patients with piflufolastat(18F) and fluorocholine (18F) PET/CT, respectively. Details of overall independent reader’sinterpretation by PSA level is given in Table 5.

Table 5: Per-patient detection rate of PET/CT by PSA level in PYTHON study (N=201)

PSA (ng/mL) level at first injection piflufolastat ( F) fluorocholine (18F)

PSA < 0.2 (n=6) 2 (33.3%) 1 (16.7%)

PSA [0.2 - 0.5] (N=68) 24 (35.3%) 21 (30.9%))

PSA [0.51 - 1] (N=31) 17 (54.8%) 10 (32.3%)

PSA [1.01 - 2] (N=19) 13 (68.4%) 6 (31.6%)

PSA >2 (N=57) 50 (87.7%) 39 (68.4%)

Per-patient sensitivity was assessed for 37 patients with a standard of truth and is reported in Table 6.

Per-patient sensitivity of (18F)-piflufolastat was significantly higher than that of (18F)-fluorocholine(p<0.0001).

Table 6: Per-patient sensitivity (n=37)

PET/CT piflufolastat (18F) fluorocholine (18F)

Sensitivity (95% CI) 58.3% (95% CI 51.5;64.9) 40.6% (95% CI 34.1;47.5)

The concordance rate between (18F)-piflufolastat PET/CT and (18F)-fluorocholine PET/CT accordingto central blind readers, per-region was remarkably high for all regions of interest, namely prostatebed: 87.3 % (81.9; 91.3), pelvic lymph nodes: 73.9 % (67.3; 79.5), extrapelvic lymph nodes: 86.5%(81.0; 90.6), bones: 86.9 % (81.5;91.0), and other organs: 92.0 % (87.3; 95.1).

Regarding the localization of recurrence, the central readers achieved an agreement of 84.2% with a

Fleiss' kappa statistic of 0.58 (95 % CI: 0.47; 0.70) for all biopsy images in OSPREY Cohort B. In

CONDOR, the central readers exhibited 76% agreement in interpreting positive or negativepiflufolastat (18F) PET/CT scans with a Fleiss' kappa statistic of 0.65 (95 % CI: 0.58; 0.73), while theconcordance between each central reader and the local reader ranged from 83% to 84%. In PYTHON,the inter-reader agreement percentage was 67.8 %, and the corresponding Fleiss' kappa was 0.55(95 % CI: 0.47; 0.63).

The European Medicines Agency has waived the obligation to submit the results of studies with

Pylclari in all subsets of the paediatric population in diagnosis of prostate cancer (see section 4.2 forinformation on paediatric use).

Blood levels decline in a biphasic fashion. The distribution half-life is 0.17 ± 0.04 hours and theelimination half-life is 3.47 ± 0.49 hours.

Organ uptake

Physiologic accumulation of piflufolastat (18F) is observed in the kidneys (16.5% of administeredactivity), liver (9.3 %), and lung (2.9 %), within 60 minutes of intravenous administration. Most of theremaining 70 % of activity at 60 minutes is with the rest of the body background region.

The only radioactive component detected in plasma samples by high-performance liquidchromatography (HPLC) up to 173 minutes post-injection was unchanged piflufolastat (18F).

Elimination is by urinary excretion. In the first 8 hours post-injection, approximately 50% ofadministered radioactivity is excreted in the urine.

Half-life

The biological and effective half-life of piflufolastat (18F) are 3.47 ± 0.49 hours and approximately 70minutes, respectively.

Renal/Hepatic impairment

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

An extended single dose toxicity study was conducted in rats with the non-radioactive pharmaceutical.

No adverse reactions were observed in any of the animals, and no deaths occurred at the highest testeddose of 0.5 mg/kg. This dose is over 875-fold higher than the maximum clinical dose of 40 µg/patient(or 0.5714 µg/kg for a reference body weight of 70 kg); on a body surface area basis, this dose isapproximately 142-fold higher, suggesting adequate safety margin.

No other studies were conducted.

This medicinal product is not intended for regular or continuous administration. At the chemicalconcentrations and the activities used for diagnostic examinations, additional studies does not appearto be necessary.

Sodium chloride 9 mg/mL (0.9 %) solution for injection

Sodium ascorbate

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

10 hours from calibration time.

Date and time of expiry are indicated on the labels.

After the first withdrawal, this medicinal product does not require any special storage conditions.

After dilution, store for up to 4 hours without exceeding the expiry time.

Store in the original lead shielding.

This medicinal product does not require any special storage conditions.

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

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

15 mL Type I glass vial, closed with a chlorobutyl stopper and an aluminium seal.

Pack size: one multidose vial contains 0.5 mL to 10 mL of solution, corresponding to:

- 500 to 10 000 MBq at calibration time of Pylclari 1 000 MBq/mL

- 750 to 15 000 MBq at calibration time of Pylclari 1 500 MBq/mL

General warning

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

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

This product is administered via an intravenous flexible catheter. The administration must be strictlyintravenous in order to avoid irradiation as a result of local extravasation, as well as imaging artefacts.

The bolus administration will be followed by a flush of 5-10 mL sodium chloride 9 mg/mL (0.9 %)solution for injection, to ensure full delivery of the dose.

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

If at any time in the preparation of this medicinal product the integrity of the vial is compromised itshould not be used.

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

The administration of radiopharmaceuticals creates risks for other persons from external radiation orcontamination from spill of urine, vomiting etc. Radiation protection precautions in accordance withnational regulations must therefore be taken.

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

CURIUM PET FRANCE3 rue Marie Curie, Biopole Clermont-Limagne63 360 Saint-Beauzire - France

EU/1/23/1746/001

EU/1/23/1746/002

Date of first authorisation: 24 July 2023

Data listed below are from sponsored clinical studies.

Assumptions:

Fluorine (18F) decays to stable oxygen (18O) with a half-life of 110 minutes by emitting a positronicradiation of maximum energy of 634 keV, followed by photonic annihilation radiations of 511 keV.

Piflufolastat (18F) exhibits bi-exponential behaviour in blood, with a distribution half-life of0.17 ± 0.044 hours and an elimination half-life of 3.47 ± 0.49 hours. It distributes to the kidneys(16.5 % of administered activity), liver (9.3 %), and lung (2.9 %), within minutes of intravenousadministration.

Methodology:

The time-integrated activity in source tissue was obtained from longitudinal imaging data. Contours orvolumes of interest (VOIs) were typically drawn around different activity-containing organs that wereidentified on each image at each time-point. The S-value was obtained by Monte Carlo simulation.

The absorbed doses calculation was performed on 3D-RD-S software. The resulting effective dose wascalculated according to ICRP 103.

ORGAN ABSORBED DOSE PER UNIT

ACTIVITY ADMINISTERED(mGy/MBq)

Adrenals 0.0326

Bone surfaces 0.00662

Brain 0.00215

Breast 0.00767

Gallbladder wall 0.0255

Gastrointestinal tract

Stomach wall 0.0127

Small Intestine wall 0.0101

Colon wall

Upper large intestine wall 0.0125

Lower Large Intestine wall 0.0101

Heart wall 0.0178

Kidneys 0.124

Liver 0.0388

Lungs 0.0121

Muscles 0.00714

Pancreas 0.0183

Red marrow 0.00851

Skin 0.0054

Spleen 0.0283

Testes 0.00638

Thymus 0.00769

Thyroid 0.00687

Urinary bladder wall 0.00712

Effective dose (mSv/MBq) 0.0121

The effective dose resulting from the administration of a maximal recommended activity of 360 MBqfor an adult weighing 70 kg is about 4.4 mSv.

For an administered activity of 360 MBq, the typical radiation doses to the critical organs (kidneys,liver and spleen) are 44.6 mGy, 14 mGy and 10.2 mGy respectively.

Method of preparation

This ready-to-use medicinal product can be diluted with sodium chloride 9 mg/mL (0.9%) solution forinjection.

Withdrawals of the appropriate volume should be performed under aseptic conditions. The vial mustnot be opened. After disinfecting the stopper, the solution should be withdrawn via the stopper using asingle dose syringe fitted with suitable protective shielding and a disposable sterile needle or using anauthorised automated and qualified application system.

If the integrity of this vial is compromised, the medicinal product should not be used.

This medicinal product should only be used when the injection volume is greater than 0.2 mL. If theinjection volume is between 0.2 and 1 mL, only syringes of an appropriate size (1 mL) should be used.

Quality control

The packaging must be checked before use and the activity of the solution must be measured using anactivimeter.

The solution should be inspected visually prior to use. Only clear solution, free of visible particlesshould be used.

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu