4.1. Therapeutic indications

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.

4.2. Posology and method of administration

Important safety instructions

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

Patient identification

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

Posology

Adults

The recommended treatment regimen of Lutathera in adults consists of 4 infusions of 7 400 MBq each. 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 in the respective section below.

Amino acid solution

For renal protection purposes, an amino acid solution containing L‑lysine and L‑arginine must be administered intravenously over 4 hours (see composition in Tables 1 and 2). The infusion of the amino acid solution should start 30 minutes prior to start of Lutathera infusion. Infusion of the amino acid solution and Lutathera through a separate venous access in each of the patient's arms is the preferred method. However, if two intravenous lines are not possible due to poor venous access or institutional/clinical preference, the amino acid solution and Lutathera may be infused through the same 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 is administered.

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

The amino acid solution can be prepared as a compounded product, in compliance with the hospital's good 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 water for injections

1 L

* 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 the specification 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

Treatment monitoring

Before each administration and during the treatment with Lutathera, laboratory tests are required to assess 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], serum albumin, 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 at least 3 months after the last infusion of Lutathera and every 6 months thereafter, in order to be able to detect possible delayed adverse reactions (see section 4.8). Dosing may need to be modified based on the test results (see Table 3).

Dose modification

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 permanent discontinuation of treatment with Lutathera (see Table 3 and Figure 1).

Table 3 Recommended dose modifications of Lutathera for adverse drug reactions

Adverse drug reaction

Severity of adverse drug reaction

Dose modification

Thrombocytopenia

First occurrence of:

Grade 2 (platelets <75‑50 x 109/L)

Grade 3 (platelets <50‑25 x 109/L)

Grade 4 (platelets <25 x 109/L)

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

Resume Lutathera at 3 700 MBq (100 mCi) in patients with complete or partial resolution. If reduced dose does not result in Grade 2, 3 or 4 thrombocytopenia, administer Lutathera at 7 400 MBq (200 mCi) as next dose.

Permanently discontinue Lutathera for Grade 2 or higher thrombocytopenia requiring a dosing interval beyond 16 weeks.

Recurrent Grade 2, 3 or 4

Permanently discontinue Lutathera.

Anaemia and neutropenia

First occurrence of anaemia:

Grade 3 (Hb <8.0 g/dL); transfusion indicated

Grade 4 (life‑threatening consequences)

First occurrence of neutropenia:

Grade 3 (absolute neutrophil count [ANC] <1.0‑0.5 x 109/L)

Grade 4 (ANC <0.5 x 109/L)

Withhold dose until complete or partial resolution (Grade 0, 1, or 2).

Resume Lutathera at 3 700 MBq (100 mCi) in patients with complete or partial resolution. If reduced dose does not result in Grade 3 or 4 anaemia or neutropenia, administer Lutathera at 7 400 MBq (200 mCi) as next dose.

Permanently discontinue Lutathera for Grade 3 or higher anaemia or neutropenia requiring a dosing interval beyond 16 weeks.

Recurrent Grade 3 or 4

Permanently discontinue Lutathera.

Renal toxicity

First occurrence of:

• Creatinine clearance less than 40 mL/min; calculated using Cockcroft‑Gault formula with actual body weight, or

• 40% increase from baseline serum creatinine, or

• 40% decrease from baseline creatinine clearance; calculated using Cockcroft‑Gault formula with actual body weight.

Withhold dose until resolution or return to baseline.

Resume Lutathera at 3 700 MBq (100 mCi) in patients with resolution or return to baseline. If reduced dose does not result in renal toxicity, administer Lutathera at 7 400 MBq (200 mCi) as next dose.

Permanently discontinue Lutathera for renal toxicity requiring a dosing interval beyond 16 weeks.

Recurrent renal toxicity

Permanently discontinue Lutathera.

Hepatotoxicity

First occurrence of:

• Bilirubinaemia greater than 3 times the upper limit of normal (Grade 3 or 4), or

• Albuminaemia less than 30 g/L with INR >1.5

Withhold dose until resolution or return to baseline.

Resume Lutathera at 3 700 MBq (100 mCi) in patients with resolution or return to baseline. If reduced Lutathera dose does not result in hepatotoxicity, administer Lutathera at 7 400 MBq (200 mCi) as next dose.

Permanently discontinue Lutathera for hepatotoxicity requiring a dosing interval beyond 16 weeks.

Recurrent hepatotoxicity

Permanently discontinue Lutathera.

Any other CTCAE* Grade 3 or Grade 4 adverse drug reaction1

First occurrence of Grade 3 or 4

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

Resume Lutathera at 3 700 MBq (100 mCi) in patients with complete or partial resolution. If reduced dose does not result in Grade 3 or 4 toxicity, administer Lutathera at 7 400 MBq (200 mCi) as next dose.

Permanently discontinue Lutathera for Grade 3 or higher adverse drug reaction requiring a dosing interval beyond 16 weeks.

Recurrent Grade 3 or 4

Permanently discontinue Lutathera.

1 No dose modification required for haematological toxicities Grade 3 or Grade 4 solely due to lymphopenia.

* 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 an intercurrent disease (e.g. urinary tract infection) which the physician considers could increase the risks associated with Lutathera administration and which should be resolved or stabilised for treatment to resume, or major surgery, in the event of which treatment should be withheld for 12 weeks after the date of surgery.

Special populations

Elderly

No dose adjustment is required in patients aged 65 years or above as clinical experience has not identified differences in responses between the elderly and younger patients. However, since increased risk of presenting with haematotoxicity has been described in elderly patients (≥70 years old), close follow‑up allowing for prompt dose adaptation (DMT) in this population is advisable.

Renal impairment

Careful consideration of the activity to be administered to patients with renal impairment is required since an increased radiation exposure is possible in these patients. The pharmacokinetic profile and safety of lutetium (177Lu) oxodotreotide in patients with baseline severe renal impairment (creatinine clearance <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 is contraindicated (see section 4.3). Treatment with Lutathera in patients with baseline creatinine clearance <40 mL/min (using Cockcroft‑Gault formula) is not recommended. No dose adjustment is recommended 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 should be 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 and section 4.4.

Hepatic impairment

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

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

Paediatric population

The safety and efficacy of Lutathera in paediatric patients aged below 18 years have not been established. Currently available data in paediatric patients aged 12 years and older are described in sections 4.8, 5.1, 5.2 and 11 but no recommendation on a posology can be made.

Method of administration

Lutathera is for intravenous use. It is a ready‑to‑use radiopharmaceutical medicinal product for single use only.

Administration instructions

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

When using the gravity method or the peristaltic pump method, Lutathera should be infused directly from its original container. The peristaltic pump method or the syringe pump method should be used when 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 may result in the delivery of the incorrect volume of Lutathera if the dose is not adjusted prior to administration. Radiation safety precautions must be considered regardless of the administration method 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(min)

Infusion rate(mL/h)

Duration

Antiemetic

At least 30 minutes prior to amino acid solution

As per prescribing information

As per prescribing information

Amino acid solution, either extemporaneously compounded (1 L) or commercial (1 to 2 L)

0

250–500 depending on volume

4 hours

Lutathera with sodium chloride 9 mg/mL (0.9%) solution for injection

30

Up to 400

30 ± 10 minutes

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

For recommendations in case of extravasation, see section 4.4.

4.3. Contraindications

• 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.

4.4. Special warnings and precautions for use

Individual benefit‑risk justification

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

Given the mechanism of action and the tolerance profile of Lutathera, it is not recommended to start treatment with Lutathera in patients with somatostatin receptor‑negative or mixed visceral lesions according to somatostatin receptor imaging.

Myelosuppression

Because of the potential for undesirable haematological effects, blood counts must be monitored at baseline and prior to each dose of Lutathera during treatment and until resolution of any eventual toxicity (see section 4.2). Patients with impaired bone marrow function and patients who have received prior chemotherapy or external beam radiotherapy (involving more than 25% of the bone marrow) may be at higher risk of haematological toxicity during Lutathera treatment. Treatment of patients 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 unless solely due to lymphopenia.

Myelodysplastic syndrome and acute leukaemia

Late‑onset myelodysplastic syndrome (MDS) and acute leukaemia (AL) have been observed after treatment with Lutathera (see section 4.8), occurring approximately 29 months (9–45) for MDS and 55 months (32‑125) for AL after the first Lutathera infusion. The aetiology of these therapy‑related secondary myeloid neoplasms (t‑MNs) is unclear. Factors such as age >70 years, impaired renal function, baseline cytopenias, prior number of therapies, prior exposure to chemotherapeutic agents (specifically alkylating agents), and prior radiotherapy are suggested as potential risks and/or predictive factors for MDS/AL.

Renal toxicity

Because lutetium (177Lu) oxodotreotide is almost exclusively eliminated through the renal system, it is mandatory to concomitantly administer an amino acid solution containing the amino acids L‑lysine and 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 absorbed dose (see section 4.2). When the recommended concomitant amino acid solution infusion is delivered over a 4‑hour time span, a mean reduction in kidney radiation exposure of about 47% has been reported.

Patients should be encouraged to remain hydrated and to urinate frequently before, on the day of and the 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 after treatment (see section 4.2).

Patients with renal impairment at baseline or with renal or urinary tract abnormalities, may be at increased 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 due to the amino acid solution should also be taken into consideration (see Warning and precaution regarding the co‑administered renal protective amino acid solution).

Hepatotoxicity

Since many patients referred for Lutathera therapy have hepatic metastasis, it may be common to observe patients with altered baseline liver function. Patients with hepatic metastasis or pre‑existing advanced 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 during treatment (see section 4.2).

Hypersensitivity

Cases of hypersensitivity reactions (including isolated angioedema events) have been reported in the post‑marketing setting in patients treated with Lutathera (see section 4.8). In the event of serious hypersensitivity reactions, the ongoing Lutathera infusion should be discontinued immediately. Appropriate medicinal products and equipment to manage such reactions should be available for immediate use.

Nausea and vomiting

To prevent treatment‑related nausea and vomiting, an intravenous bolus of an antiemetic medicinal product should be injected at least 30 minutes prior to the start of amino acid solution infusion to reach the 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 the efficacy of Lutathera (see section 4.5).

Neuroendocrine hormonal crises

Crises due to excessive release of hormones or bioactive substances may occur following treatment with Lutathera, therefore observation of patients by overnight hospitalisation should be considered in some 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

Tumour lysis syndrome has been reported following therapy with medicinal products containing lutetium‑177. Patients with a history of renal insufficiency and high tumour burden may be at greater risk and should be treated with increased caution. Renal function and electrolyte balance should be assessed at baseline and during treatment.

Radioprotection rules

Patients under treatment with Lutathera should be kept away from others during administration and until the radiation emission limits stipulated by the applicable laws are reached, usually within the 4‑5 hours following medicinal product administration. The healthcare professional should determine when the patient can leave the controlled area of the hospital, i.e. when the radiation exposure to third parties does not exceed regulatory thresholds.

Patients should be encouraged to remain hydrated and to urinate frequently before, on the day of and the 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 faeces should 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 or because of urinary incontinence, radioactivity contamination is not expected on the skin and in the vomited mass. However, it is recommended that when conducting standard care or examinations with medical 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 the material/electrode before the start of radiopharmaceutical infusion, changing the material/electrode after measurement, and eventually monitoring the radioactivity of equipment after use.

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

After each administration, the following general recommendations can be considered along with national, 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 less than 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 be immediately ceased and the administration device (catheter, etc.) removed. The nuclear medicine physician and the radiopharmacist should be informed.

All the administration device materials should be kept in order to measure the residual radioactivity and the activity actually administered and the absorbed dose should be determined. The extravasation area should be delimited with an indelible pen and a picture should be taken if possible. It is also recommended 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 a contralateral venous access.

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

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

Symptoms, especially inflammation and/or pain, should be treated. Depending on the situation, the nuclear medicine physician should inform the patient about the risks linked to extravasation injury and give advice about potential treatment and necessary follow‑up requirements. The extravasation area must be monitored until the patient is discharged from the hospital. Depending on its severity, this event should be declared as an adverse reaction.

Patients with urinary incontinence

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

Patients with brain metastases

There are no efficacy data in patients with known brain metastases, therefore individual benefit‑risk must be assessed in these patients.

Secondary malignant neoplasms

Exposure to ionising radiation is linked with cancer induction and a potential for development of hereditary defects. The radiation dose resulting from therapeutic exposure may result in higher incidence of cancer and mutations. In all cases it is necessary to ensure that the risks of the radiation exposure 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. Please see Table 3 in case of dose modifying toxicity.

• Bone metastasis;

• Previous oncological radiometabolic therapies with 131I compounds or any other therapy using unshielded radioactive sources;

• History of other malignant tumours unless the patient is considered to have been in remission for at least 5 years.

Contraception in males and females

Female patients of reproductive potential should be advised to use effective contraception during treatment 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 effective contraception 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

Hyperkalaemia

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 of hyperkalaemia, the patient's history of hyperkalaemia and concomitant medicinal product should be checked. Hyperkalaemia must be corrected accordingly before starting the infusion.

In case of pre‑existing clinically significant hyperkalaemia, a second monitoring prior to amino acid solution infusion must confirm that hyperkalaemia has been successfully corrected. The patient should be monitored closely for signs and symptoms of hyperkalaemia, e.g. dyspnoea, weakness, numbness, chest pain and cardiac manifestations (conduction abnormalities and cardiac arrhythmias). An electrocardiogram (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 and the day after administration (e.g. 1 glass of water every hour) to facilitate elimination of excess serum potassium.

In case hyperkalaemia symptoms develop during amino acid solution infusion, appropriate corrective measures must be taken. In case of severe symptomatic hyperkalaemia, discontinuation of amino acid solution infusion should be considered, taking into consideration the benefit‑risk of renal protection versus acute hyperkalaemia.

Heart failure

Due to potential for clinical complications related to volume overload, care should be taken with use of 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 or class IV in the NYHA classification should only be treated after a careful benefit‑risk assessment, taking into consideration the volume and osmolality of the amino acid solution.

Metabolic acidosis

Metabolic acidosis has been observed with complex amino acid solutions administered as part of total parenteral nutrition (TPN) protocols. Shifts in acid‑base balance alter the balance of extracellular‑intracellular potassium and the development of acidosis may be associated with rapid increases in plasma potassium.

Specific warnings

Sodium content

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.

4.5. Interaction with other medicinal products and other forms of interaction

Somatostatin analogues

Somatostatin and its analogues competitively bind to somatostatin receptors and may interfere with the efficacy of Lutathera. Therefore, administration of long‑acting somatostatin analogues should be avoided within 30 days prior to the administration of this medicinal product. If necessary, patients may be 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 somatostatin receptors (SSTR2). Therefore, as a matter of caution, repeated administration of high doses of glucocorticoids should be avoided during Lutathera treatment. Patients with a history of chronic use of glucocorticoids should be carefully evaluated for sufficient somatostatin receptor expression. It is not known whether the intermittent use of glucocorticoids for the prevention of nausea and vomiting during 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 the treatment administered for the prevention of nausea and vomiting before the amino acid solution infusion proves insufficient, a single glucocorticoid dose can be used, provided it is not given before initiating or within one hour after the end of Lutathera infusion.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential

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

Contraception in males and females

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

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

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

Pregnancy

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 pregnancy has not been excluded due to the risk associated with the ionising radiation (see section 4.3). Pregnant women should be advised of the risk to a foetus.

Breast‑feeding

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

Fertility

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

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of the safety profile

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), as well as data from the NETTER-P phase II study and from compassionate use programmes.

The most common adverse reactions in patients receiving Lutathera treatment were nausea and vomiting, 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 concomitant amino acid solution administered for renal protection.

Due to the bone marrow toxicity of Lutathera, the most expected adverse reactions were related to haematological 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 each study arm, the safety profile remained consistent with that previously reported.

Tabulated list of adverse reactions

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‑marketing surveillance

MedDRA System Organ Class (SOC)

Very common

Common

Uncommon

Not known

Infections and infestations

Conjunctivitis

Respiratory tract infection

Cystitis

Pneumonia

Herpes zoster

Ophthalmic herpes zoster

Influenza

Staphylococcal infections

Streptococcal bacteraemia

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Refractory cytopenia with multilineage dysplasia (myelodysplastic syndrome)

Acute myeloid leukaemia

Acute leukaemia

Chronic myelomonocytic leukaemia

Blood and lymphatic system disorders

Thrombocytopenia2

Lymphopenia3

Anaemia4

Pancytopenia

Leukopenia5

Neutropenia6

Refractory cytopenia with unilineage dysplasia

Nephrogenic anaemia

Bone marrow failure

Thrombocytopenic purpura

Immune system disorders

Hypersensitivity

Angioedema

Endocrine disorders

Secondary hypothyroidism

Hypothyroidism

Diabetes mellitus

Carcinoid crisis

Hyperparathyroidism

Metabolism and nutrition disorders

Decreased appetite

Hyperglycaemia

Dehydration

Hypomagnesaemia

Hyponatraemia

Hypoglycaemia

Hypernatraemia

Hypophosphataemia

Tumour lysis syndrome

Hypercalcaemia

Hypocalcaemia

Hypoalbuminaemia

Metabolic acidosis

Psychiatric disorders

Sleep disorders

Anxiety

Hallucination

Disorientation

Nervous system disorders

Dizziness

Dysgeusia

Headache10

Lethargy

Syncope

Formication

Hepatic encephalopathy

Paraesthesia

Parosmia

Somnolence

Spinal cord compression

Eye disorders

Eye disorders

Ear and labyrinth disorders

Vertigo

Cardiac disorders

Electrocardiogram QT prolonged

Atrial fibrillation

Palpitations

Myocardial infarction

Angina pectoris

Cardiogenic shock

Vascular disorders

Hypertension7

Flushing

Hot flush

Hypotension

Vasodilatation

Peripheral coldness

Pallor

Orthostatic hypotension

Phlebitis

Respiratory, thoracic and mediastinal disorders

Dyspnoea

Oropharyngeal pain

Pleural effusion

Sputum increased

Choking sensation

Gastrointestinal disorders

Nausea

Vomiting

Abdominal distension

Diarrhoea

Abdominal pain

Constipation

Abdominal pain upper

Dyspepsia

Gastritis

Dry mouth

Flatulence

Ascites

Gastrointestinal pain

Stomatitis

Haematochezia

Abdominal discomfort

Intestinal obstruction

Colitis

Pancreatitis acute

Rectal haemorrhage

Melaena

Abdominal pain lower

Haematemesis

Haemorrhagic ascites

Ileus

Hepatobiliary disorders

Hyperbilirubinaemia9

Pancreatic enzymes decreased

Hepatocellular injury

Cholestasis

Hepatic congestion

Hepatic failure

Skin and subcutaneous tissue disorders

Alopecia

Rash

Dry skin

Swelling face

Hyperhidrosis

Pruritus generalised

Musculoskeletal and connective tissue disorders

Musculoskeletal pain8

Muscle spasms

Renal and urinary disorders

Acute kidney injury

Haematuria

Renal failure

Proteinuria

Leukocyturia

Urinary incontinence

Glomerular filtration rate decreased

Renal disorder

Acute pre‑renal failure

Renal impairment

General disorders and administration site conditions

Fatigue1

Injection site reaction11

Oedema peripheral

Administration site pain

Chills

Influenza‑like illness

Injection site mass

Chest discomfort

Chest pain

Pyrexia

Malaise

Pain

Death

Feeling abnormal

Investigations

Blood creatinine increased

GGT* increased

ALT** increased

AST*** increased

Blood ALP**** increased

Blood potassium decreased

Blood urea increased

Glycosylated haemoglobin increased

Haematocrit decreased

Protein urine

Weight decreased

Blood creatine phosphokinase increased

Blood lactate dehydrogenase increased

Blood catecholamines

C‑reactive protein increased

Injury, poisoning and procedural complications

Clavicle fracture

Surgical and medical procedures

Transfusion

Abdominal cavity drainage

Dialysis

Gastrointestinal tube insertion

Stent placement

Abscess drainage

Bone marrow harvest

Polypectomy

Social circumstances

Physical disability

1 Includes asthenia and fatigue

2 Includes thrombocytopenia and platelet count decreased

3 Includes lymphopenia and lymphocyte count decreased

4 Includes anaemia and haemoglobin decreased

5 Includes leukopenia and white blood cell count decreased

6 Includes neutropenia and neutrophil count decreased

7 Includes hypertension and hypertensive crisis

8 Includes arthralgia, pain in extremity, back pain, bone pain, flank pain, musculoskeletal chest pain and neck pain

9 Includes blood bilirubin increased and hyperbilirubinaemia

10 Includes headache and migraine

11 Includes injection site reaction, injection site hypersensibility, injection site induration, injection site swelling

*Gamma‑glutamyltransferase

**Alanine aminotransferase

***Aspartate aminotransferase

****Alkaline phosphatase

Description of selected adverse reactions

Myelosuppression

Mostly mild/moderate bone marrow toxicity (myelo‑/haematotoxicity) manifested with reversible/transient reductions in blood counts affecting all lineages (cytopenias in all combinations, i.e. pancytopenia, bicytopenias, isolated monocytopenias – anaemia, neutropenia, lymphocytopenia and thrombocytopenia). In spite of an observed significant selective B‑cell depletion, no increase in the rate of infectious complications occurs after peptide receptor radionuclide therapy (PRRT). Cases of 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 the 59 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 platelet recovery 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 the clinical studies confirms that Lutathera‑related nephropathy is a chronic kidney disease that develops progressively over months or years after exposure. An individual benefit‑risk assessment is recommended 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 neuroendocrine tumour cells) have rarely been observed and resolved after appropriate medical treatment (see section 4.4).

Paediatric population

Based on published literature and on clinical data from 11 adolescents with somatostatin receptor-positive GEP-NET or phaeochromocytoma or paraganglioma (PPGL) enrolled in NETTER-P, no new safety signals were reported.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system:

Yellow Card Scheme

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

4.9. Overdose

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

In the event of administration of a radiation overdose with Lutathera, the absorbed dose to the patient should be reduced where possible by increasing the elimination of the radionuclide from the body by frequent micturition or by forced diuresis and frequent bladder voiding during the first 48 hours after infusion. 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 and haemoglobin

• Blood chemistry monitoring: serum creatinine and glycaemia.