LUTATHERA 370 MBQ/ml infusion solution medication leaflet

Lutathera 370 MBq/mL solution for infusion

One mL of solution contains 370 MBq of lutetium (177Lu) oxodotreotide at the date and time ofcalibration.

The total amount of radioactivity per single-dose vial is 7 400 MBq at the date and time of infusion.

Given the fixed volumetric activity of 370 MBq/mL at the date and time of calibration, the volume ofthe solution in the vial ranges between 20.5 and 25.0 mL in order to provide the required amount ofradioactivity at the date and time of infusion.

Physical characteristics

Lutetium-177 has a half-life of 6.647 days. Lutetium-177 decays by β- emission to stable hafnium-177with the most abundant β- (79.3%) having a maximum energy of 0.498 MeV. The average beta energyis approximately 0.13 MeV. Low gamma energy is also emitted, for instance at 113 keV (6.2%) and208 keV (11%).

Each mL of solution contains up to 0.14 mmol (3.2 mg) of sodium.

For the full list of excipients, see section 6.1.

Solution for infusion.

Clear, colourless to slightly yellow solution.

Lutathera is indicated for the treatment of unresectable or metastatic, progressive, well-differentiated(G1 and G2), somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumours(GEP-NETs) in adults.

Important safety instructions

Lutathera should be administered only by persons authorised to handle radiopharmaceuticals indesignated clinical settings (see section 6.6) and after evaluation of the patient by a qualifiedphysician.

Patient identification

Before starting treatment with Lutathera, somatostatin receptor imaging (scintigraphy or positronemission tomography [PET]) must confirm the overexpression of these receptors in the tumour tissuewith the tumour uptake at least as high as normal liver uptake.

The recommended treatment regimen of Lutathera in adults consists of 4 infusions of 7 400 MBqeach. The recommended interval between each administration is 8 weeks (±1 week).

Information on dose modifications to manage severe or intolerable adverse drug reactions is given inthe respective section below.

Amino acid solution

For renal protection purposes, an amino acid solution containing L-lysine and L-arginine must beadministered intravenously over 4 hours (see composition in Tables 1 and 2). The infusion of theamino acid solution should start 30 minutes prior to start of Lutathera infusion. Infusion of the aminoacid solution and Lutathera through a separate venous access in each of the patient’s arms is thepreferred method. However, if two intravenous lines are not possible due to poor venous access orinstitutional/clinical preference, the amino acid solution and Lutathera may be infused through thesame line via a three-way valve, taking into consideration flow rate and maintenance of venous access.

The dose of the amino acid solution should not be decreased even if a reduced dose of Lutathera isadministered.

An amino acid solution containing just L-lysine and L-arginine in the amounts specified in Table 1 isconsidered the medicinal product of choice, due to the lower total volume to be infused and lowerosmolality.

The amino acid solution can be prepared as a compounded product, in compliance with the hospital’sgood preparation practices for sterile medicinal products and according to the composition specified in

Table 1.

Table 1 Composition of the compounded amino acid solution

Compound Amount

L-lysine HCl 25 g*

L-arginine HCl 25 g**

Sodium chloride 9 mg/mL (0.9%) solution for injection, or 1 Lwater for injections

*equivalent to 20.0 g L-lysine

**equivalent to 20.7 g L-arginine

Alternatively, commercially available amino acid solutions can be used if compliant with thespecification described in Table 2.

Table 2 Specification of commercially available amino acid solutions

Characteristic Specification

L-lysine HCl Between 18 and 25 g*

L-arginine HCl Between 18 and 25 g**

Volume 1 to 2 L

Osmolality <1 200 mOsmol/kg

*equivalent to 14.4-20 g L-lysine

**equivalent to 14.9-20.7 g L-arginine

Before each administration and during the treatment with Lutathera, laboratory tests are required toassess the patient’s condition and adapt the therapeutic protocol as necessary (dose, infusion interval,number of infusions) (see Table 3).

The minimum laboratory tests needed before each infusion are:

* Haematology (haemoglobin [Hb], white blood cell count with differential counts, platelet count)

* Kidney function (serum creatinine and creatinine clearance by Cockcroft-Gault formula)

* Liver function (alanine aminotransferase [ALT], aspartate aminotransferase [AST], serumalbumin, international normalised ratio [INR] and bilirubin)

These laboratory tests should be performed at least once in the 2 to 4 weeks prior to administration,and shortly before administration. It is also recommended to perform these tests every 4 weeks for atleast 3 months after the last infusion of Lutathera and every 6 months thereafter, in order to be able todetect possible delayed adverse reactions (see section 4.8). Dosing may need to be modified based onthe test results (see Table 3).

Management of severe or intolerable adverse drug reactions may require temporary dose interruption(extension of the dosing interval from 8 weeks up to 16 weeks), dose reduction, or permanentdiscontinuation of treatment with Lutathera (see Table 3 and Figure 1).

Table 3 Recommended dose modifications of Lutathera for adverse drug reactions

Adverse drug Severity of adverse drug Dose modificationreaction reaction

Withhold dose until complete or partialresolution (Grade 0 to 1).

First occurrence of:

Grade 2 (platelets <75-50 x Resume Lutathera at 3 700 MBq (100 mCi) in109/L) patients with complete or partial resolution. Ifreduced dose does not result in Grade 2, 3 or

Thrombocytopenia Grade 3 (platelets <50-25 x 4 thrombocytopenia, administer Lutathera at109/L) 7 400 MBq (200 mCi) as next dose.

Grade 4 (platelets <25 x 109/L) Permanently discontinue Lutathera for

Grade 2 or higher thrombocytopenia requiringa dosing interval beyond 16 weeks.

Recurrent Grade 2, 3 or 4 Permanently discontinue Lutathera.

First occurrence of anaemia: Withhold dose until complete or partial

Grade 3 (Hb <8.0 g/dL); resolution (Grade 0, 1, or 2).transfusion indicated

Resume Lutathera at 3 700 MBq (100 mCi) in

Grade 4 (life-threatening patients with complete or partial resolution. Ifconsequences) reduced dose does not result in Grade 3 or 4

Anaemia andanaemia or neutropenia, administer Lutatheraneutropenia

First occurrence of neutropenia: at 7 400 MBq (200 mCi) as next dose.

Grade 3 (absolute neutrophilcount [ANC] <1.0-0.5 x 109/L) Permanently discontinue Lutathera for

Grade 3 or higher anaemia or neutropenia

Grade 4 (ANC <0.5 x 109/L) requiring a dosing interval beyond 16 weeks.

Recurrent Grade 3 or 4 Permanently discontinue Lutathera.

First occurrence of: Withhold dose until resolution or return to

* Creatinine clearance less than baseline.

40 mL/min; calculated using

Cockcroft-Gault formula with Resume Lutathera at 3 700 MBq (100 mCi) inactual body weight, or patients with resolution or return to baseline.

If reduced dose does not result in renal

* 40% increase from baseline toxicity, administer Lutathera at 7 400 MBq

Renal toxicityserum creatinine, or (200 mCi) as next dose.

* 40% decrease from baseline Permanently discontinue Lutathera for renalcreatinine clearance; calculated toxicity requiring a dosing interval beyondusing Cockcroft-Gault formula 16 weeks.

with actual body weight.

Recurrent renal toxicity Permanently discontinue Lutathera.

Withhold dose until resolution or return tobaseline.

First occurrence of:

Resume Lutathera at 3 700 MBq (100 mCi) in

* Bilirubinaemia greater thanpatients with resolution or return to baseline.3 times the upper limit of normal

If reduced Lutathera dose does not result in(Grade 3 or 4), or

Hepatotoxicity hepatotoxicity, administer Lutathera at7 400 MBq (200 mCi) as next dose.

* Albuminaemia less than30 g/L with INR >1.5

Permanently discontinue Lutathera forhepatotoxicity requiring a dosing intervalbeyond 16 weeks.

Recurrent hepatotoxicity Permanently discontinue Lutathera.

Withhold dose until complete or partialresolution (Grade 0 to 2).

Resume Lutathera at 3 700 MBq (100 mCi) inpatients with complete or partial resolution. If

Any other CTCAE* reduced dose does not result in Grade 3 or 4

First occurrence of Grade 3 or 4

Grade 3 or Grade 4 toxicity, administer Lutathera at 7 400 MBqadverse drug reaction1 (200 mCi) as next dose.

Permanently discontinue Lutathera for

Grade 3 or higher adverse drug reactionrequiring a dosing interval beyond 16 weeks.

Recurrent Grade 3 or 4 Permanently discontinue Lutathera.1No dose modification required for haematological toxicities Grade 3 or Grade 4 solely due tolymphopenia.

* CTCAE: Common Terminology Criteria for Adverse Events, National Cancer Institute

Figure 1 Overview of instructions for dose modifications

DMT: Dose-modifying toxicity

Other reasons to consider temporary dose interruption of Lutathera include occurrence of anintercurrent disease (e.g. urinary tract infection) which the physician considers could increase the risksassociated with Lutathera administration and which should be resolved or stabilised for treatment toresume, or major surgery, in the event of which treatment should be withheld for 12 weeks after thedate of surgery.

No dose adjustment is required in patients aged 65 years or above as clinical experience has notidentified differences in responses between the elderly and younger patients. However, since increasedrisk of presenting with haematotoxicity has been described in elderly patients (≥70 years old), closefollow-up allowing for prompt dose adaptation (DMT) in this population is advisable.

Careful consideration of the activity to be administered to patients with renal impairment is requiredsince an increased radiation exposure is possible in these patients. The pharmacokinetic profile andsafety of lutetium (177Lu) oxodotreotide in patients with baseline severe renal impairment (creatinineclearance <30 mL/min by Cockcroft-Gault formula) or end-stage renal disease have not been studied.

Treatment with Lutathera in patients with kidney failure with creatinine clearance <30 mL/min iscontraindicated (see section 4.3). Treatment with Lutathera in patients with baseline creatinineclearance <40 mL/min (using Cockcroft-Gault formula) is not recommended. No dose adjustment isrecommended for renally impaired patients with baseline creatinine clearance ≥40 mL/min. However,as this medicinal product is known to be substantially excreted by the kidneys, renal function shouldbe more frequently monitored during treatment as these patients may be at greater risk of toxicity.

For additional details about the treatment of patients with renal toxicity, see Table 3 in section 4.2 andsection 4.4.

Careful consideration of the activity to be administered to patients with hepatic impairment is requiredsince an increased radiation exposure is possible in these patients. The pharmacokinetic profile andsafety of lutetium (177Lu) oxodotreotide in patients with baseline severe hepatic impairment (totalbilirubin >3 times upper limit of normal, regardless of AST level) have not been studied. Patients withbaseline hepatic impairment with either total bilirubin >3 times the upper limit of normal oralbuminaemia <30 g/L and INR >1.5 should only be treated with Lutathera after careful benefit-riskassessment. No dose adjustment is recommended for patients with baseline mild or moderate hepaticimpairment.

For additional details about the treatment of patients with hepatotoxicity, see Table 3 in section 4.2and section 4.4.

There is no relevant use of Lutathera in the paediatric population in the indication of treatment of

GEP-NETs (excluding neuroblastoma, neuroganglioblastoma and phaeochromocytoma).

Lutathera is for intravenous use. It is a ready-to-use radiopharmaceutical medicinal product for singleuse only.

The gravity method, the peristaltic pump method or the syringe pump method may be used foradministration of the recommended dose. Treating healthcare professionals may use other methodsdeemed appropriate and safe, particularly when dose reduction is required.

When using the gravity method or the peristaltic pump method, Lutathera should be infused directlyfrom its original container. The peristaltic pump method or the syringe pump method should be usedwhen administering a reduced dose of Lutathera following dose modification for an adverse reaction(see Table 3 in section 4.2). Using the gravity method to administer a reduced dose of Lutathera mayresult in the delivery of the incorrect volume of Lutathera if the dose is not adjusted prior toadministration. Radiation safety precautions must be considered regardless of the administrationmethod used (see section 6.6).

The following table summarises the whole administration procedure for Lutathera:

Table 4 Procedure for administration of antiemetic, amino acid solution and Lutathera

Administered agents Start time Infusion rate Duration(min) (mL/h)

Antiemetic At least As per prescribing As per30 minutes prior information prescribingto amino acid informationsolution

Amino acid solution, either250-500 depending onextemporaneously compounded 0 4 hoursvolume(1 L) or commercial (1 to 2 L)

Lutathera with sodium chloride9 mg/mL (0.9%) solution for 30 Up to 400 30 ± 10 minutesinjection

For instructions on the method of preparation and intravenous methods of administration, seesection 12.

For recommendations in case of extravasation, see section 4.4.

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

* Established or suspected pregnancy or when pregnancy has not been excluded (see section 4.6).

* Kidney failure with creatinine clearance <30 mL/min.

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 requiredtherapeutic effect.

Given the mechanism of action and the tolerance profile of Lutathera, it is not recommended to starttreatment with Lutathera in patients with somatostatin receptor-negative or mixed visceral lesionsaccording to somatostatin receptor imaging.

Because of the potential for undesirable haematological effects, blood counts must be monitored atbaseline and prior to each dose of Lutathera during treatment and until resolution of any eventualtoxicity (see section 4.2). Patients with impaired bone marrow function and patients who havereceived prior chemotherapy or external beam radiotherapy (involving more than 25% of the bonemarrow) may be at higher risk of haematological toxicity during Lutathera treatment. Treatment ofpatients with severely impaired haematological function at baseline and during treatment (e.g. Hb<4.9 mmol/L or 8 g/dL, platelets <75 x 109/L, or leukocytes <2 x 109/L) is not recommended unlesssolely due to lymphopenia.

Myelodysplastic syndrome and acute leukaemia

Late-onset myelodysplastic syndrome (MDS) and acute leukaemia (AL) have been observed aftertreatment with Lutathera (see section 4.8), occurring approximately 29 months (9-45) for MDS and55 months (32-125) for AL after the first Lutathera infusion. The aetiology of these therapy-relatedsecondary myeloid neoplasms (t-MNs) is unclear. Factors such as age >70 years, impaired renalfunction, baseline cytopenias, prior number of therapies, prior exposure to chemotherapeutic agents(specifically alkylating agents), and prior radiotherapy are suggested as potential risks and/orpredictive factors for MDS/AL.

Renal toxicity

Because lutetium (177Lu) oxodotreotide is almost exclusively eliminated through the renal system, it ismandatory to concomitantly administer an amino acid solution containing the amino acids L-lysineand L-arginine. The amino acid solution will help to decrease reabsorption of lutetium (177Lu)oxodotreotide through the proximal tubules, resulting in a significant reduction in the kidney absorbeddose (see section 4.2). When the recommended concomitant amino acid solution infusion is deliveredover a 4-hour time span, a mean reduction in kidney radiation exposure of about 47% has beenreported.

Patients should be encouraged to remain hydrated and to urinate frequently before, on the day of andthe day after administration of Lutathera (e.g. 1 glass of water every hour).

Renal function as determined by serum creatinine and calculated creatinine clearance using

Cockcroft-Gault formula must be assessed at baseline, during and for at least the first year aftertreatment (see section 4.2).

Patients with renal impairment at baseline or with renal or urinary tract abnormalities, may be atincreased risk of toxicity due to increased radiation exposure (see section 4.2).

For patients with creatinine clearance <50 mL/min, an increased risk for transient hyperkalaemia dueto the amino acid solution should also be taken into consideration (see Warning and precautionregarding the co-administered renal protective amino acid solution).

Since many patients referred for Lutathera therapy have hepatic metastasis, it may be common toobserve patients with altered baseline liver function. Patients with hepatic metastasis or pre-existingadvanced hepatic impairment may be at increased risk of hepatotoxicity due to radiation exposure.

Therefore, it is recommended to monitor ALT, AST, bilirubin, serum albumin and INR duringtreatment (see section 4.2).

Cases of hypersensitivity reactions (including isolated angioedema events) have been reported in thepost-marketing setting in patients treated with Lutathera (see section 4.8). In the event of serioushypersensitivity reactions, the ongoing Lutathera infusion should be discontinued immediately.

Appropriate medicinal products and equipment to manage such reactions should be available forimmediate use.

Nausea and vomiting

To prevent treatment-related nausea and vomiting, an intravenous bolus of an antiemetic medicinalproduct should be injected at least 30 minutes prior to the start of amino acid solution infusion to reachthe full antiemetic efficacy (see section 4.2).

Concomitant use of somatostatin analogues

Somatostatin and its analogues competitively bind to somatostatin receptors and may interfere with theefficacy of Lutathera (see section 4.5).

Neuroendocrine hormonal crises

Crises due to excessive release of hormones or bioactive substances may occur following treatmentwith Lutathera, therefore observation of patients by overnight hospitalisation should be considered insome cases (e.g. patients with poor pharmacological control of symptoms). In case of hormonal crises,recommended treatments are: intravenous high-dose somatostatin analogues, intravenous fluids,corticosteroids, and correction of electrolyte disturbances in patients with diarrhoea and/or vomiting.

Tumour lysis syndrome has been reported following therapy with medicinal products containinglutetium-177. Patients with a history of renal insufficiency and high tumour burden may be at greaterrisk and should be treated with increased caution. Renal function and electrolyte balance should beassessed at baseline and during treatment.

Radioprotection rules

Patients under treatment with Lutathera should be kept away from others during administration anduntil the radiation emission limits stipulated by the applicable laws are reached, usually within the4-5 hours following medicinal product administration. The healthcare professional should determinewhen the patient can leave the controlled area of the hospital, i.e. when the radiation exposure to thirdparties does not exceed regulatory thresholds.

Patients should be encouraged to remain hydrated and to urinate frequently before, on the day of andthe day after administration of Lutathera (e.g. 1 glass of water every hour) to facilitate elimination.

They should also be encouraged to defecate every day and to use a laxative if needed. Urine and faecesshould be disposed of according to the national regulations.

Provided the patient’s skin is not contaminated, such as from the leakage of the infusion system orbecause of urinary incontinence, radioactivity contamination is not expected on the skin and in thevomited mass. However, it is recommended that when conducting standard care or examinations withmedical devices or other instruments which come into contact with the skin (e.g. electrocardiogram[ECG]), basic protection measures should be observed such as wearing gloves, installing thematerial/electrode before the start of radiopharmaceutical infusion, changing the material/electrodeafter measurement, and eventually monitoring the radioactivity of equipment after use.

Before being discharged, the patient should be instructed in the necessary radioprotection rules forinteracting with other members of the same household and the general public, and the generalprecautions the patient must follow during daily activities after treatment (as given in the nextparagraph and the package leaflet) to minimise radiation exposure to others.

After each administration, the following general recommendations can be considered along withnational, local and institutional procedures and regulations:

* Close contact (less than 1 metre) with other people should be limited for 7 days.

* For children and/or pregnant women, close contact (less than 1 metre) should be limited to lessthan 15 minutes per day for 7 days.

* Patients should sleep in a separate bedroom from other people for 7 days.

* Patients should sleep in a separate bedroom from children and/or pregnant women for 15 days.

Recommended measures in case of extravasation

Disposable waterproof gloves should be worn. The infusion of the medicinal product must beimmediately ceased and the administration device (catheter, etc.) removed. The nuclear medicinephysician and the radiopharmacist should be informed.

All the administration device materials should be kept in order to measure the residual radioactivityand the activity actually administered and the absorbed dose should be determined. The extravasationarea should be delimited with an indelible pen and a picture should be taken if possible. It is alsorecommended to record the time of extravasation and the estimated volume extravasated.

To continue Lutathera infusion, it is mandatory to use a new catheter, possibly placing it in acontralateral venous access.

No additional medicinal product can be administered to the same side where the extravasationoccurred.

In order to accelerate medicinal product dispersion and to prevent its stagnation in tissue, it isrecommended to increase blood flow by elevating the affected arm. Depending on the case, aspirationof extravasation fluid, flush injection of sodium chloride 9 mg/mL (0.9%) solution for injection, orapplication of warm compresses or a heating pad to the infusion site to accelerate vasodilation shouldbe considered.

Symptoms, especially inflammation and/or pain, should be treated. Depending on the situation, thenuclear medicine physician should inform the patient about the risks linked to extravasation injury andgive advice about potential treatment and necessary follow-up requirements. The extravasation areamust be monitored until the patient is discharged from the hospital. Depending on its severity, thisevent should be declared as an adverse reaction.

Patients with urinary incontinence

During the first 2 days following administration of this medicinal product, special precautions shouldbe taken with patients with urinary incontinence to avoid spread of radioactive contamination. Thisincludes the handling of any materials possibly contaminated with urine.

There are no efficacy data in patients with known brain metastases, therefore individual benefit-riskmust be assessed in these patients.

Secondary malignant neoplasms

Exposure to ionising radiation is linked with cancer induction and a potential for development ofhereditary defects. The radiation dose resulting from therapeutic exposure may result in higherincidence of cancer and mutations. In all cases it is necessary to ensure that the risks of the radiationexposure are less than from the disease itself.

Other patients with risk factors

Patients presenting with any of the conditions below are more prone to develop adverse reactions.

Therefore, it is recommended to monitor such patients more frequently during the treatment. Pleasesee Table 3 in case of dose modifying toxicity.

* Bone metastasis;

* Previous oncological radiometabolic therapies with 131I compounds or any other therapy usingunshielded radioactive sources;

* History of other malignant tumours unless the patient is considered to have been in remissionfor at least 5 years.

Female patients of reproductive potential should be advised to use effective contraception duringtreatment and for 7 months after the last dose of Lutathera (see section 4.6).

Male patients with female partners of reproductive potential should be advised to use effectivecontraception during treatment and for 4 months after the last dose of Lutathera (see section 4.6).

Specific warnings and precautions regarding the co-administered renal protective amino acid solution

A transient increase in serum potassium levels may occur in patients receiving arginine and lysine,usually returning to normal levels within 24 hours from the start of the amino acid solution infusion.

Patients with reduced creatinine clearance may be at increased risk for transient hyperkalaemia (see“Renal toxicity” in section 4.4).

Serum potassium levels must be tested before each administration of amino acid solution. In case ofhyperkalaemia, the patient’s history of hyperkalaemia and concomitant medicinal product should bechecked. Hyperkalaemia must be corrected accordingly before starting the infusion.

In case of pre-existing clinically significant hyperkalaemia, a second monitoring prior to amino acidsolution infusion must confirm that hyperkalaemia has been successfully corrected. The patient shouldbe monitored closely for signs and symptoms of hyperkalaemia, e.g. dyspnoea, weakness, numbness,chest pain and cardiac manifestations (conduction abnormalities and cardiac arrhythmias). Anelectrocardiogram (ECG) should be performed prior to discharging the patient.

Vital signs should be monitored during the infusion regardless of baseline serum potassium levels.

Patients should be encouraged to remain hydrated and to urinate frequently before, on the day of andthe day after administration (e.g. 1 glass of water every hour) to facilitate elimination of excess serumpotassium.

In case hyperkalaemia symptoms develop during amino acid solution infusion, appropriate correctivemeasures must be taken. In case of severe symptomatic hyperkalaemia, discontinuation of amino acidsolution infusion should be considered, taking into consideration the benefit-risk of renal protectionversus acute hyperkalaemia.

Due to potential for clinical complications related to volume overload, care should be taken with useof arginine and lysine in patients with severe heart failure defined as class III or class IV in the NYHA(New York Heart Association) classification. Patients with severe heart failure defined as class III orclass IV in the NYHA classification should only be treated after careful benefit-risk assessment, takinginto consideration the volume and osmolality of the amino acid solution.

Metabolic acidosis has been observed with complex amino acid solutions administered as part of totalparenteral nutrition (TPN) protocols. Shifts in acid-base balance alter the balance ofextracellular-intracellular potassium and the development of acidosis may be associated with rapidincreases in plasma potassium.

Specific warnings

This medicinal product contains up to 3.5 mmol (81.1 mg) sodium per vial, equivalent to 4% of the

WHO recommended maximum daily intake of 2 g sodium for an adult.

Precautions with respect to environmental hazard see section 6.6.

Somatostatin analogues

Somatostatin and its analogues competitively bind to somatostatin receptors and may interfere with theefficacy of Lutathera. Therefore, administration of long-acting somatostatin analogues should beavoided within 30 days prior to the administration of this medicinal product. If necessary, patients maybe treated with short-acting somatostatin analogues up to 24 hours preceding Lutathera administration.

Glucocorticoids

There is some evidence that glucocorticoids can induce down-regulation of subtype 2 somatostatinreceptors (SSTR2). Therefore, as a matter of caution, repeated administration of high doses ofglucocorticoids should be avoided during Lutathera treatment. Patients with a history of chronic use ofglucocorticoids should be carefully evaluated for sufficient somatostatin receptor expression. It is notknown whether the intermittent use of glucocorticoids for the prevention of nausea and vomitingduring Lutathera administration could induce SSTR2 down-regulation. As a matter of caution,glucocorticoids should also be avoided as preventive antiemetic treatment. In the event that thetreatment administered for the prevention of nausea and vomiting before the amino acid solutioninfusion proves insufficient, a single glucocorticoid dose can be used, provided it is not given beforeinitiating or within one hour after the end of Lutathera infusion.

When an administration of radiopharmaceuticals to a woman of childbearing potential is intended, it isimportant to determine whether or not she is pregnant. Any woman who has missed a period should beassumed to be pregnant until proven otherwise. If in any doubt about her potential pregnancy (if thewoman has missed a period, if the period is very irregular, etc.), alternative techniques not usingionising radiation (if there are any) should be offered to the patient. Before the use of Lutathera,pregnancy should be excluded using an adequate/validated test.

Lutathera can cause foetal harm when administered to a pregnant woman.

Female patients of reproductive potential should be advised to use effective contraception duringtreatment and for 7 months after the last dose of Lutathera.

Male patients with female partners of reproductive potential should be advised to use effectivecontraception during treatment and for 4 months after the last dose of Lutathera.

No studies on animal reproductive function have been conducted with lutetium (177Lu) oxodotreotide.

Radionuclide procedures carried out on pregnant women also involve a radiation dose to the foetus.

The use of Lutathera is contraindicated during established or suspected pregnancy or when pregnancyhas not been excluded due to the risk associated with the ionising radiation (see section 4.3). Pregnantwomen should be advised of the risk to a foetus.

It is unknown whether lutetium (177Lu) oxodotreotide is excreted in breast milk. A risk to thebreast-fed child associated with ionising radiation cannot be excluded. Breast-feeding should beavoided during treatment with this medicinal product. If treatment with Lutathera duringbreast-feeding is necessary, the child must be weaned.

No animal studies have been performed to determine the effects of lutetium (177Lu) oxodotreotide onmale and female fertility. Ionising radiations of lutetium (177Lu) oxodotreotide may potentially havetemporary toxic effects on female and male gonads. Genetic consultation is recommended if thepatient wishes to have children after treatment. Cryopreservation of sperm or eggs can be discussed asan option for patients before treatment.

Lutathera has no or negligible influence on the ability to drive and use machines. Nevertheless, thegeneral condition of the patient and the possible adverse reactions to treatment must be taken intoaccount before driving or using machines.

The overall safety profile of Lutathera is based on pooled data from patients from clinical studies(NETTER-1 phase III and Erasmus phase I/II Dutch patients) and from compassionate useprogrammes.

The most common adverse reactions in patients receiving Lutathera treatment were nausea andvomiting, which occurred at the beginning of the infusion in 58.9% and 45.5% of patients,respectively. The causality of nausea/vomiting is confounded by the emetic effect of the concomitantamino acid solution administered for renal protection.

Due to the bone marrow toxicity of Lutathera, the most expected adverse reactions were related tohaematological toxicity: thrombocytopenia (25%), lymphopenia (22.3%), anaemia (13.4%),pancytopenia (10.2%).

Other very common adverse reactions reported include fatigue (27.7%) and decreased appetite(13.4%).

At the time of the NETTER-1 final analysis, after a median follow-up duration of 76 months in eachstudy arm, the safety profile remained consistent with that previously reported.

The adverse reactions are listed in Table 5 according to frequency and MedDRA System Organ Class(SOC). The frequencies are categorised as follows: 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) and not known(cannot be estimated from the available data).

Table 5 Frequency of adverse reactions reported from clinical studies and post-marketingsurveillance

MedDRA System Very common Common Uncommon Not known

Organ Class (SOC)

Infections and Conjunctivitisinfestations Respiratory tract infection

Cystitis

Herpes zoster

Ophthalmic herpes zoster

Influenza

Staphylococcal infections

Streptococcal bacteraemia

Neoplasms benign, Refractory cytopenia with Acute myeloid leukaemiamalignant and multilineage dysplasia Acute leukaemiaunspecified (including (myelodysplastic Chronic myelomonocyticcysts and polyps) syndrome) leukaemia

Blood and lymphatic Thrombocytopenia2 Leukopenia5 Refractory cytopenia withsystem disorders Lymphopenia3 Neutropenia6 unilineage dysplasia

Anaemia4 Nephrogenic anaemia

Pancytopenia Bone marrow failure

Thrombocytopenic purpura

Immune system Hypersensitivity Angioedemadisorders

Endocrine disorders Secondary hypothyroidism Hypothyroidism

Diabetes mellitus

Carcinoid crisis

Metabolism and Decreased appetite Hyperglycaemia Hypoglycaemianutrition disorders Dehydration Hypernatraemia

Hypomagnesaemia Hypophosphataemia

Hyponatraemia Tumour lysis syndrome

Hypercalcaemia

Hypoalbuminaemia

Psychiatric disorders Sleep disorders Anxiety

Hallucination

Disorientation

Nervous system Dizziness Formicationdisorders Dysgeusia Hepatic encephalopathy

Headache10 Paraesthesia

Lethargy Parosmia

Syncope Somnolence

Spinal cord compression

Eye disorders Eye disorders

Ear and labyrinth Vertigodisorders

Cardiac disorders Electrocardiogram QT Atrial fibrillationprolonged Palpitations

Angina pectoris

Cardiogenic shock

Vascular disorders Hypertension7 Vasodilatation

Flushing Peripheral coldness

Hot flush Pallor

Hypotension Orthostatic hypotension

Phlebitis

Respiratory, thoracic Dyspnoea Oropharyngeal painand mediastinal Pleural effusiondisorders Sputum increased

Choking sensation

Gastrointestinal Nausea Abdominal distension Dry mouthdisorders Vomiting Diarrhoea Flatulence

Abdominal pain Ascites

Constipation Gastrointestinal pain

Abdominal pain upper Stomatitis

Dyspepsia Haematochezia

Gastritis Abdominal discomfort

Intestinal obstruction

Pancreatitis acute

Rectal haemorrhage

Melaena

Abdominal pain lower

Haematemesis

Haemorrhagic ascites

Ileus

Hepatobiliary Hyperbilirubinaemia9 Pancreatic enzymesdisorders decreased

Hepatocellular injury

Cholestasis

Hepatic congestion

Hepatic failure

Skin and Alopecia Rashsubcutaneous tissue Dry skindisorders Swelling face

Hyperhidrosis

Pruritus generalised

Musculoskeletal and Musculoskeletal pain8connective tissue Muscle spasmsdisorders

Renal and urinary Acute kidney injury Leukocyturiadisorders Haematuria Urinary incontinence

Renal failure Glomerular filtration rate

Proteinuria decreased

Renal disorder

Acute pre-renal failure

General disorders and Fatigue1 Injection site reaction11 Injection site massadministration site Oedema peripheral Chest discomfortconditions Administration site pain Chest pain

Chills Pyrexia

Influenza-like illness Malaise

Death

Feeling abnormal

Investigations Blood creatinine increased Blood potassium decreased

GGT* increased Blood urea increased

ALT** increased Glycosylated haemoglobin

AST*** increased increased

Blood ALP**** increased Haematocrit decreased

Protein urine

Weight decreased

Blood creatinephosphokinase increased

Blood lactate dehydrogenaseincreased

Blood catecholamines

C-reactive protein increased

Injury, poisoning and Clavicle fractureproceduralcomplications

Surgical and medical Transfusion Abdominal cavity drainageprocedures Dialysis

Gastrointestinal tubeinsertion

Stent placement

Abscess drainage

Bone marrow harvest

Polypectomy

Social circumstances Physical disability1 Includes asthenia and fatigue2 Includes thrombocytopenia and platelet count decreased3 Includes lymphopenia and lymphocyte count decreased4 Includes anaemia and haemoglobin decreased5 Includes leukopenia and white blood cell count decreased6 Includes neutropenia and neutrophil count decreased7 Includes hypertension and hypertensive crisis8 Includes arthralgia, pain in extremity, back pain, bone pain, flank pain, musculoskeletal chest pain and neckpain9 Includes blood bilirubin increased and hyperbilirubinaemia10 Includes headache and migraine11 Includes injection site reaction, injection site hypersensibility, injection site induration, injection site swelling

*Gamma-glutamyltransferase

**Alanine aminotransferase

***Aspartate aminotransferase

****Alkaline phosphatase

Mostly mild/moderate bone marrow toxicity (myelo-/haematotoxicity) manifested withreversible/transient reductions in blood counts affecting all lineages (cytopenias in all combinations,i.e. pancytopenia, bicytopenias, isolated monocytopenias - anaemia, neutropenia, lymphocytopeniaand thrombocytopenia). In spite of an observed significant selective B-cell depletion, no increase inthe rate of infectious complications occurs after peptide receptor radionuclide therapy (PRRT). Casesof irreversible haematological pathologies, i.e. premalignant and malignant blood neoplasms (i.e.

myelodysplastic syndrome and acute myeloid leukaemia, respectively) have been reported following

Lutathera treatment.

In NETTER-1, platelet nadir occurred at a median of 5.1 months following the first dose. Of the59 patients who developed thrombocytopenia, 68% had platelet recovery to baseline or normal levels.

The median time to platelet recovery was 2 months. Fifteen of the nineteen patients in whom plateletrecovery was not documented had post-nadir platelet counts.

Renal toxicity

Lutetium (177Lu) oxodotreotide is excreted by the kidney.

The long-term trend of progressive glomerular filtration function deterioration demonstrated in theclinical studies confirms that Lutathera-related nephropathy is a chronic kidney disease that developsprogressively over months or years after exposure. An individual benefit-risk assessment isrecommended prior to treatment with Lutathera in patients with mild or moderate renal impairment.

For additional details see section 4.2 (Table 3 and “Renal impairment” subsection) and section 4.4.

The use of Lutathera is contraindicated in patients with kidney failure with creatinine clearance<30 mL/min (see section 4.3).

Neuroendocrine hormonal crises

Hormonal crises related to release of bioactive substances (probably due to lysis of the neuroendocrinetumour cells) have rarely been observed and resolved after appropriate medical treatment (seesection 4.4).

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.

Overdose is unlikely with Lutathera as this medicinal product is supplied as a single-dose andready-to-use product containing a predefined amount of radioactivity and it is administered by personsauthorised to handle radiopharmaceuticals after evaluation of the patient by a qualified physician. Inthe event of overdose, an increase in the frequency of the adverse reactions related to radiotoxicity isexpected.

In the event of administration of a radiation overdose with Lutathera, the absorbed dose to the patientshould be reduced where possible by increasing the elimination of the radionuclide from the body byfrequent micturition or by forced diuresis and frequent bladder voiding during the first 48 hours afterinfusion. It might be helpful to estimate the effective dose that was applied.

The following laboratory tests should be carried out every week, for the next 10 weeks:

* Haematological monitoring: white blood cell count with differential counts, platelets andhaemoglobin

* Blood chemistry monitoring: serum creatinine and glycaemia.

Pharmacotherapeutic group: Therapeutic radiopharmaceuticals, Other therapeuticradiopharmaceuticals, ATC code: V10XX04

Lutetium (177Lu) oxodotreotide has a high affinity for subtype 2 somatostatin receptors (SSTR2). Itbinds to malignant cells which overexpress SSTR2.

Lutetium-177 is a β- emitting radionuclide with a maximum penetration range in tissue of 2.2 mm(mean penetration range of 0.67 mm), causing death of the targeted tumour cells with a limited effecton neighbouring normal cells.

At the concentration used (about 10 μg/mL in total, for both free and radiolabelled forms), the peptideoxodotreotide does not exert any clinically relevant pharmacodynamic effect.

NETTER-1

The NETTER-1 phase III study was a multicentre, stratified, open-label, randomised,comparator-controlled, parallel-group study comparing treatment with Lutathera (4 doses of7 400 MBq, one dose every 8 weeks [±1 week]) co-administered with an amino acid solution and bestsupportive care (octreotide long-acting release [LAR] 30 mg after each Lutathera dose and every4 weeks after completion of Lutathera treatment for symptom control, replaced by short-actingoctreotide in the 4-week interval before Lutathera administration) to high-dose octreotide LAR (60 mgevery 4 weeks) in patients with inoperable, progressive, somatostatin receptor-positive, midgutcarcinoid tumours. The primary endpoint for the study was progression-free survival (PFS) evaluatedby response evaluation criteria in solid tumours (RECIST v1.1), based on blinded independent reviewcommittee assessment. Secondary efficacy endpoints included objective response rate (ORR), overallsurvival (OS), time to tumour progression (TTP), safety and tolerability of the medicinal product, andhealth-related quality of life (HRQoL).

At the time of the primary analysis, 229 patients were randomised to receive either Lutathera (n=116)or high-dose octreotide LAR (n=113). Demographic and baseline disease characteristics were wellbalanced between the treatment arms with a median age of 64 years and 82.1% Caucasian in thegeneral population.

At the time of the primary PFS analysis (cut-off date 24 July 2015), the number of centrally confirmeddisease progressions or deaths was 21 events in the Lutathera arm and 70 events in the high-doseoctreotide LAR arm (Table 6). PFS differed significantly (p<0.0001) between the treatment arms. Themedian PFS for the Lutathera arm was not reached at the cut-off date, whereas the median PFS for thehigh-dose octreotide LAR arm was 8.5 months. The hazard ratio (HR) for the Lutathera arm comparedto the high-dose octreotide LAR arm was 0.18 (95% CI: 0.11; 0.29), indicating 82% reduction in therisk of disease progression or death in favour of the Lutathera arm.

Table 6 PFS observed in the NETTER-1 phase III study in patients with progressive midgutcarcinoid tumours - cut-off date 24 July 2015 (full analysis set [FAS], N=229)

Lutathera and octreotide High-dose octreotide LAR

LAR

N 116 113

Patients with events 21 70

Censored patients 95 43

Median in months (95% CI) Not reached 8.5 (5.8; 9.1)p-value of Log-rank test <0.0001

Hazard ratio (95% CI) 0.177 (0.108; 0.289)

N: number of patients, CI: confidence interval.

The PFS Kaplan-Meier graph for the full analysis set (FAS) at the cut-off date 24 July 2015 isdepicted in Figure 2.

Figure 2 PFS Kaplan-Meier curves for patients with progressive midgut carcinoid tumours -cut-off date 24 July 2015 (NETTER-1 phase III study; FAS, N=229)

At the cut-off date for post-hoc statistical analysis (cut-off date 30 June 2016) including two additionalrandomised patients (N=231), the number of centrally confirmed disease progressions or deaths was30 events in the Lutathera arm and 78 events in the high-dose octreotide LAR arm (Table 7). PFSdiffered significantly (p<0.0001) between the treatment arms. The median PFS for the Lutathera armwas 28.4 months whereas the median PFS for the high-dose octreotide LAR arm was 8.5 months. Thehazard ratio for the Lutathera arm compared to the high-dose octreotide LAR arm was 0.21 (95% CI:

0.14; 0.33), indicating 79% reduction in the risk of disease progression or death in favour of the

Lutathera arm.

Table 7 PFS observed in the NETTER-1 phase III study in patients with progressive midgutcarcinoid tumours - cut-off date 30 June 2016 (FAS, N=231)

Lutathera and octreotide High-dose octreotide LAR

LAR

N 117 114

Patients with events 30 78

Censored patients 87 36

Median in months (95% CI) 28.4 (28.4; NE) 8.5 (5.8; 11.0)p-value of Log-rank test <0.0001

Hazard ratio (95% CI) 0.214 (0.139; 0.330)

N: number of patients, CI: confidence interval.

The PFS Kaplan-Meier graph for the FAS at the cut-off date 30 June 2016 is depicted in Figure 3.

Figure 3 PFS Kaplan-Meier curves for patients with progressive midgut carcinoid tumours -cut-off date 30 June 2016 (NETTER-1 phase III study; FAS, N=231)

At the time of the interim OS analysis (cut-off date 24 July 2015), there were 17 deaths in the

Lutathera arm and 31 deaths in the high-dose octreotide LAR arm, yielding a HR of 0.459 (99.9915%

CI: 0.140; 1.506) in favour of the Lutathera arm. The median OS was not reached in the Lutathera armat the cut-off date, while it was 27.4 months in the high-dose octreotide LAR arm. The interim OSresults did not reach statistical significance. An update conducted about one year later (cut-off date 30

June 2016) including two additional randomised patients (N=231) showed a similar trend, with28 deaths in the Lutathera arm and 43 deaths in the high-dose octreotide LAR arm, yielding a HR of0.536 in favour of the Lutathera arm. The median OS was still not reached in the Lutathera arm at thecut-off date, while it was 27.4 months in the high-dose octreotide LAR arm.

At the time of the final OS analysis, which occurred 5 years after the last patient was randomised(N=231, cut-off date 18 January 2021), the median follow-up duration was 76 months in each studyarm. There were 73 deaths in the Lutathera arm (62.4%) and 69 deaths in the high-dose octreotide

LAR arm (60.5%), yielding a HR of 0.84 (95% CI: 0.60; 1.17; unstratified Log-rank test p=0.3039,two-sided) in favour of the Lutathera arm. The median OS was prolonged by a clinically relevantextent of 11.7 months in patients randomised to the Lutathera arm compared to patients randomised tohigh-dose octreotide LAR, with a median OS of 48.0 months (95% CI: 37.4; 55.2) and 36.3 months(95% CI: 25.9; 51.7), respectively. The final OS results did not reach statistical significance. In thehigh-dose octreotide LAR arm, 22.8% of patients received subsequent radioligand therapy (includinglutetium (177Lu) oxodotreotide) within 24 months of randomisation, and 36% of patients receivedsubsequent radioligand therapy by the final OS cut-off date, which along with other factors may haveinfluenced the OS in this subset of patients.

The OS Kaplan-Meier graph for the FAS at the cut-off date 18 January 2021 is depicted in Figure 4.

Figure 4 OS Kaplan-Meier curves for patients with progressive midgut carcinoid tumours -cut-off date 18 January 2021 (NETTER-1 phase III study; FAS, N=231)+○ Censoring times++(a) Lutathera and octreotide LAR○○(b) High-dose octreotide LAR

Number of subjects at risk Time from randomisation (months)(a)(b)

In presence of non-proportional hazards, an additional sensitivity analysis (Restricted mean survivaltime) was performed at the time of the final OS analysis to further estimate the treatment effect(Table 8). At 60 months after randomisation, the average OS benefit was 5.1 months (95% CI: -0.5;10.7) longer in the Lutathera arm compared to the high-dose octreotide LAR arm.

Table 8 OS by restricted mean survival time (RMST) observed in the NETTER-1 phase IIIstudy in patients with progressive midgut carcinoid tumours (FAS, N=231)

Lutathera and High-dose octreotideoctreotide LAR N=117 LAR N=11424 months Deaths, n (%) 26 (22.2) 39 (34.2)

RMST (95% CI) 21.2 (20.2; 22.3) 19.3 (18.0; 20.7)

Difference (95% CI) 1.9 (0.1; 3.6)36 months Deaths, n (%) 41 (35.0) 51 (44.7)

RMST (95% CI) 29.7 (27.7; 31.6) 26.0 (23.7; 28.3)

Difference (95% CI) 3.7 (0.7; 6.7)48 months Deaths, n (%) 53 (45.3) 58 (50.9)

RMST (95% CI) 36.2 (33.4; 39.0) 31.5 (28.3; 34.8)

Difference (95% CI) 4.6 (0.3; 8.9)60 months Deaths, n (%) 65 (55.6) 63 (55.3)

RMST (95% CI) 41.2 (37.6; 44.9) 36.1 (31.9; 40.4)

Difference (95% CI) 5.1 (-0.5; 10.7)

Health-Related Quality of Life (HRQoL) was assessed using the European Organisation for Researchand Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) (generic instrument) andits neuroendocrine tumour module (EORTC QLQ-GI.NET-21).

The results indicate an improvement in the overall global health-related quality of life up to week 84,for patients in the Lutathera treatment arm as compared to patients in the high-dose octreotide LARarm.

Event-free probability (%)

ERASMUS

The Erasmus phase I/II study was a monocentric single-arm open-label study to evaluate the efficacyof Lutathera (4 doses of 7 400 MBq each, one dose every 8 weeks) co-administered with amino acidsolution in patients with somatostatin receptor-positive tumours. The median age of patients enrolledin the study was 59 years. Most patients were Dutch (811) with the remaining (403) residents ofvarious European and non-European countries. The main analysis included 811 Dutch patients withdifferent somatostatin receptor-positive neuroendocrine tumour types (NETs). The ORR (includingcomplete response [CR] and partial response [PR] according to RECIST criteria) and duration ofresponse (DoR) for the FAS Dutch population with gastroenteropancreatic (GEP) and bronchial NETs(360 patients) as well as per tumour type are presented in Table 9.

Table 9 Best response, ORR and DoR observed in the Erasmus phase I/II study in Dutchpatients with GEP and bronchial NETs - (FAS, N=360)

N CR PR SD ORR DoR (months)

Tumour n % n % N % n % 95%CI Median 95%CItype

All NETs* 360 11 3% 151 42% 183 51% 162 45% 40% 50% 16.3 12.2 17.8

Bronchial 19 0 0% 7 37% 11 58% 7 37% 16% 62% 23.9 1.7 30.0

Pancreatic 133 7 5% 74 56% 47 35% 81 61% 52% 69% 16.3 12.1 21.8

Foregut** 12 1 8% 6 50% 4 33% 7 58% 28% 85% 22.3 0.0 38.0

Midgut 183 3 2% 58 32% 115 63% 61 33% 27% 41% 15.3 10.5 17.7

Hindgut 13 0 0% 6 46% 6 46% 6 46% 19% 75% 17.8 6.2 29.9

CR = Complete response; PR = Partial response; SD = Stable disease; ORR = Objective response rate (CR+PR); DoR = Duration of response

* Includes foregut, midgut and hindgut; **Foregut NETs other than bronchial and pancreatic

The overall median PFS and OS for the FAS Dutch population with GEP and bronchial NETs as wellas per tumour type are presented in Table 10.

Table 10 PFS and OS observed in the Erasmus phase I/II study in Dutch patients with GEPand bronchial NETs - (FAS, N=360)

PFS OS

Time (months) Time (months)

Median 95%CI Median 95%CI

All NETs* 360 28.5 24.8 31.4 61.2 54.8 67.4

Bronchial 19 18.4 10.4 25.5 50.6 31.3 85.4

Pancreatic 133 30.3 24.3 36.3 66.4 57.2 80.9

Foregut** 12 43.9 10.9 ND NR 21.3 ND

Midgut 183 28.5 23.9 33.3 54.9 47.5 63.2

Hindgut 13 29.4 18.9 35.0 NR ND ND

PFS = Progression free survival; OS = Overall survival; ND = Not detected, NR = Not reached

* Includes foregut, midgut and hindgut; **Foregut NETs other than bronchial and pancreatic

In the Erasmus phase I/II study 188 patients (52%) received and 172 (48%) did not receiveconcomitant octreotide LAR during Lutathera treatment. No statistically significant difference in PFSwas observed between the subgroup of patients who did not receive octreotide LAR (25.4 months[95% CI 22.8; 30.6]) and the subgroup of patients who did receive concomitant treatment withoctreotide LAR (30.9 months [95% CI 25.6; 34.8]) (p= 0.747).

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

Lutathera in all subsets of the paediatric population in the treatment of GEP-NETs (excludingneuroblastoma, neuroganglioblastoma and phaeochromocytoma) (see section 4.2 for information onpaediatric use).

This medicinal product is administered intravenously and is immediately and completely bioavailable.

An analysis performed with human plasma to determine the extent of plasma protein binding ofnon-radioactive compound (lutetium (175Lu) oxodotreotide) showed that about 50% of the compoundis bound to plasmatic proteins.

Transchelation of lutetium-177 from lutetium (175Lu) oxodotreotide into serum proteins has not beenobserved.

Organ uptake

Within 4 hours after administration, the distribution pattern of lutetium (177Lu) oxodotreotide shows arapid uptake in kidneys, tumour lesions, liver, and spleen, and in some patients, in the pituitary glandand in the thyroid. The co-administration of amino acid solution decreases the kidney uptake,enhancing the elimination of radioactivity (see section 4.4). Biodistribution studies show that lutetium(177Lu) oxodotreotide is rapidly cleared from the blood.

There is evidence, from the analysis of urine samples of 20 patients included in the NETTER-1phase III dosimetry, pharmacokinetic and ECG sub-study, that lutetium (177Lu) oxodotreotide is poorlymetabolised and is excreted mainly as intact compound via the renal route.

The high performance liquid chromatography (HPLC) analyses performed on urine samples collectedup to 48 hours post infusion showed unchanged lutetium (177Lu) oxodotreotide close to 100% in mostof the analysed samples (with lowest value being greater than 92%), indicating that the compound iseliminated in urine mainly as intact compound.

This evidence confirms what was previously observed in the Erasmus phase I/II study, in which HPLCanalysis of a urine specimen collected 1 hour post administration of lutetium (177Lu) oxodotreotidefrom one patient receiving 1.85 MBq of lutetium (177Lu) oxodotreotide indicated that the main portion(91%) was excreted unchanged.

These findings are supported by in vitro metabolism data in human hepatocytes, in which no metabolicdegradation of lutetium (175Lu) oxodotreotide was observed.

Based on the data collected during the Erasmus phase I/II and NETTER-1 phase III studies, lutetium(177Lu) oxodotreotide is primarily eliminated by renal excretion: about 60% of the medicinal product iseliminated in the urine within 24 hours, and about 65% within 48 hours following the administration.

The pharmacokinetic profile in elderly patients (≥75 years) has not been established. No data areavailable.

In vitro evaluation of interaction potential

Metabolic and transporter based interaction

The absence of inhibition or significant induction of the human CYP450 enzymes, and the absence ofspecific interaction with P-glycoprotein (efflux transporter) or OAT1, OAT3, OCT1, OCT2,

OATP1B1, OATP1B3 and BCRP transporters in pre-clinical studies, suggest that Lutathera has a lowprobability of causing significant metabolism- or transporter-mediated interactions.

Toxicological studies in rats demonstrated that a single intravenous injection of up to 4 550 MBq/kgwas well tolerated and no deaths were observed. When testing the cold compound (non-radioactivelutetium (175Lu) oxodotreotide) as a single intravenous injection in rats and dogs at doses up to20 000 µg/kg (rats) and 3 200 µg/kg (dogs), the cold compound (non-radioactive lutetium (175Lu)oxodotreotide) was well tolerated in both species and no deaths were observed. Toxicity with4 repeated administrations, once every 2 weeks, of 1 250 µg/kg of the cold compound in rats and80 µg/kg in dogs was not observed. This medicinal product is not intended for regular or continuousadministration.

Mutagenicity studies and long-term carcinogenicity studies have not been carried out.

Non-clinical data on the cold compound (non-radioactive lutetium (175Lu) oxodotreotide) reveal nospecial hazard for humans based on conventional studies of safety pharmacology, repeated dosetoxicity, and genotoxicity.

Acetic acid

Sodium acetate

Gentisic acid

Ascorbic acid

Pentetic acid

Sodium chloride

Sodium hydroxide

Water for injections

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

72 hours from the date and time of calibration.

Store below 25°C.

Do not freeze.

Store in the original package to protect from ionising radiation (lead shielding).

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

Clear, colourless Type I glass vial, closed with a bromobutyl rubber stopper and aluminium seal.

Each vial contains a volume that ranges from 20.5 to 25.0 mL of solution, corresponding to an activityof 7 400 MBq at date and time of infusion.

The vial is enclosed within a lead container for protective shielding.

For single use only.

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.

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

If at any time in the preparation of this medicinal product the integrity of the lead container or the vialis compromised it should 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.

It is necessary to wear waterproof gloves and follow suitable aseptic techniques when handling themedicinal product.

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.

This preparation is likely to result in a relatively high radiation dose to most patients. Theadministration of 7 400 MBq may result in significant environmental hazard.

This may be of concern to others living in the same household as individuals undergoing treatment orto the general public depending on the level of activity administered, hence radioprotection rulesshould be followed (see section 4.4). Suitable precautions in accordance with national regulationsshould be taken concerning the activity eliminated by the patients in order to avoid anycontaminations.

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

Lutetium-177 for Lutathera may be prepared using two different sources of stable nuclides (eitherlutetium-176 or ytterbium-176) resulting in different waste management. The user must consult thedocumentation provided before using Lutathera to ensure appropriate waste management.

Advanced Accelerator Applications8-10 Rue Henri Sainte-Claire Deville92500 Rueil-Malmaison

France

EU/1/17/1226/001

Date of first authorisation: 26 September 2017

Date of latest renewal: 08 July 2022

The following conclusions on treatment with Lutathera were determined from radiation dosimetryevaluations performed in clinical studies:

* The critical organ is the bone marrow. However, with the recommended Lutathera cumulativedose of 29 600 MBq (4 administrations of 7 400 MBq), no correlation between haematologicaltoxicity and the total radioactivity administered or bone marrow absorbed dose has beenobserved either in the Erasmus phase I/II or in the NETTER-1 phase III study.

* The kidney is not a critical organ if a co-infusion of an appropriate amino acid solution isperformed (see section 4.2).

Overall, the results of the dosimetric analysis performed in the NETTER-1 phase III dosimetrysub-study and in the Erasmus phase I/II study are in agreement and indicate that the Lutathera doseregimen (4 administrations of 7 400 MBq) is safe.

Table 11 Absorbed dose estimates for lutetium (177Lu) oxodotreotide from NETTER-1phase III study (Olinda output)

Organ absorbed dose per unit activity

Organ (mGy/MBq)(n = 20)

Mean SD

Adrenals 0.037 0.016

Brain 0.027 0.016

Breasts 0.027 0.015

Gallbladder wall 0.042 0.019

Lower large intestine wall 0.029 0.016

Small intestine 0.031 0.015

Stomach wall 0.032 0.015

Upper large intestine wall 0.032 0.015

Heart wall 0.032 0.015

Kidneys 0.654 0.295

Liver* 0.299 0.226

Lungs 0.031 0.015

Muscle 0.029 0.015

Ovaries*** 0.031 0.013

Pancreas 0.038 0.016

Red marrow 0.035 0.029

Osteogenic cells 0.151 0.268

Skin 0.027 0.015

Spleen 0.846 0.804

Testes** 0.026 0.018

Thymus 0.028 0.015

Thyroid 0.027 0.016

Urinary bladder wall 0.437 0.176

Uterus*** 0.032 0.013

Total body 0.052 0.027

*n=18 (two patients excluded because the liver absorbed dose was biased by the uptake of the livermetastases)

**n=11 (male patients only)

***n=9 (female patients only)

Radiation dose to specific organs, which may not be the target organ of therapy, can be influencedsignificantly by pathophysiological changes induced by the disease process. This should be taken intoconsideration when using the following information.

The user must consult the documentation provided before using Lutathera to ensure appropriate wastemanagement (see section 6.6).

* Use aseptic technique and radiation shielding when administering the Lutathera solution. Usetongs when handling the vial to minimise radiation exposure.

* Visually inspect the product under a shielded screen for particulate matter and discolorationprior to administration. Discard the vial if particulates and/or discoloration are present.

* Inspect the package for damage and use a calibrated radioactivity measurement system todetermine if any radioactive contamination is present. Do not use the product if the integrity ofthe vial or the lead container is compromised.

* Do not inject the Lutathera solution directly into any other intravenous solution.

* Confirm the amount of radioactivity of Lutathera delivered to the patient with a calibratedradioactivity measurement system prior to and after each Lutathera administration to confirmthat the actual amount of radioactivity administered is equal to the planned amount.

* Do not administer Lutathera as an intravenous bolus.

* Soon after the start of the infusion, monitor the radioactivity emission from the patient using acalibrated radioactivity measurement system to ensure the dose is delivered. During theinfusion, the radioactivity emission from the patient should steadily increase, while that fromthe Lutathera vial should decrease.

* Careful monitoring of the patient’s vital signs during the infusion is recommended.

Intravenous methods of administration

Instructions for the gravity method (using a clamp or an infusion pump)1. Insert a 2.5 cm, 20 gauge needle (short needle) into the Lutathera vial and connect via a catheterto 500 mL 0.9% sterile sodium chloride solution (used to transport the Lutathera solution duringthe infusion). Ensure that the short needle does not touch the Lutathera solution in the vial anddo not connect this short needle directly to the patient. Do not allow the sodium chloridesolution to flow into the Lutathera vial prior to the initiation of the Lutathera infusion and do notinject the Lutathera solution directly into the sodium chloride solution.

2. Insert a second needle that is 9 cm, 18 gauge (long needle) into the Lutathera vial, ensuring thatthis long needle touches and is secured to the bottom of the Lutathera vial during the entireinfusion. Connect the long needle to the patient by an intravenous catheter that is pre-filled with0.9% sterile sodium chloride solution and that is used for the Lutathera infusion into the patient.

3. Use a clamp or an infusion pump to regulate the flow of the sodium chloride solution via theshort needle into the Lutathera vial. The sodium chloride solution entering the vial through theshort needle will carry the Lutathera solution from the vial to the patient via the intravenouscatheter connected to the long needle over a total duration of 30±10 minutes, at an infusion rateof up to 400 mL/h. The infusion should start at a lower rate of <100 mL/h for the first 5 to10 minutes and should then be increased depending on the patient’s venous status. Constantintra-vial pressure should be maintained during the entire infusion.

4. During the infusion, ensure that the level of solution in the Lutathera vial remains constant byrepeated direct visual control when transparent shielded container is used, or using a pair oftongs to handle the vial when the lead shipping container is used.

5. Monitor the flow of Lutathera from the vial to the patient during the entire infusion.

6. Disconnect the vial from the long needle line and clamp the sodium chloride solution line oncethe level of radioactivity is stable for at least five minutes.

7. Follow the infusion with an intravenous flush of 25 mL of 0.9% sterile sodium chloride solutionthrough the intravenous catheter to the patient.

Instructions for the peristaltic pump method1. Insert a filtered 2.5 cm, 20 gauge needle (short venting needle) into the Lutathera vial. Ensurethat the short needle does not touch the Lutathera solution in the vial and do not connect theshort needle directly to the patient or to the peristaltic pump.

2. Insert a second needle that is 9 cm, 18 gauge (long needle) into the Lutathera vial, ensuring thatthe long needle touches and is secured to the bottom of the Lutathera vial during the entireinfusion. Connect the long needle and a 0.9% sterile sodium chloride solution to a 3-waystopcock valve via appropriate tubing.

3. Connect the output of the 3-way stopcock valve to tubing installed on the input side of theperistaltic pump following the pump manufacturer’s instructions.

4. Prime the line by opening the 3-way stopcock valve and pumping the Lutathera solutionthrough the tubing until it reaches the exit of the valve.

5. Prime the intravenous catheter which will be connected to the patient by opening the 3-waystopcock valve to the 0.9% sterile sodium chloride solution and pumping the 0.9% sterilesodium chloride solution until it exits the end of the catheter tubing.

6. Connect the primed intravenous catheter to the patient and set the 3-way stopcock valve suchthat the Lutathera solution is in line with the peristaltic pump.

7. Infuse an appropriate volume of Lutathera solution over a 30±10-minute period to deliver thedesired radioactivity.

8. When the desired Lutathera radioactivity has been delivered, stop the peristaltic pump, and thenchange the position of the 3-way stopcock valve so that the peristaltic pump is in line with the0.9% sterile sodium chloride solution. Restart the peristaltic pump and infuse an intravenousflush of 25 mL of 0.9% sterile sodium chloride solution through the intravenous catheter to thepatient.

Instructions for the syringe pump method1. Withdraw an appropriate volume of Lutathera solution to deliver the desired radioactivity byusing a disposable syringe fitted with a syringe shield and a disposable sterile needle that is9 cm, 18 gauge (long needle). To aid the withdrawal of the solution, it is possible to use afiltered 2.5 cm, 20 gauge needle (short venting needle) to reduce the resistance from thepressurised vial. Ensure that the short needle does not touch the Lutathera solution in the vial.

2. Fit the syringe into the shielded pump and include a 3-way stopcock valve between the syringeand an intravenous catheter that is pre-filled with 0.9% sterile sodium chloride solution and thatis used for Lutathera administration to the patient.

3. Infuse an appropriate volume of Lutathera solution over a 30±10-minute period to deliver thedesired radioactivity.

4. When the desired Lutathera radioactivity has been delivered, stop the syringe pump and thenchange the position of the 3-way stopcock valve so as to flush the syringe with 25 mL of 0.9%sterile sodium chloride solution. Restart the syringe pump.

5. After the flush of the syringe has been completed, perform an intravenous flush with 25 mL of0.9% sterile sodium chloride solution through the intravenous catheter to the patient.

Figure 5 Overview of methods of administration

GRAVITY METHOD

AMINO ACID

NaCl 0.9%

SOLUTION500mL

LUTATHERA® vial must LUTATHERA® vial with needlebe tip touching the bottom

CLAMP OR CLAMP OR

INFUSION INFUSION

PUMP PUMP

SHORT NEEDLE LONG NEEDLE

LUTATHERA® VIAL

AMINO ACID

SOLUTION

NaCl 0.9%500mL

CLAMP OR

VENT NEEDLE INFUSION

PUMP

LONG NEEDLE3 WAY STOPCOCK VALVE

PERISTALTIC

Long needle inserted PUMPin LUTATHERA® vialwith needle tiptouching the bottom

LUTATHERA® VIAL

AMINO ACID

SOLUTION

NaCI 0.9%

FLUSH

CLAMP OR

INFUSION

PUMP3 WAY

STOPCOCK

VALVE

SYRINGE PUMP

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

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