VUEWAY 0.5mmol / ml injectible solution medication leaflet

Vueway 0.5 mmol/mL solution for injection

1 mL of solution contains 485.1 mg gadopiclenol (equivalent to 0.5 mmol of gadopiclenol and to 78.6 mgof gadolinium).

For the full list of excipients, see section 6.1.

Solution for injection

Clear, colourless to pale yellow solution

Mean osmolality at 37 °C 850 mOsm/kg H2OpH 7.0-7.8

Viscosity at 20 °C 12.5 mPa s

Viscosity at 37 °C 7.7 mPa s

This medicinal product is for diagnostic use only.

Vueway is indicated in adults and children aged 2 years and older for contrast-enhanced magneticresonance imaging (MRI) to improve detection and visualization of pathologies with disruption of theblood-brain-barrier (BBB) and/or abnormal vascularity of:

- the brain, spine, and associated tissues of the central nervous system (CNS);

- the liver, kidney, pancreas, breast, lung, prostate, and musculoskeletal system.

It should be used only when diagnostic information is essential and not available with unenhanced MRI.

This medicinal product should only be administered by trained healthcare professionals with technicalexpertise in performing gadolinium enhanced MRI.

The recommended dose of Vueway is 0.1 mL/kg body weight (BW) (equivalent to 0.05 mmol/kg BW) toprovide diagnostically adequate contrast for all indications.

The dose should be calculated based on the patient’s BW and should not exceed the recommended doseper kilogram of BW detailed in this section.

Table 1 below indicates the volume to be administered according to BW.

Table 1: Volume of Vueway to be administered per BW

BW Volume Quantitykilograms (kg) millilitres (mL) millimoles (mmol)10 1 0.520 2 1.030 3 1.540 4 2.050 5 2.560 6 3.070 7 3.580 8 4.090 9 4.5100 10 5.0110 11 5.5120 12 6.0130 13 6.5140 14 7.0

No dose adjustment is necessary. Caution should be exercised in elderly patients (see section 4.4 and 5.2).

No dose adjustment is necessary for patients with any level of renal impairment. Gadopiclenol shouldonly be used in patients with severe renal impairment (GFR < 30 mL/min/1.73 m2) and in patients in theperioperative liver transplantation period after careful risk/benefit assessment and if the diagnosticinformation is essential and not available with non-contrast enhanced MRI (see section 4.4). If it isnecessary to use gadopiclenol, the dose should not exceed 0.1 mL/kg BW (equivalent to 0.05 mmol/kg

BW). More than one dose should not be used during a scan. Because of the lack of information onrepeated administration, gadopiclenol injections should not be repeated unless the interval betweeninjections is at least 7 days.

No dose adjustment is considered necessary for patients with hepatic impairment. Caution isrecommended, especially in the case of perioperative liver transplantation period (see above “renalimpairment”).

Paediatric population (2 years and older)

The recommended and maximum dose of Vueway is 0.1 mL/kg BW (equivalent to 0.05 mmol/kg BW)for all indications. More than one dose should not be used during a scan.

The safety and efficacy of Vueway in children less than 2 years has not yet been established. No data areavailable.

The medicinal product is for intravenous use only.

The recommended dose is administered intravenously as a bolus injection at approximatively 2 mL/secfollowed by a flush of sodium chloride 9 mg/ml (0.9%), solution for injection via manual injection orpower injector.

Intravenous administration of contrast agent should, if possible, be done with the patient lying down.

Since experience shows that most undesirable effects occur within minutes after administration, thepatient should be kept under observation during and following administration for at least half an hour (seesection 4.4).

For instructions on the medicinal product before administration, see section 6.6.

In children, Vueway in vials with a single use syringe of a volume adapted to the amount to be injectedshould be used in order to have better precision of the injected volume.

Image acquisition

Contrast-enhanced MRI can start after the injection depending on the pulse sequences used and theprotocol for the examination. Optimal signal enhancement is generally observed during arterial phase andwithin a period of about 15 minutes after injection. Longitudinal relaxation times (T1)-weightedsequences are particularly suitable for contrast-enhanced examinations.

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

Gadopiclenol must not be used intrathecally. Serious, life-threatening and fatal cases, primarily withneurological reactions (e.g. coma, encephalopathy, seizures), have been reported with intrathecal use ofgadolinium-based contrast agents.

The usual precautions for MRI examination should be applied, such as exclusion of patients withpacemakers, ferromagnetic vascular clips, infusion pumps, nerve stimulators, cochlear implants, orsuspected intracorporal metallic foreign bodies, particularly in the eye.

MRI images produced with this medicinal product should only be analysed and interpreted by thehealthcare professionals trained in interpretation of gadolinium enhanced MRI.

There are no or limited clinical data investigating the performance of gadopiclenol for CNS imaging inpatients with inflammatory, infectious, autoimmune or demyelinating disorders (such as multiplesclerosis), patients with acute or chronic infarct, or patients with intramedullary spine lesions.

There are also no or limited clinical data investigating the performance of gadopiclenol for body imagingin patients with inflammatory, infectious and autoimmune conditions, including acute/chronicpancreatitis, inflammatory bowel disease, inflammatory diseases of head and neck region andendometriosis.

Potential for hypersensitivity or anaphylactic reactions

- As with other gadolinium-containing contrast agents, hypersensitivity reactions can occur,including life-threatening. Hypersensitivity reactions may be either allergic (described asanaphylactic reactions when serious) or non-allergic. They can occur either immediately (less than60 minutes) after injection or delayed (up to 7 days). Anaphylactic reactions occur immediately andcan be fatal. They are independent of the dose, can occur after even the first dose of the product,and are often unpredictable.

- During the examination, supervision by a physician is necessary. If hypersensitivity reactionsoccur, administration of the contrast agent must be discontinued immediately and - if necessary - aspecific therapy must be instituted. A venous access should thus be kept during the entireexamination. To permit immediate emergency countermeasures, appropriate drugs (e.g.epinephrine and antihistamines), an endotracheal tube and a respirator should be ready at hand.

- The risk of hypersensitivity reaction may be higher in patients with a history of previous reaction togadolinium-containing contrast agents, bronchial asthma or allergy.

Renal impairment and nephrogenic systemic fibrosis (NSF)

Prior to administration of gadopiclenol, it is recommended that all patients are screened for renaldysfunction by obtaining laboratory tests.

There have been reports of nephrogenic systemic fibrosis (NSF) associated with use of some gadolinium-containing contrast agents in patients with acute or chronic severe renal impairment(GFR < 30 mL/min/1.73 m2). Patients undergoing liver transplantation are at particular risk since theincidence of acute renal failure is high in this group. As there is a possibility that NSF may occur withgadopiclenol, it should only be used in patients with severe renal impairment and in patients in theperioperative liver transplantation period after careful benefit/risk assessment and if the diagnosticinformation is essential and not available with non-contrast enhanced MRI.

Haemodialysis shortly after gadopiclenol administration may be useful at removing it from the body.

There is no evidence to support the initiation of haemodialysis for prevention or treatment of NSF inpatients not already undergoing haemodialysis.

As the renal clearance of gadopiclenol may be impaired in the elderly, it is particularly important toscreen patients aged 65 years and older for renal dysfunction. Caution should be exercised in patients withrenal impairment (see section 4.2).

As with other gadolinium-containing contrast agents, special caution is necessary in patients with alowered threshold for seizures. All equipment and drugs necessary to counter convulsions occurringduring the MRI examination must be made ready for use beforehand.

Caution during administration is necessary to avoid any extravasation. In case of extravasation, theinjection must be stopped immediately. In case of local reactions, evaluation and treatment should becarried out as necessary.

In patients with severe cardiovascular disease gadopiclenol should only be administrated after careful riskbenefit assessment because no data are available so far.

This medicinal product contains less than 1 mmol sodium (23 mg) per 15 mL, that is to say essentially‘sodium-free’.

No interaction studies have been performed.

Concomitant medicinal products to be taken into account

Beta-blockers, vasoactive substances, angiotensin-converting enzyme inhibitors, angiotensin II receptorantagonists decrease the efficacy of the mechanisms of cardiovascular compensation for blood pressuredisorders. The physician must obtain information before injection of gadopiclenol about the concomitantintake of those medicinal products.

Data on the use of gadolinium-based contrast agents including gadopiclenol in pregnant women islimited. Gadolinium can cross the placenta. It is unknown whether exposure to gadolinium is associatedwith adverse effects in the foetus. Animal studies showed little placental transfer and do not indicatedirect or indirect harmful effects with respect to reproductive toxicity (see section 5.3). Vueway shouldnot be used during pregnancy unless the clinical condition of the woman requires use of gadopiclenol.

Gadolinium-containing contrast agents are excreted into breast milk in very small amounts. At clinicaldoses, no effects on the infant are anticipated due to the small amount excreted in milk and poorabsorption from the gut. Continuing or discontinuing breast feeding for a period of 24 hours afteradministration of Vueway, should be at the discretion of the doctor and breast-feeding mother.

Animals studies do not indicate impairment of fertility (see section 5.3).

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

The most frequent adverse reactions were injection site pain, headache, nausea, injection site coldness,fatigue and diarrhoea.

Table 2 below presents adverse reactions based on clinical trials including 1047 subjects exposed togadopiclenol ranging from 0.05 mL/kg BW (equivalent to 0.025 mmol/kg BW) to 0.6 mL/kg BW(equivalent to 0.3 mmol/kg BW).

The adverse reactions are listed below by SOC (System Organ Class) and by frequency with thefollowing guidelines: 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).

Table 2: Adverse reactions reported following gadopiclenol administration

Frequency

System Organ Class

Common Uncommon

Immune system disorders - Hypersensitivity*

Nervous system disorders Headache Dysgeusia

Gastrointestinal disorders - Diarrhoea, Nausea,

Abdominal pain, Vomiting

General disorders and Injection site reaction** Fatigue, Feeling hotadministration site conditions

* Including immediate (dermatitis allergic, erythema, dyspnoea, dysphonia, throat tightness, throatirritation, paraesthesia oral and flushing) and delayed (periorbital oedema, swelling, rash and pruritus)reactions.

** Injection site reaction includes the following terms: injection site pain, injection site oedema, injectionsite coldness, injection site warmth, injection site haematoma and injection site erythema.

Immediate reactions include one or more effects, which appear simultaneously or sequentially, which aremost often cutaneous, respiratory and/or vascular reactions. Each sign may be a warning sign of a startingshock and go very rarely to death.

Nephrogenic systemic fibrosis (NSF)

Isolated cases of NSF have been reported with other gadolinium-containing contrast agents (see section4.4).

Paediatric population (2 years and older)

A total of 80 paediatric patients aged 2 years and older were included in the clinical trial.

As compared to adults, the safety profile of gadopiclenol in this population did not show any specificsafety concern.

A total of 31 Treatment Emergent Adverse Events (TEAEs) occurred during and/or after gadopiclenoladministration for 14 patients (17.5%). Twelve TEAEs were reported in the CNS cohort and 2 in the

Body cohort.

Among these TEAEs, 1 event in 1 patient (1.25%) from the CNS cohort was considered related togadopiclenol.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allowscontinued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals areasked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

The maximum daily single dose tested in humans was 0.6 mL/kg BW (equivalent to 0.3 mmol/kg BW),which corresponds to 6 times the recommended dose.

No signs of intoxication from an overdose have so far been reported.

Gadopiclenol can be removed by haemodialysis. However, there is no evidence that haemodialysis issuitable for prevention of nephrogenic systemic fibrosis (NSF).

Pharmacotherapeutic group: paramagnetic contrast media, ATC code: V08CA12.

Gadopiclenol is a paramagnetic agent for Magnetic Resonance Imaging (MRI).

The contrast-enhancing effect is mediated by gadopiclenol which is a macrocyclic non-ionic complex ofgadolinium, the active moiety which enhances the relaxation rates of water protons in its vicinity in thebody, leading to an increase in signal intensity (brightness) of tissues.

When placed in a magnetic field (patient in MRI machine), gadopiclenol shortens the T1 and T2 relaxationtimes in targeted tissues. The extent to which a contrast agent can affect the relaxation rate of tissue water(1/T1 or 1/T2) is termed relaxivity (r1 or r2).

Gadopiclenol presents a high relaxivity in water (see Table 3) due to its chemical structure, because it canexchange two water molecules, which are linked to the gadolinium to complete its coordination numberin addition to the four nitrogens and the three oxygens of the carboxylate functions of the gadopiclenolchelate. This explains that, gadopiclenol given at half dose of gadolinium compared to other non-specificgadolinium-containing contrast agents, may provide the same contrast enhancement.

Table 3: Relaxivity at 37 °C for gadopiclenolr1 (mmol-1.l.s-1) r2 (mmol-1.l.s-1)

Magnetic field 0.47 T 1.5 T 3 T 0.47 T 1.5 T 3 T

Relaxivity in water 12.5 12.2 11.3 14.6 15.0 13.5

Relaxivity in biological medium 13.2 12.8 11.6 15.1 15.1 14.7

Two pivotal studies included adult patients undergoing MRI with gadopiclenol at 0.1 mL/kg BW(equivalent to 0.05 mmol/kg BW) and MRI with gadobutrol at 0.1 mL/kg BW (equivalent to 0.1 mmol/kg

BW). One study (Study 1; PICTURE) included 256 patients presenting with known or highly suspected

CNS lesions with focal areas of disrupted BBB (e.g. primary and secondary tumors). The majority ofpatients (72%) presented with brain tumors, 20% had brain or spine metastases and 8% presented withother pathologies.

The other study (Study 2; PROMISE) included 304 patients with known or suspected abnormalities orlesions in other body regions (8% in head and neck, 28% in thorax, 35% in abdomen, 22% in pelvis and7% in musculo-skeletal system) both based on results of a previous imaging procedure such as CT or

MRI. The most frequent pathologies were breast tumors (23%) and liver tumors (21%).

The primary endpoint was the evaluation of lesion visualization, based on 3 co-criteria (borderdelineation, internal morphology and degree of contrast enhancement) by three independent blindedreaders, using a 4-point scale. The mean of scores for each of the 3 lesion visualization co-criteria wascalculated as the sum of scores for up to 3 most representative lesions divided by the number of lesions.

Both studies demonstrated:

- Superiority of the combined unenhanced/contrast-enhanced MRI (Paired) with gadopiclenol overunenhanced MRI (Pre) for all 3 lesion visualization criteria (p < 0.0001 for all three readers, pairedt-tests on matching lesions).

- Non-inferiority of gadopiclenol at 0.1 mL/kg BW (equivalent to 0.05 mmol/kg BW) to gadobutrolat 0.1 mL/kg BW (equivalent to 0.1 mmol/kg BW) (p < 0.0001 for all three readers, paired t-testson matching lesions).

The pooled analysis of the primary outcome over the three readers, and for each lesion visualizationcriterion also demonstrated the non-inferiority of gadopiclenol at 0.05 mmol/kg to gadobutrol at0.1 mmol/kg in both studies, as shown in table 4 below.

Table 4: Lesion visualization - Off-site readings - Full analysis setn patients LS Mean (SE) 95% CI

Gadopiclenol Gadobutrol Difference difference p-value

Study 1 (PICTURE)

Border delineation 239 3.83 ( 0.02) 3.82 ( 0.02) 0.01 ( 0.02) [ -0.02 ; 0.05] 0.5025

Internal morphology 239 3.83 ( 0.02) 3.81 ( 0.02) 0.02 ( 0.02) [ -0.01 ; 0.05] 0.2006

Degree of contrastenhancement 239 3.73 ( 0.03) 3.68 ( 0.03) 0.05 ( 0.02) [ 0.01 ; 0.09] 0.0172

Study 2 (PROMISE)

Border delineation 273 3.60 ( 0.03) 3.60 ( 0.03) -0.00 ( 0.02) [ -0.05 ; 0.04] 0.8987

Internal morphology 273 3.75 ( 0.02) 3.76 ( 0.02) -0.01 ( 0.02) [ -0.05 ; 0.03] 0.6822

Degree of contrastenhancement 273 3.30 ( 0.04) 3.29 ( 0.04) 0.01 ( 0.03) [ -0.05 ; 0.07] 0.8546

CI: Confidence Interval ; LS: Least Squares ; SE: Standard Error.

The secondary criteria evaluated included quantitative evaluations (Contrast to Noise Ratio, Lesion to

Brain (background) Ratio and percentage of lesion enhancement), overall diagnostic preference andimpact on patient management.

In Study 1, Lesion to Brain Ratio, and percentage of lesion enhancement were statistically significantlyhigher with gadopiclenol at 0.1 mL/kg BW (equivalent to 0.05 mmol/kg BW) compared to gadobutrol at0.1 mL/kg BW (equivalent to 0.1 mmol/kg BW) for all 3 readers. Contrast to Noise Ratio was statisticallysignificantly higher for 2 readers. In Study 2, percentage of lesion enhancement was significantly higherwith gadopiclenol at 0.1 mL/kg BW (equivalent to 0.05 mmol/kg BW) compared to gadobutrol at0.1 mL/kg BW (equivalent to 0.1 mmol/kg BW) and no statistically significant difference was observedfor Lesion to Background Ratio.

Lesion visualisation parameters (e.g., co-primary endpoints and quantitative assessments, such as,

Contrast to Noise Ratio, Lesion to Brain (background) Ratio and percentage of lesion enhancement) wereassessed in all the lesions identified by the blinded readers, independently of their size, in more than 86%of patients in CNS study and in more than 81% of patients in Body study, who had no more than 3lesions. In the remaining patients with more than 3 lesions visible, a subset of 3 most representativelesions were selected for assessment of the co-primary endpoints. Therefore, in those patients, theadditional lesions were not assessed. Consequently, the technical capability of lesion visualisation forboth contrast agents cannot be extrapolated for those non-selected lesions.

The overall diagnostic preference was assessed in a global matched-pairs fashion (reading of images fromboth MRI assessed side by side) by three additional blinded readers in each study. The results aresummarized in the Table 5 below. In Study 1, in majority, the readers expressed a preference for imagesacquired with gadopiclenol. In Study 2, in majority, the readers expressed no diagnostic preferencebetween images acquired with gadopiclenol and with gadobutrol.

Table 5: Results on overall diagnostic preference for Study 1 (CNS) and Study 2 (Body)

Reader N gadopiclenol No preference gadobutrol p-preferred preferred value*

Study 1 (CNS) 4 241 108 (44.8 %) 98 (40.7 %) 35 (14.5 %) < 0.00015 241 131 (54.4 %) 52 (21.6 %) 58 (24.1 %) < 0.00016 241 138 (57.3 %) 56 (23.2 %) 47 (19.5 %) < 0.0001

Study 2 (Body) 4 276 36 (13.0 %) 216 (78.3 %) 24 (8.7 %) 0.12235 276 40 (14.5 %) 206 (74.6 %) 30 (10.9 %) 0.23466 276 33 (12.0 %) 228 (82.6 %) 15 (5.4 %) 0.0079

* Wilcoxon signed-rank test.

A change in patient treatment plan was reported after administration of gadopiclenol at 0.1 mL/kg BW(equivalent to 0.05 mmol/kg BW) in 23.3 % and 30.1 % of patients in Study 1 and Study 2, respectively.

Analysis per subgroups in Study 1 revealed that treatment plan could be changed for 64 % of the 22patients for whom the investigator considered that diagnosis was not assessable (or grade of glial tumorcould not be determined) based on unenhanced MRI, 28 % of 81 patients with malignant diagnosis andabout 12 % of 111 patients with non-malignant diagnosis.

In Study 2, treatment plan could be changed after MRI with gadopiclenol for 41 % of the 22 patients withnon-assessable diagnosis based on unenhanced MRI, 32 % of 165 patients with malignant diagnosis and14 % of 64 patients with non-malignant diagnosis.

A post-hoc reading of all images from both pivotal studies for CNS and Body indications was conductedin a fully blinded, unpaired, randomised manner . A high level of concordance in lesion detectabilitybetween gadopiclenol at 0.05 mmol/kg and gadobutrol at 0.1 mmol/kg was observed at lesion and atpatient level. The results are summarized in Table 6 below.

Table 6: Concordance in lesion detectability between gadopiclenol at 0.05 mmol/kg and gadobutrolat 0.1 mmol/kg

Perfect match at lesion level* Perfect match at patient level*

Study 1 (CNS) 88.0% to 89.8% 84.3% to 86.0%

Study 2 (Body) overall 92.3% to 95.5% 81.3% to 85.0%

Head & Neck 89.5% to 100% 70.6% to 94.1%

Thorax 88.3% to 93.2% 69.8% to 73.2%

Pelvis 91.7% to 100% 87.5% to 94.6%

Abdomen 94.6% to 95.2% 84.0% to 87.2%

Musculoskeletal 100% 100%

*Range of values according to the reader (3 readers per region)

One exploratory study (Study 3) with a single dose of gadopiclenol (0.1 mL/kg BW equivalent to0.05 mmol/kg BW) included 80 paediatric patients aged 2 to 17 years old with 60 patients undergoing

CNS MRI and 20 patients undergoing Body MRI.

Diagnostic efficacy was evaluated and there was no difference among the paediatric age groups.

The European Medicines Agency has deferred the obligation to submit the results of studies with Vuewayin one or more subsets of the paediatric population in the detection and visualisation of disorders orlesions with suspected abnormal vascularity in various body regions for diagnostic purposes. (see section4.2 for information on paediatric use).

The absolute bioavailability of gadopiclenol (in humans) is 100%, as it is only administered via theintravenous route.

After an intravenous dose of 0.1 to 0.2 mL/kg BW (equivalent respectively to 0.05 and 0.1 mmol/kg

BW), the Cmax was 525 ± 70 mcg/mL and 992 ± 233 mcg/mL, respectively.

The Cmax increased 1.1-fold, 1.1-fold and 1.4-fold and the AUCinf increased 1.5-fold, 2.5-fold and 8.7-foldin patients with mild, moderate and severe renal impairment, respectively after a dose of 0.2 mL/kg BW(equivalent to 0.1 mmol/kg BW).

In addition, the increase in Cmax and AUCinf is expected to be similar with a dose of 0.1 mL/kg BW(equivalent to 0.05 mmol/kg BW) based on the results of population pharmacokinetic simulations.

After intravenous administration gadopiclenol is rapidly distributed in the extracellular fluids.

After a dose of 0.1 ml/kg BW (equivalent to 0.05 mmol/kg BW) the distribution volume Vd was 12.9 ±1.7 L.

The in vitro binding of 153Gd-gadopiclenol to human plasma proteins is negligible and independent ofthe gadopiclenol concentration, as 153Gd-gadopiclenol bound 0.0-1.8% to human plasma proteins and0.0-0.1% to human red blood cells.

Gadopiclenol is not metabolised.

The lack of metabolism is confirmed by in vitro data using pooled human liver microsomes incubatedwith 153Gd-gadopiclenol. After 120 minutes ≥ 95% of the 153Gd-gadopiclenol remained in unchangedform. The results were similar when heat inactivated pooled human liver microsomes (negative controls)were incubated with 153Gd-gadopiclenol, indicating that 153Gd-gadopiclenol is not metabolised.

Gadopiclenol is eliminated rapidly in unchanged form through the kidneys by glomerular filtration. Aftera dose of 0.1 to 0.2 mL/kg BW (equivalent respectively to 0.05 and 0.1 mmol/kg BW), the mean plasmaelimination half-life (t1/2) in healthy volunteers with a normal renal function was1.5 and 1.7 hour,respectively, and the clearance was 100 ± 10 mL/min and 96 ± 12 mL/min, respectively. Urinaryexcretion is the major route of elimination of gadopiclenol, with approximately 98 % of the doseexcreted in urine after 48 hours regardless of the dose administered.

The pharmacokinetic profile of gadopiclenol is linear in the studied dose range (0.05 to 0.6 mL/kg BWequivalent to 0.025 to 0.3 mmol/kg BW), without difference between males and females. Mean maximumconcentration (Cmax) and Area Under the Curve (AUCinf) increased proportionally to the dose.

One Phase II study (Study 3) with a single dose of gadopiclenol at 0.1 mL/kg BW (equivalent to0.05 mmol/kg BW) was conducted and included 60 paediatric patients aged 2 to 17 years old undergoing

CNS MRI.

Individual parameters predicted from the population pharmacokinetic model and normalised by BW weresimilar between adults and children. The terminal half-life was 1.77 hour for age group 12-17 years old,1.48 hour for age group 7-11 years old and 1.29 hour for age group 2-6 years old. The median clearanceranged from 0.08 L/h/kg (for age group 12-17 years old) to 0.12 l/h/kg (for age group 2-11 years old).

The pharmacokinetics of gadopiclenol in children aged 2 to 17 years are comparable to thepharmacokinetics in adults.

Renal impairment and dialysability

The elimination half-life (t1/2) is prolonged in subjects with renal impairment, increasing with the degreeof renal impairment. In patients with mild (60 ≤ eGFR < 90 mL/min), moderate(30 ≤ eGFR < 60 mL/min) and severe (15 ≤ eGFR < 30 mL/min) renal impairment, the mean t1/2 was 3.3,3.8 and 11.7 hours, respectively and the clearance was 1.02, 0.62 and 0.17 mL/min/kg, respectively.

The Cmax increased 1.1-fold, 1.1-fold and 1.4-fold and the AUCinf increased 1.5-fold, 2.5-fold and 8.7-foldin patients with mild, moderate and severe renal impairment, respectively after a dose of 0.2 mL/kg BW(equivalent to 0.1 mmol/kg BW).

In addition, the increase in Cmax and AUCinf is expected to be similar with a dose of 0.1 mL/kg BW(equivalent to 0.05 mmol/kg BW) based on the results of population pharmacokinetic simulations.

Urinary excretion is delayed with the progression of renal impairment level. In patients with mild ormoderate renal impairment, more than 90 % of the administered dose was recovered in the urine within48 hours. In patients with severely impaired renal function about 84 % of the administered dose wasrecovered in the urine within 5 days.

In patients with End Stage Renal Disease (ESRD), 4 hour haemodialysis effectively removedgadopiclenol from plasma as the percentage of decrease in blood concentrations was 95 to 98 % at theend of the first haemodialysis session.

Weight

The effect of weight was investigated with population pharmacokinetic simulations of patients with a BWranging from 40 kg to 150 kg receiving a gadopiclenol dose of 0.1 mL/kg BW (equivalent to0.05 mmol/kg BW). The ratios of median AUCinf of gadopiclenol between a typical healthy subject of70 kg and subjects weighing 40 kg and 150 kg was 0.86 and 2.06, respectively. The ratios of the plasmaconcentrations 10, 20 and 30 minutes after administration between a typical healthy subject of 70 kg andsubjects weighing 40 kg and 150 kg ranged from 0.93 to 1.26.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity and toxicity to reproduction and development.

Juvenile animal toxicity studies have not revealed any relevant findings.

Tetraxetan

Trometamol

Hydrochloric acid (for pH adjustment)

Sodium hydroxide (for pH adjustment)

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

3 years.

For vials

Chemical and physical in-use stability has been demonstrated for 24 hours at up to 25 °C.

From a microbiological point of view, the product should be used immediately. If not used immediately,in-use storage times and conditions prior to use are the responsibility of the user and would normally notbe longer than 24 hours at 2 to 8 °C, unless the opening has taken place in controlled and validatedaseptic conditions.

For vials

This medicinal product does not require any special storage conditions.

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

For pre-filled syringes

Do not freeze.

3 mL solution for injection in a 10 mL vial (glass type I) with elastomeric stopper in pack size of 1.

7.5 mL solution for injection in a 10 mL vial (glass type I) with elastomeric stopper in pack sizes of 1 or25.

10 mL solution for injection in a 10 mL vial (glass type I) with elastomeric stopper in pack sizes of 1 or25.

15 mL solution for injection in a 20 mL vial (glass type I) with elastomeric stopper in pack sizes of 1 or25.

30 mL solution for injection in a 50 mL vial (glass type I) with elastomeric stopper in pack size of 1.

50 mL solution for injection in a 50 mL vial (glass type I) with elastomeric stopper in pack size of 1.

100 mL solution for injection in a 100 mL vial (glass type I) with elastomeric stopper in pack size of 1.

7.5 mL, 10 mL or 15 mL of solution for injection in a 15 mL plastic (polypropylene) pre-filled syringe,graduated every 0.5 mL, without a needle, with an elastomeric (bromobutyl) plunger stopper and cappedwith an elastomeric (bromobutyl) tip cap. Pack size of 1 or a multipack containing 10 (10 packs of 1) pre-filled syringes.

7.5 mL, 10 mL or 15 mL of solution for injection in 15 a mL plastic (polypropylene) pre-filled syringe,graduated every 0.5 mL, with an elastomeric (bromobutyl) plunger stopper and capped with anelastomeric (bromobutyl) tip cap with administration set for manual injection (one extension line and onecatheter) in pack size of 1.

7.5 mL, 10 mL or 15 mL of solution for injection in 15 mL plastic (polypropylene) pre-filled syringe,graduated every 0.5 mL, with an elastomeric (bromobutyl) plunger stopper and capped with anelastomeric (bromobutyl) tip cap with administration set for Optistar Elite injector (one extension line,one catheter and one empty 60 mL plastic syringe) in pack size of 1.

7.5 mL, 10 mL or 15 mL of solution for injection in 15 mL plastic (polypropylene) pre-filled syringe,graduated every 0.5 mL, with an elastomeric (bromobutyl) plunger stopper and capped with anelastomeric (bromobutyl) tip cap with administration set for Medrad Spectris Solaris EP injector (oneextension line, one catheter and one empty 115 mL plastic syringe) in pack size of 1.

Not all pack sizes may be marketed.

Do not use if the medicinal product including packaging is opened or damaged.

The solution for injection should be inspected visually prior to use.

Solution with visible signs of deterioration (such as particles in the solution, fissures in the vial) must notbe used.

Before and during the use of the product, follow the safety, hygiene and asepsis rules.

For vials

The vial stopper should be pierced only once.

For pre-filled syringes

Do not use the pre-filled syringe if there are any signs of leakage.

The pre-filled syringe is for single use only. Do not attempt to re-use even after cleaning or sterilizing thesingle use pre-filled syringe.

Screw the push rod into the syringe plunger. It is important to rotate and push the push rod an additional½ turn so that the plunger can rotate freely.

Before using the pre-filled syringe, remove the tip cap by spinning it.

Connection is compatible with luer 6%.

All luer connections should be gently hand tightened without over tightening to ensure secure connectionand to prevent damage to the device.

Before connecting to the patient, prime completely the intravenous line and check the absence of air: holdthe syringe erect and push plunger forward until all of the air is evacuated and fluid either appears at thetip of the needle or the tubing is filled.

The dose volume accuracy has been checked and is conform to ISO 7886-1.

The delivered dose accuracy for 15 mL syringes, graduated every 0.5 mL, depends on the injectedvolume. For a volume range of 5 to 15 mL, it may vary up to ± 0.6 mL.

When used with a power injector, follow injector instructions for use.

Any unused product should be discarded at the end of the examination session.

The peel-off tracking label available on the vial or the pre-filled syringe should be stuck onto the patientrecord to enable accurate recording of the gadolinium contrast agent used. The dose used should also berecorded. If electronic patient records are used, the name of the product, the batch number and the doseshould be entered into the patient record.

Any unused portions and waste material derived from disposal and items which come into contact withthe product when administering this product with an automatic application system should be disposed ofin accordance with local requirements.

Bracco Imaging SPA

Via Egidio Folli, 5020134 Milan

Italy

EU/1/23/1773/001-025

Date of first authorisation: 07 December 2023

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

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