TEPKINLY 48mg 60mg / ml solution for injection medication leaflet

Tepkinly 48 mg solution for injection

Each 0.8 ml vial contains 48 mg of epcoritamab at a concentration of 60 mg/ml.

Each vial contains an overfill that allows withdrawal of the labelled amount.

Epcoritamab is a humanised immunoglobulin G1 (IgG1)-bispecific antibody against CD3 and

CD20 antigens, produced in Chinese hamster ovary (CHO) cells by recombinant DNA technology.

Each vial of Tepkinly contains 21.9 mg of sorbitol and 0.42 mg of polysorbate 80.

For the full list of excipients, see section 6.1.

Solution for injection (injection)

Colourless to slightly yellow solution, pH 5.5 and osmolality of approximately 211 mOsm/kg.

Tepkinly as monotherapy is indicated for the treatment of adult patients with relapsed or refractorydiffuse large B-cell lymphoma (DLBCL) after two or more lines of systemic therapy.

Tepkinly as monotherapy is indicated for the treatment of adult patients with relapsed or refractoryfollicular lymphoma (FL) after two or more lines of systemic therapy.

Tepkinly must only be administered under the supervision of a healthcare professional qualified in theuse of anti-cancer therapy. At least 1 dose of tocilizumab for use in the event of CRS should be availableprior to epcoritamab administration for Cycle 1. Access to an additional dose of tocilizumab within8 hours of use of the previous tocilizumab dose should be available.

Recommended pre-medication and dose schedule

Tepkinly should be administered according to the following step-up dose schedule in 28-day cycleswhich is outlined in Table 1 for patients with diffuse large B-cell lymphoma and Table 2 for patientswith follicular lymphoma.

Table 1 Tepkinly 2-step step-up dose schedule for patients with diffuse large B-cell lymphomaa

Dosing schedule Cycle of Days Epcoritamab dose (mg)treatment

Weekly Cycle 1 1 0.16 mg (Step-up dose 1)8 0.8 mg (Step-up dose 2)15 48 mg (First full dose)22 48 mg

Weekly Cycles 2 - 3 1, 8, 15, 22 48 mg

Every two weeks Cycles 4 - 9 1, 15 48 mg

Every four weeks Cycles 10 + 1 48 mga0.16 mg is a priming dose, 0.8 mg is an intermediate dose and 48 mg is a full dose.

Table 2: Tepkinly 3-step step-up dose schedule for patients with follicular lymphomaa

Dosing schedule Cycle of Days Epcoritamab dose (mg)treatment

Weekly Cycle 1 1 0.16 mg (Step-up dose 1)8 0.8 mg (Step-up dose 2)15 3 mg (Step-up dose 3)22 48 mg (First full dose)

Weekly Cycles 2 - 3 1, 8, 15, 22 48 mg

Every two weeks Cycles 4 - 9 1, 15 48 mg

Every four weeks Cycles 10 + 1 48 mga0.16 mg is a priming dose, 0.8 mg is an intermediate dose, 3 mg is a second intermediate doseand 48 mg is a full dose.

Tepkinly should be administered until disease progression or unacceptable toxicity.

Details on recommended pre-medication for cytokine release syndrome (CRS) are shown in Table 3.

Table 3 Epcoritamab pre-medication

Cycle Patient requiring Pre-medication Administrationpre-medication

Cycle 1 All patients Dexamethasone b (15 mg oral * 30-120 minutes prior toor intravenous) or each weekly

Prednisolone (100 mg oral or administration ofintravenous) or equivalent epcoritamab

* And for three consecutivedays following eachweekly administration ofepcoritamab in Cycle 1

* Diphenhydramine * 30-120 minutes prior to(50 mg oral or each weeklyintravenous) or administration ofequivalent epcoritamab

* Paracetamol(650 to 1 000 mg oral)

Cycle 2 and Patients who Dexamethasone b (15 mg oral * 30-120 minutes prior tobeyond experienced Grade 2 or intravenous) or next administration ofor 3a CRS with Prednisolone (100 mg oral or epcoritamab after a gradeprevious dose intravenous) or equivalent 2 or 3a CRS event

* And for three consecutivedays following the nextadministration ofepcoritamab untilepcoritamab is givenwithout subsequent anygrade of CRSaPatients will be permanently discontinued from epcoritamab after a Grade 4 CRS event.bDexamethasone is the preferred corticosteroid for CRS prophylaxis based on the GCT3013-01 Optimisationstudy.

Prophylaxis against Pneumocystis jirovecii pneumonia (PCP) and herpes virus infections is stronglyrecommended especially during concurrent use of steroids.

Tepkinly should be administered to adequately hydrated patients.

It is strongly recommended that all patients adhere to the following fluid guidelines during Cycle 1,unless medically contraindicated:

* 2-3 L of fluid intake during the 24 hours prior to each epcoritamab administration

* Hold antihypertensive medications for 24 hours prior to each epcoritamab administration

* Administer 500 ml isotonic intravenous (IV) fluids on the day of epcoritamab prior to doseadministration; AND

* 2-3 L of fluid intake during the 24 hours following each epcoritamab administration.

Patients at an increased risk for clinical tumour lysis syndrome (CTLS) are recommended to receivehydration and prophylactic treatment with a uric acid lowering agent.

Patients should be monitored for signs and symptoms of CRS and/or immune effector cell-associatedneurotoxicity syndrome (ICANS) and managed per current practice guidelines following epcoritamabadministration. Patients should be counselled on the signs and symptoms associated with CRS and

ICANS and on seeking immediate medical attention should signs or symptoms occur at any time (seesection 4.4).

Patients with DLBCL should be hospitalised for 24 hours after administration of the Cycle 1 Day 15dose of 48 mg to monitor for signs and symptoms of CRS and/or ICANS.

Dose modifications and management of adverse reactions

Patients treated with epcoritamab may develop CRS.

Evaluate for and treat other causes of fever, hypoxia, and hypotension. If CRS is suspected, manageaccording to the recommendations in Table 4. Patients who experience CRS should be monitored morefrequently during next scheduled epcoritamab administration.

Table 4 CRS grading and management guidancea

Grade Recommended therapy Epcoritamab dose modification

Grade 1 Provide supportive care such as Hold epcoritamab until resolution

* Fever (temperature ≥ 38 °C) antipyretics and intravenous of CRS eventhydration

Dexamethasoneb may be initiated

In cases of advanced age, hightumour burden, circulating tumoura

Grade Recommended therapy Epcoritamab dose modificationcells, fever refractory toantipyretics

* Anti-cytokine therapy,tocilizumabd, should beconsidered

For CRS with concurrent ICANSrefer to Table 5

Grade 2 Provide supportive care such as Hold epcoritamab until resolution

* Fever (temperature ≥ 38 °C) antipyretics and intravenous of CRS eventhydrationand

Dexamethasoneb should be

* Hypotension not requiring consideredvasopressors

Anti-cytokine therapy,and/or tocilizumabd, is recommended

* Hypoxia requiring low-flow If CRS is refractory tooxygene by dexamethasone and tocilizumab:

nasal cannula * Alternativeor blow-by immunosuppressantsg andmethylprednisolone1 000 mg/dayintravenously should beadministered until clinicalimprovement

For CRS with concurrent ICANSrefer to Table 5

Grade 3 Provide supportive care such as Hold epcoritamab until resolution

* Fever (temperature ≥ 38 °C) antipyretics and of CRS eventintravenous hydrationand In the event of Grade 3 CRS

Dexamethasonec should be lasting longer than 72 hours,

* Hypotension requiring a administered epcoritamab should bevasopressor with or without Anti-cytokine therapy, discontinuedvasopressin tocilizumabd, is recommended

If more than 2 separate events ofand/or If CRS is refractory to Grade 3 CRS, even if each eventdexamethasone and tocilizumab: resolved to Grade 2 within

* Hypoxia requiring high-flow * Alternative 72 hours, epcoritamab should beoxygenf by nasal cannula, immunosuppressantsg and discontinuedfacemask, non-rebreather methylprednisolonemask, or venturi mask 1 000 mg/dayintravenously should beadministered until clinicalimprovementa

Grade Recommended therapy Epcoritamab dose modification

For CRS with concurrent ICANSrefer to Table 5

Grade 4 Provide supportive care such as Permanently discontinue

* Fever (temperature ≥ 38 °C) antipyretics and epcoritamabintravenous hydrationand

Dexamethasonec should be

Hypotension requiring ≥ 2 administeredvasopressors (excluding Anti-cytokine therapy,vasopressin) tocilizumabd is recommendedand/or If CRS is refractory todexamethasone and tocilizumab:

* Hypoxia requiring positive * Alternativepressure ventilation (e.g., immunosuppressantsg and

CPAP, BiPAP, intubation and methylprednisolonemechanical ventilation) 1 000 mg/dayintravenously should beadministered until clinicalimprovement

For CRS with concurrent ICANSrefer to Table 5aCRS graded according to ASTCT consensus criteriabDexamethasone should be administered at 10-20 mg per day (or equivalent)cDexamethasone should be administered at 10-20 mg intravenously every 6 hoursdTocilizumab 8 mg/kg intravenously over 1 hour (not to exceed 800 mg per dose). Repeat tocilizumabafter at least 8 hours as needed. Maximum of 2 doses in a 24-hour periodeLow-flow oxygen is defined as oxygen delivered at < 6 L/minutefHigh-flow oxygen is defined as oxygen delivered at ≥ 6 L/minutegRiegler L et al. (2019)

Immune effector cell-associated neurotoxicity syndrome (ICANS)

Patients should be monitored for signs and symptoms of ICANS. Other causes of neurologic symptomsshould be ruled out. If ICANS is suspected, manage according to the recommendations in Table 5.

Table 5 ICANS grading and management guidancea

Grade Recommended therapy Epcoritamab dosemodificationb

Grade 1 Treatment with dexamethasoned Hold epcoritamab

ICE scorec 7-9 b until resolution ofor, depressed level of Consider non-sedating anti-seizure medicinal products (e.g., eventconsciousnessb: awakens levetiracetam) until resolution of ICANSspontaneously

No concurrent CRS:

* Anti-cytokine therapy not recommended

For ICANS with concurrent CRS:

* Treatment with dexamethasoneda

Grade Recommended therapy Epcoritamab dosemodification

* Choose immunosuppressant alternativese totocilizumab, if possibleb

Grade 2 Treatment with dexamethasonef Hold epcoritamab

ICE scorec 3-6 until resolution ofor, depressed level of Consider non-sedating anti-seizure medicinal products (e.g., eventconsciousnessb: awakens levetiracetam) until resolution of ICANSto voice

No concurrent CRS:

* Anti-cytokine therapy not recommended

For ICANS with concurrent CRS:

* Treatment with dexamethasoned

* Choose immunosuppressant alternativese totocilizumab, if possibleb

Grade 3 Treatment with dexamethasoneg. Permanently

ICE scorec 0-2 * If no response, initiate methylprednisolone discontinueor, depressed level of 1 000 mg/day epcoritamabconsciousnessb: awakensonly to tactile stimulus, Consider non-sedating anti-seizure medicinal products (e.g.,or levetiracetam) until resolution of ICANSseizuresb, either: No concurrent CRS:

* any clinical seizure, * Anti-cytokine therapy not recommendedfocal or generalisedthat resolves rapidly, For ICANS with concurrent CRS:

or

* Treatment with dexamethasone

* non-convulsiveo If no response, initiate methylprednisoloneseizures on1 000 mg/dayelectroencephalogram

* Choose immunosuppressant alternativese to(EEG) that resolvewith intervention, or tocilizumab, if possibleraised intracranialpressure: focal/localoedemab onneuroimagingcb

Grade 4 Treatment with dexamethasoneg Permanently

ICE scorec, b 0 * If no response, initiate methylprednisolone discontinue1 000 mg/day epcoritamabor, depressed level ofconsciousnessb either: Consider non-sedating anti-seizure medicinal products (e.g.,

* patient is unarousable levetiracetam) until resolution of ICANSor requires vigorousor repetitive tactile No concurrent CRS:stimuli to arouse, or * Anti-cytokine therapy not recommended

* stupor or coma, or

For ICANS with concurrent CRS:seizuresb, either: * Treatment with dexamethasone

* life-threatening o If no response, initiate methylprednisoloneprolonged seizure 1 000 mg/day(> 5 minutes), ora

Grade Recommended therapy Epcoritamab dosemodification

* repetitive clinical or * Choose immunosuppressant alternativese toelectrical seizures tocilizumab, if possiblewithout return tobaseline in between,ormotor findingsb:

* deep focal motorweakness such ashemiparesis orparaparesis, orraised intracranialpressure/cerebraloedemab, withsigns/symptoms such as:

* diffuse cerebraloedema onneuroimaging, or

* decerebrate ordecorticate posturing,or

* cranial nerve VIpalsy, or

* papilloedema, or

* cushing’s triadaICANS graded according to ASTCT ICANS Consensus GradingbICANS grade is determined by the most severe event (ICE score, level of consciousness, seizures, motorfindings, raised ICP/cerebral oedema) not attributable to any other causecIf patient is arousable and able to perform Immune Effector Cell-Associated Encephalopathy (ICE) Assessment,assess: Orientation (oriented to year, month, city, hospital = 4 points); Naming (name 3 objects, e.g., point toclock, pen, button = 3 points); Following Commands (e.g., “show me 2 fingers” or “close your eyes and stick outyour tongue” = 1 point); Writing (ability to write a standard sentence = 1 point); and Attention (count backwardsfrom 100 by ten = 1 point). If patient is unarousable and unable to perform ICE Assessment (Grade 4 ICANS) = 0points.dDexamethasone should be administered at 10 mg intravenously every 12 hourseRiegler L et al. (2019)fDexamethasone 10-20 mg intravenously every 12 hoursgDexamethasone 10-20 mg intravenously every 6 hours

Table 6 Recommended dose modifications for other adverse reactions1 1

Adverse Reaction Severity Action

Infections (see section 4.4) Grades 1-4 * Withhold epcoritamab inpatients with active infection,until the infection resolves

* For Grade 4, consider permanentdiscontinuation of epcoritamab

Neutropenia or febrile Absolute neutrophil count * Withhold epcoritamab untilneutropenia (see section 4.8) less than 0.5 x 109/L absolute neutrophil count is0.5 x 109/L or higher

Thrombocytopenia (see section Platelet count * Withhold epcoritamab until4.8) less than 50 x 109/L platelet count is 50 x 109/L orhigher1 1

Adverse Reaction Severity Action

Other adverse reactions (see Grade 3 or higher * Withhold epcoritamab until thesection 4.8) toxicity resolves to Grade 1 orbaseline1Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI

CTCAE), Version 5.0.

Missed or delayed dose

Diffuse large B-cell lymphoma

A re-priming Cycle (identical to Cycle 1 with standard CRS prophylaxis) is required:

* If there are more than 8 days between the priming dose (0.16 mg) and intermediate dose(0.8 mg), or

* If there are more than 14 days between the intermediate dose (0.8 mg) and first full dose(48 mg), or

* If there are more than 6 weeks between full doses (48 mg)

After the re-priming cycle, the patient should resume treatment with Day 1 of the next planned treatmentcycle (subsequent to the cycle during which the dose was delayed).

A re-priming Cycle (identical to Cycle 1 with standard CRS prophylaxis) is required:

* If there are more than 8 days between the priming dose (0.16 mg) and intermediate dose(0.8 mg), or

* If there are more than 8 days between the intermediate dose (0.8 mg) and the secondintermediate dose (3 mg), or

* If there are more than 14 days between the second intermediate dose (3 mg) and first full dose(48 mg), or

* If there are more than 6 weeks between any two full doses (48 mg)

After the re-priming cycle, the patient should resume treatment with Day 1 of the next planned treatmentcycle (subsequent to the cycle during which the dose was delayed).

Dose adjustments are not considered necessary in patients with mild to moderate renal impairment.

Epcoritamab has not been studied in patients with severe renal impairment to end stage renal disease. Nodose recommendations can be made for patients with severe renal impairment to end-stage renal disease(see section 5.2).

Dose adjustments are not considered necessary in patients with mild hepatic impairment. Epcoritamabhas not been studied in patients with severe hepatic impairment (defined as total bilirubin > 3 times ULNand any AST) and data are limited in patients with moderate hepatic impairment (defined as totalbilirubin > 1.5 to 3 times ULN and any AST). No dose recommendations can be made for patients withmoderate to severe hepatic impairment (see section 5.2).

No dose adjustment is necessary in patients ≥ 65 years of age (see sections 5.1 and 5.2).

The safety and efficacy of Tepkinly in children aged less than 18 years of age have not yet beenestablished. No data are available.

Tepkinly is for subcutaneous use. It should be administered by subcutaneous injection only, preferably inthe lower part of the abdomen or the thigh. Change of injection site from left to right side or vice versa isrecommended especially during the weekly administration schedule (i.e., Cycles 1-3).

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

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

In order to improve the traceability of biological medicinal products, the name and the batch number ofthe administered product should be clearly recorded.

CRS, which may be life-threatening or fatal, occurred in patients receiving epcoritamab. The mostcommon signs and symptoms of CRS include pyrexia, hypotension and hypoxia. Other signs andsymptoms of CRS in more than two patients include chills, tachycardia, headache and dyspnoea.

Most CRS events occurred in Cycle 1 and were associated with the first full dose of epcoritamab.

Administer prophylactic corticosteroids to mitigate the risk of CRS (see section 4.2).

Patients should be monitored for signs and symptoms of CRS following epcoritamab administration.

At the first signs or symptoms of CRS, treatment should be instituted of supportive care with tocilizumaband/or corticosteroids as appropriate (see section 4.2, Table 4). Patients should be counselled on the signsand symptoms associated with CRS and patients should be instructed to contact their healthcareprofessional and seek immediate medical attention should signs or symptoms occur at any time.

Management of CRS may require either temporary delay or discontinuation of epcoritamab based on theseverity of CRS (see section 4.2).

Patients with DLBCL should be hospitalised for 24 hours after administration of the Cycle 1 Day 15dose of 48 mg to monitor for signs and symptoms of CRS.

Immune effector cell-associated neurotoxicity syndrome (ICANS)

ICANS, including a fatal event, have occurred in patients receiving epcoritamab. ICANS may manifestas aphasia, altered level of consciousness, impairment of cognitive skills, motor weakness, seizures, andcerebral oedema.

The majority of cases of ICANS occurred within Cycle 1 of epcoritamab treatment, however someoccurred with delayed onset.

Patients should be monitored for signs and symptoms of ICANS following epcoritamab administration.

At the first signs or symptoms of ICANS, treatment with corticosteroids and non-sedating-anti-seizuremedicinal products should be instituted as appropriate (see section 4.2, Table 5). Patients should becounselled on the signs and symptoms of ICANS and that the onset of events may be delayed. Patientsshould be instructed to contact their healthcare professional and seek immediate medical attention shouldsigns or symptoms occur at any time. Epcoritamab should be delayed or discontinued as recommended(see section 4.2).

Patients with DLBCL should be hospitalised for 24 hours after administration of the Cycle 1 Day 15dose of 48 mg to monitor for signs and symptoms of ICANS.

Treatment with epcoritamab may lead to an increased risk of infections. Serious or fatal infections wereobserved in patients treated with epcoritamab in clinical studies (see section 4.8).

Administration of epcoritamab should be avoided in patients with clinically significant active systemicinfections.

As appropriate, prophylactic antimicrobials should be administered prior to and during treatment withepcoritamab (see section 4.2). Patients should be monitored for signs and symptoms of infection, beforeand after epcoritamab administration, and treated appropriately. In the event of febrile neutropenia,patients should be evaluated for infection and managed with antibiotics, fluids and other supportive care,according to local guidelines.

TLS has been reported in patients receiving epcoritamab (see section 4.8). Patients at an increased riskfor TLS are recommended to receive hydration and prophylactic treatment with a uric acid loweringagent. Patients should be monitored for signs or symptoms of TLS, especially patients with high tumourburden or rapidly proliferative tumours, and patients with reduced renal function. Patients should bemonitored for blood chemistries and abnormalities should be managed promptly.

Tumour flare has been reported in patients treated with epcoritamab (see section 4.8). Manifestationscould include localised pain and swelling. Consistent with the mechanism of action of epcoritamab,tumour flare is likely due to the influx of T-cells into tumour sites following epcoritamab administration.

There are no specific risk factors for tumour flare that have been identified; however, there is aheightened risk of compromise and morbidity due to mass effect secondary to tumour flare in patientswith bulky tumours located in close proximity to airways and/or a vital organ. Patients treated withepcoritamab should be monitored and evaluated for tumour flare at critical anatomical sites.

CD20-negative disease

There are limited data available on patients with CD20-negative DLBCL and patients with CD20-negative FL treated with epcoritamab, and it is possible that patients with CD20-negative DLBCL andpatients with CD20 negative FL may have less benefit compared to patients with CD20-positive DLBCLand patients with CD20-positive FL, respectively. The potential risks and benefits associated withtreatment of patients with CD20-negative DLBCL and FL with epcoritamab should be considered.

The doctor must inform the patient of the risk of CRS and ICANS and any signs and symptoms of CRSand ICANS. Patients must be instructed to seek immediate medical attention if they experience signs andsymptoms of CRS and/or ICANS. Patients should be provided with a patient card and instructed to carrythe card at all times. This card describes symptoms of CRS and ICANS which, if experienced, shouldprompt the patient to seek immediate medical attention.

Live and/or live-attenuated vaccines should not be given during epcoritamab therapy. Studies have notbeen conducted in patients who received live vaccines.

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

This medicinal product contains 21.9 mg of sorbitol per vial, which is equivalent to 27.33 mg/ml.

This medicinal product contains 0.42 mg of polysorbate 80 per vial, equivalent to 0.4 mg/ml. Polysorbate80 may cause allergic reactions.

No interaction studies have been performed.

Transient elevation of certain proinflammatory cytokines by epcoritamab may suppress CYP450 enzymeactivities. On initiation of epcoritamab therapy in patients being treated with CYP450 substrates with anarrow therapeutic index, therapeutic monitoring should be considered.

Women of childbearing potential should be advised to use effective contraception during treatment withepcoritamab and for at least 4 months after the last dose. Verify pregnancy status in females ofreproductive potential prior to initiating epcoritamab treatment.

Based on its mechanism of action, epcoritamab may cause foetal harm, including B-celllymphocytopenia and alterations in normal immune responses, when administered to pregnant women.

There are no data on the use of epcoritamab in pregnant women. Animal reproduction studies have notbeen conducted with epcoritamab. IgG1 antibodies, such as epcoritamab, can cross the placenta resultingin foetal exposure. Advise pregnant women of the potential risk to a foetus.

Epcoritamab is not recommended during pregnancy and in women of childbearing potential not usingcontraception.

It is not known whether epcoritamab is excreted in human milk or its effect on milk production. Since

IgGs are known to be present in milk, neonatal exposure to epcoritamab may occur via lactationaltransfer. Breast-feeding should be discontinued during treatment with epcoritamab and for at least4 months after the last dose.

No fertility studies have been conducted with epcoritamab (see section 5.3). The effect of epcoritamab onmale and female fertility is unknown.

Epcoritamab has minor influence on the ability to drive and use machines. Due to the potential for

ICANS, patients should be advised to exercise caution while (or avoid if symptomatic) driving, cyclingor using heavy or potentially dangerous machines.

The safety of epcoritamab was evaluated in a non-randomised, single-arm GCT3013-01 study in 382patients with relapsed or refractory large B-cell lymphoma (N=167), follicular lymphoma (N=129) andfollicular lymphoma (3-step step-up dose schedule N=86) after two or more lines of systemic therapyand included all the patients who enrolled to the 48 mg dose and received at least one dose ofepcoritamab.

The median duration of exposure to epcoritamab was 4.9 months (range: <1 to 30 months).

The most common adverse reactions (≥ 20%) were CRS injection site reactions, fatigue, viral infection,neutropenia, musculoskeletal pain, pyrexia, and diarrhoea.

Serious adverse reactions occurred in 50% of patients. The most frequent serious adverse reaction(≥ 10%) was cytokine release syndrome (34%). Fourteen patients (3.7%) experienced a fatal adversereaction (pneumonia in 9 (2.4%) patients, viral infection in 4 (1.0%) patients, and ICANS in 1 (0.3%)patient).

Adverse reactions that led to discontinuation occurred in 6.8% of patients. Discontinuation ofepcoritamab due to pneumonia occurred in 14 (3.7%) patients, viral infection in 8 (2.1%) patients,fatigue in 2 (0.5%) patients, and CRS, ICANS, or diarrhoea, in 1 (0.3%) patient each.

Dose delays due to adverse reactions occurred in 42% of patients. Adverse reactions leading to dosedelays (≥ 3%) were viral infections (17%), CRS (11%), neutropenia (5.2%), pneumonia (4.7%), upperrespiratory tract infection (4.2%), and pyrexia (3.7%).

Adverse reactions for epcoritamab from clinical studies (Table 7) are listed by MedDRA system organclass and are based on the following convention: 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); and very rare (< 1/10 000).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 7 Adverse reactions reported in patients with relapsed or refractory LBCL or FL treatedwith epcoritamab in GCT3013-01 study

System organ class/All grades Grade 3-4preferred term or adversereaction

Viral infectiona Very common Common

Pneumoniab Very common Common

Upper respiratory tract Very common Commoninfectionc

Fungal infectiond Common

Sepsise Common Common

Cellulitis Common Common

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

Tumour flare Common

Neutropeniaf Very common Very common

Anaemiag Very common Common

Thrombocytopeniah Very common Common

Lymphopeniai Very common Common

Febrile neutropenia Common Common

Cytokine release syndromej Very common Common

Decreased appetite Very common Uncommon

Hypokalaemia Common Common

Hypophosphatemia Common Common

Hypomagnesaemia Common Uncommon

Tumour lysis syndromek Common Uncommon

Headache Very common Uncommon

Immune effector cell-associated Commonneurotoxicity syndromej

Cardiac arrhythmiasl Common Uncommon

Pleural effusion Common Common

Diarrhoea Very common Uncommon

Abdominal painm Very common Common

Nausea Very common Uncommon

Vomiting Common Uncommon

Rashn Very common

Pruritus Common

Musculoskeletal paino Very common Common

Injection site reactionsp Very common

Fatigueq Very common Common

Pyrexiar Very common Common

Oedemas Very common Common

Alanine aminotransferase Common Commonincreased

Aspartate aminotransferase Common Commonincreased

Blood creatinine increased Common

Blood sodium decreasedt Common Uncommon

Alkaline phosphatase increased Common

Adverse reactions were graded using NCI CTCAE version 5.0aViral infection includes COVID-19, cytomegalovirus chorioretinitis, cytomegalovirus colitis,cytomegalovirus infection, cytomegalovirus infection reactivation, gastroenteritis viral, herpes simplex,herpes simplex reactivation, herpes virus infection, herpes zoster, oral herpes, post-acute COVID-19 syndrome, and varicella zoster virus infectionbPneumonia includes COVID-19 pneumonia and pneumoniacUpper respiratory tract infection includes laryngitis, pharyngitis, respiratory syncytial virus infection,rhinitis, rhinovirus infection, and upper respiratory tract infectiondFungal infection includes candida infection, oesophageal candidiasis, oral candidiasis andoropharyngeal candidiasiseSepsis includes bacteraemia, sepsis, and septic shockfNeutropenia includes neutropenia and neutrophil count decreasedgAnaemia includes anaemia and serum ferritin decreasedhThrombocytopenia includes platelet count decreased and thrombocytopeniaiLymphopenia includes lymphocyte count decreased and lymphopeniaj Events graded using American Society for Transplantation and Cellular Therapy (ASTCT) consensuscriteriak Clinical Tumour Lysis Syndrome was graded based on Cairo-BishoplCardiac arrhythmias include bradycardia, sinus bradycardia, sinus tachycardia, supraventriculartachycardia, and tachycardiamAbdominal pain includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal painupper, and abdominal tendernessnRash includes rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic,rash pustular, and rash vesicularoMusculoskeletal pain includes back pain, bone pain, flank pain, musculoskeletal chest pain,musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain, pain, pain in extremity, and spinal painpInjection site reactions include injection site bruising, injection site erythema, injection site hypertrophy,injection site inflammation, injection site mass, injection site nodule, injection site oedema, injection sitepain, injection site pruritus, injection site rash, injection site reaction, injection site swelling, andinjection site urticaria.qFatigue includes asthenia, fatigue, and lethargyrPyrexia includes body temperature increased and pyrexiasOedema includes face oedema, generalised oedema, oedema, oedema peripheral, peripheral swelling,swelling, and swelling facetBlood sodium decreased includes blood sodium decreased and hyponatraemia

Cytokine release syndrome2-step step-up dose schedule (large B-cell lymphoma and follicular lymphoma)

In study GCT3013-01, CRS of any grade occurred in 58% (171/296) of patients with large B-celllymphoma and follicular lymphoma treated with epcoritamab at the 2-step step-up dose schedule. Theincidence of Grade 1 was 35%, Grade 2 was 21%, and Grade 3 occurred in 2.4% of patients. Recurrent

CRS occurred in 21% of patients. CRS of any grade occurred in 9.8% of patients after the priming dose(Cycle 1 Day 1); 13% after the intermediate dose (Cycle 1, Day 8); 51% after the first full dose (Cycle 1,

Day 15), 6.5% after the second full dose (Cycle 1 Day 22) and 3.7% after the third full dose (Cycle 2

Day 1) or beyond. The median time to onset of CRS from the most recent administered epcoritamab dosewas 2 days (range: 1 to 12 days). The median time to onset after the first full dose was 19.3 hours (range:

<0.1 to 7 days). CRS resolved in 99% of patients, and the median duration of CRS events was 2 days(range 1 to 54 days).

Of the 171 patients that experienced CRS, the most common signs and symptoms of CRS includedpyrexia 99%, hypotension 32% and hypoxia 16%. Other signs and symptoms of CRS in ≥3% of patientsincluded chills (11%), tachycardia (including sinus tachycardia (11%)), headache (8.2%), nausea(4.7%), and vomiting (4.1%). Transient elevated liver enzymes (ALT or AST > 3xULN) were concurrentwith CRS in 4.1% of patients with CRS. See section 4.2 and 4.4 for monitoring and managementguidance.

3-step step-up dose schedule follicular lymphoma

In study GCT3013-01, CRS of any grade occurred in 49% (42/86) of patients treated with epcoritamab atthe recommended follicular lymphoma 3-step step-up dose schedule. The incidence of Grade 1 was 40%,

Grade 2 was 9%. There were no Grade ≥3 CRS events reported. Recurrent CRS occurred in 23% ofpatients. Most CRS events occurred during Cycle 1, where 48% of patients experienced an event. In

Cycle 1, CRS occurred in 12% of patients after the priming dose (Cycle 1 Day 1), 5.9% of patients after theintermediate dose (Cycle 1 Day 8), 15% of patients after the second intermediate dose (Cycle 1 Day 15),and 37% of patients after the first full dose (Cycle 1 Day 22). The median time to onset of CRS from themost recent administered epcoritamab dose was 59 hours (range: 1 to 8 days). The median time to onsetafter the first full dose was 61 hours (range: 1 to 8 days). CRS resolved in 100% of patients and the medianduration of CRS events was 2 days (range 1 to 14 days).

Serious adverse reactions due to CRS occurred in 28% of patients who received epcoritamab.

Dose delays due to CRS occurred in 19% of patients who received epcoritamab.

Of the 42 patients that experienced CRS at the recommended dose, the most common (≥10%) signs andsymptoms of CRS included pyrexia (100%) and hypotension (14%). In addition to corticosteroid use,tocilizumab was used to manage CRS event in 12% of patients.

Immune effector cell-associated neurotoxicity syndrome

In study GCT3013-01, ICANS occurred in 4.7% (18/382) of patients treated with epcoritamab; 3.1%experienced Grade 1 and 1.3% experienced Grade 2. One patient (0.3%) experienced an ICANS event of

Grade 5 (fatal). The median time to first ICANS onset from the start of epcoritamab treatment (Cycle 1

Day 1) was 18 days (range: 8 to 141 days). ICANS resolved in 94% (17/18) of patients with supportivecare. The median time to resolution of ICANS was 2 days (range: 1 to 9 days). In the 18 patients with

ICANS, the onset of ICANS was prior to CRS in 11% of patients, concurrent with CRS in 44%,following onset of CRS in 17%, and in the absence of CRS in 28%.

Large B-cell lymphoma

In study GCT3013-01, serious infections of any grade occurred in 25% (41/167) of patients with large B-cell lymphoma treated with epcoritamab. The most frequent serious infections included COVID-19(6.6%), COVID-19 pneumonia (4.2%), pneumonia (3.6%), sepsis (2.4%), upper respiratory tractinfection (1.8%), bacteraemia (1.2%), and septic shock (1.2%). The median time to onset of first seriousinfection from the start of epcoritamab treatment (Cycle 1 Day 1) was 56 days (range: 4 to 631 days),with median duration of 15 days (range: 4 to 125 days). Grade 5 events of infections occurred in 7(4.2%) patients.

In study GCT3013-01, serious infections of any grade occurred in 32% (68/215) of patients withfollicular lymphoma treated with epcoritamab. The most frequent serious infections included COVID-19(8.8%), COVID-19 pneumonia (5.6%), pneumonia (3.7%), urinary tract infection (1.9%), andpneumocystis jirovecii pneumonia (1.4%). The median time to onset of first serious infection from thestart of epcoritamab treatment (Cycle 1 Day 1) was 81 days (range: 1 to 636 days), with median durationof 18 days (range: 4 to 249 days). Grade 5 events of infection occurred in 8 (3.7%) patients, 6 (2.8%) ofwhich were attributed to COVID-19 or COVID-19 pneumonia.

In study GCT3013-01, neutropenia of any grade occurred in 28% (105/382) of patients, including 23%

Grade 3-4 events. The median time to onset of first neutropenia/neutrophil count decreased event was65 days (range: 2 to 750 days), with median duration of 15 days (range: 2 to 415 days). Of the 105patients who had neutropenia/neutrophil count decreased events, 61% received G-CSF to treat theevents.

In study GCT3013-01, TLS occurred in 1.0% (4/382) of patients. Median time to onset was 18 days(range 8 to 33 days), and median duration was 3 days (range 2 to 4 days).

In study GCT3013-01, tumour flare occurred in 1.6% (6/382) of patients, all of which were grade 2. Themedian time to onset was 19.5 days (range 9 to 34 days), and median duration was 9 days (range 1 to50 days).

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

In the event of overdose, monitor the patient for any signs or symptoms of adverse reactions andadminister appropriate supportive treatment.

Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents, ATC code: L01FX27

Epcoritamab is a humanised IgG1-bispecific antibody that binds to a specific extracellular epitope of

CD20 on B cells and to CD3 on T cells. The activity of epcoritamab is dependent upon simultaneousengagement of CD20-expressing cancer cells and CD3-expressing endogenous T cells by epcoritamabthat induces specific T-cell activation and T-cell-mediated killing of CD20-expressing cells.

Epcoritamab Fc region is silenced to prevent target-independent immune effector mechanisms, such asantibody-dependent cellular cytotoxicity (ADCC), complement-dependent cellular cytotoxicity (CDC),and antibody-dependent cellular phagocytosis (ADCP).

Epcoritamab induced rapid and sustained depletion of circulating B-cells (defined as CD19 B-cell counts≤ 10 cell/µl) in the subjects who have detectable B cells at treatment initiation. There were 21% subjects(n=33) with DLBCL and 50% subjects (n=56) with FL who had detectable circulating B-cells attreatment initiation. Transient reduction in circulating T cells was observed immediately after each dosein Cycle 1 and followed by T cell expansion in subsequent cycles.

In study GCT3013-01, following subcutaneous administration of epcoritamab at the recommended 2-stepstep-up dose schedule in patients with LBCL, transient and modest elevations of circulating levels ofselected cytokines (IFN-γ, TNFα, IL-6, IL-2, and IL-10) occurred mostly after the first full dose (48 mg),with peak levels between 1 to 4 days post dose. Cytokine levels returned to baseline prior to the next fulldose, however elevations of cytokines could also be observed after Cycle 1.

In study GCT3013-01, following subcutaneous administration of epcoritamab at the recommended 3-stepstep-up dose schedule in patients with FL, median IL-6 levels associated with CRS risk remainedconsistently low after each dose in Cycle 1 and beyond, particularly after the first full dose, compared topatients who received the 2-step step-up dose.

Anti-drug antibodies (ADA) were commonly detected. The incidence of treatment-emergent ADAs withthe 2-step step-up dose schedule (0.16/0.8/48 mg) in the combined population of DLBCL and FL was3.4% (3.4 % positive, 93.9% negative and 2.7% indeterminate, N=261 evaluable patients) and 3.3%(3.3% positive, 95% negative and 1.7% indeterminate, N= 60 evaluable patients), in studies GCT3013-01 and GCT3013-04, respectively.

The incidence of treatment-emergent ADAs with the 3-step step-up dose schedule (0.16/0.8/3/48 mg) inthe FL optimisation cohort was 7% (7% positive, 91.5% negative and 1.4% indeterminate, N=71evaluable patients) in study GCT3013-01. A subject is classified as indeterminate if the patient isconfirmed ADA positive at baseline but there is no confirmed positive on-treatment record or ifconfirmed ADA positive on treatment record titre are equal or lower than baseline.

No evidence of ADA impact on pharmacokinetics, efficacy or safety was observed, however, data arestill limited. Neutralising antibodies were not evaluated.

Diffuse large B-cell lymphoma

Study GCT3013-01 was an open-label, multi-cohort, multicentre, single-arm study that evaluatedepcoritamab as monotherapy in patients with relapsed or refractory large B-cell lymphoma (LBCL) aftertwo or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL). The studyincludes a dose escalation part and an expansion part. The expansion part of the study included anaggressive non-Hodgkin lymphoma (aNHL) cohort, an indolent NHL (iNHL) cohort and a mantle-celllymphoma (MCL) cohort. The pivotal aNHL cohort consisted of patients with LBCL (N=157), includingpatients with DLBCL (N=139, 12 patients of which had MYC, BCL2, and/or BCL6 rearrangements i.e.,

DH/TH), with high-grade B-cell lymphoma (HGBCL) (N=9), with follicular lymphoma grade 3B (FL)(N=5) and patients with primary mediastinal B-cell lymphoma (PMBCL) (N=4). In the DLBCL cohort,29% (40/139) of patients had transformed DLBCL arising from indolent lymphoma. Patients included inthe study were required to have documented CD20+ mature B-cell neoplasm according to WHOclassification 2016 or WHO classification 2008 based on representative pathology report, failed priorautologous hematopoietic stem cell transplantation (HSCT) or were ineligible for autologous HSCT,patients who had lymphocyte counts < 5×109/L, and patients with at least 1 prior anti-CD20 monoclonalantibody-containing therapy.

The study excluded patients with central nervous system (CNS) involvement of lymphoma, priortreatment with allogeneic HSCT or solid organ transplant, chronic ongoing infectious diseases, anypatients with known impaired T-cell immunity, a creatinine clearance of less than 45 ml/min, alanineaminotransferase > 3 times the upper limit of normal, cardiac ejection fraction less than 45%, and knownclinically significant cardiovascular disease. Efficacy was evaluated in 139 patients with DLBCL whohad received at least one dose of epcoritamab SC in cycles of 4 weeks, i.e., 28 days. Epcoritamabmonotherapy was administered at the recommended 2-step step-up dose schedule as follows:

* Cycle 1: epcoritamab 0.16 mg on Day 1, 0.8 mg on Day 8, 48 mg on Day 15 and Day 22

* Cycles 2-3: epcoritamab 48 mg on Days 1, 8, 15, and 22

* Cycles 4-9: epcoritamab 48 mg on Days 1 and 15

* Cycles 10 and beyond: epcoritamab 48 mg on Day 1

Patients continued to receive epcoritamab until disease progression or unacceptable toxicity.

The demographics and baseline characteristics are shown in Table 8.

Table 8 Demographics and baseline characteristics of patients with DLBCL in GCT3013-01 study

Characteristics (N=139)

Median, years (min, max) 66 (22, 83)< 65 years, n (%) 66 (47)65 to < 75 years, n (%) 44 (32)≥ 75 years, n (%) 29 (21)

Males, n (%) 85 (61)

Race, n (%)

White 84 (60)

Asian 27 (19)

Other 5 (4)

Not Reported 23 (17)

ECOG performance status; n (%)0 67 (48)1 67 (48)2 5 (4)

Disease stagec at initial diagnosis, n (%)

III 16 (12)

IV 86 (62)

Number of prior lines of anti-lymphoma therapy

Median (min, max) 3 (2, 11)2, n (%) 41 (30)3, n (%) 47 (34)≥ 4, n (%) 51 (37)

DLBCL Disease history; n (%)

De Novo DLBCL 97 (70)

DLBCL transformed from indolent lymphoma 40 (29)

FISH Analysis Per Central labd, N=88

Double-hit/Triple-hit lymphoma, n (%) 12 (14)

Prior autologous HSCT 26 (19)

Prior therapy; n (%)

Prior CAR-T 53 (38)

Primary refractory diseasea 82 (59)

Refractory to ≥ 2 consecutive lines of prior anti-lymphoma 104 (75)therapyb

Refractory to the last line of systemic antineoplastic therapyb 114 (82)

Refractory to prior anti-CD20 therapy 117 (84)

Refractory to CAR-T 39 (28)aA patient is considered to be primary refractory if the patient is refractory to frontlineanti-lymphoma therapy.bA patient is considered to be refractory if the patient either experiences diseaseprogression during therapy or disease progression within < 6 months after therapycompletion. A patient is considered relapsed if the patient had recurred disease≥ 6 months after therapy completion.

cPer Ann Arbor Staging.dPost hoc central lab FISH analysis was performed on available diagnosticbaseline tumour tissue sections from 88 DLBCL patients.

The primary efficacy endpoint was overall response rate (ORR) determined by Lugano criteria (2014) asassessed by Independent Review Committee (IRC). The median follow-up time was 15.7 months (range:

0.3 to 23.5 months). The median duration of exposure was 4.1 months (range: 0 to 23 months).

a

Table 9 Efficacy results in study GCT3013-01 in patients with DLBCL

Endpoint Epcoritamab

IRC assessment (N=139)

ORRb, n (%) 86 (62)(95% CI) (53.3, 70)

CRb, n (%) 54 (39)(95% CI) (30.7, 47.5)

PR, n (%) 32 (23)(95% CI) (16.3, 30.9)

DORb

Median (95% CI), months 15.5 (9.7, NR)

DOCRb

Median (95% CI), months NR (12.0, NR)

TTR, median (range), months 1.4 (1, 8.4)

CI = confidence interval; CR = complete response; DOR = duration ofresponse; DOCR = duration of complete response; IRC = independentreview committee; ORR = overall response rate; PR = partial response;

TTR = time to responseaDetermined by Lugano criteria (2014) as assessed by independent reviewcommittee (IRC)bIncluded patients with initial PD by Lugano or IR by LYRIC who laterobtained PR/CR.

The median time to CR was 2.6 months (range: 1.2 to 10.2 months).

Study GCT3013-01 was an open-label, multi-cohort, multicentre, single-arm trial that evaluatedepcoritamab as monotherapy in patients with relapsed or refractory follicular lymphoma (FL) after twoor more lines of systemic therapy. The study includes a dose escalation part, an expansion part and a3-step step-up dose optimisation part. The expansion part of the study included an aggressive non-

Hodgkin lymphoma (aNHL) cohort, an indolent NHL (iNHL) cohort and a mantle-cell lymphoma(MCL) cohort. The pivotal iNHL cohort, included patients with FL. Patients included in the study wererequired to have documented CD20+ mature B-cell neoplasm according to WHO classification 2016 or

WHO classification 2008 based on representative pathology report with histologic confirmed FL 1-3A atinitial diagnosis without clinical or pathological evidence of transformation. All patients had relapsed orrefractory disease to the last prior line therapy and previously treated with at least 2 lines of systemicantineoplastic therapy, including at least 1 anti-CD20 monoclonal antibody-containing therapy and analkylating agent or lenalidomide. The study excluded patients with CNS involvement of lymphoma,allogeneic HSCT or solid organ transplant, ongoing active infectious diseases, any patients with knownimpaired T-cell immunity, a creatinine clearance of less than 45 ml/min, alanine aminotransferase >3times the upper limit of normal and cardiac ejection fraction less than 45%. Efficacy was evaluated in128 patients who had received epcoritamab subcutaneously (SC) in cycles of 4 weeks, i.e., 28 days.

Epcoritamab was administered as a monotherapy in a 2-step step-up dose schedule as follows:

* Cycle 1: epcoritamab 0.16 mg on Day 1, 0.8 mg on Day 8, 48 mg on Day 15 and 48 mg on Day 22

* Cycles 2-3: epcoritamab 48 mg on Days 1, 8, 15, and 22

* Cycles 4-9: epcoritamab 48 mg on Days 1 and 15

* Cycles 10 and beyond: epcoritamab 48 mg on Day 1

Patients continued to receive epcoritamab until disease progression or unacceptable toxicity.

The median number of cycles initiated was 8 and 60% received 6 cycles.

The demographics and baseline characteristics are shown in Table 10.

Table 10 Demographics and baseline characteristics of patients with FL in GCT3013-01 study(N = 128)

Characteristics

Median, years (min, max) 65 (39, 84)< 65 years, n (%) 61 (48)65 to < 75 years, n (%) 50 (39)≥ 75 years, n (%) 17 (13)

Males, (%) 79 (62)

Race, n (%)

White 77 (60)

Asian 7 (6)

Other 2 (1.6)

Not Reported 42 (33)

ECOG performance status; n (%)0 70 (55)1 51 (40)2 7 (6)

Number of prior lines of therapies, n (%)

Median (min, max) 3 (2, 9)2 47 (37)3 41 (32)≥4 40 (31)

Ann Arbor Staging; (%)

Stage III/IV 109 (85)

FLIPI at baseline, n (%)2 31 (24)3- 5 78 (61)

Bulky Disease, n (%) 33 (26)

Prior Therapy; n (%)

Autologous stem cell transplant 24 (19)

Chimeric antigen receptor (CAR)-T cell therapy 6 (5)

Rituximab plus lenalidomide therapy 27 (21)

PI3K inhibitor 29 (23)

Progression of disease within 24 months of first systemic 67 (52)therapy

Refractory to:

≥ 2 consecutive lines of prior anti-lymphoma therapy 70 (55)

The last line of systemic antineoplastic therapy 88 (69)

Prior anti-CD20 monoclonal antibody therapy 101 (79)

Both anti-CD20 monoclonal antibody and alkylator 90 (70)therapy(N = 128)

Characteristics

Efficacy was established based on overall response rate (ORR) determined by Lugano criteria (2014) asassessed by Independent Review Committee (IRC). The median follow-up for DOR was 16.2 months.

Efficacy results are summarised in Table 11.

Table 11 Efficacy Results in Study GCT3013-01 in FL Patients

Endpoint a Epcoritamab

IRC assessment (N=128)

ORRb , n (%) 106 (83)(95% CI) (75.1, 88.9)

CRb, n (%) 81 (63)(95% CI) (54.3, 71.6)

PRb, n (%) 25 (20)(95% CI) (13.1, 27.5)

DORb

Median (95% CI), months 21.4 (13.7, NR)

DOCRb

Median (95% CI), months NR (21.4, NR)12-month estimate, % (95% CI) 78.6 (67.3 ,86.4 )

TTR, median (range), months 1.4 (1, 3)

CI = confidence interval; CR = complete response; DOR = duration of response;

DOCR = duration of complete response; IRC = independent review committee;

ORR = overall response rate; PFS = progression-free survival; TTR = time toresponsea determined by Lugano criteria (2014) as assessed by independent reviewcommittee (IRC)bIncluded patients with initial PD by Lugano or IR by LYRIC who later obtained

PR/CR.

The median time to CR was 1.5 months (range: 1.2 to 11.1 months).

The European Medicines Agency has deferred the obligation to submit the results of studies withepcoritamab in one or more subsets of the paediatric population in the treatment of mature B-cellmalignancies, as per paediatric investigation plan (PIP) decision, for the granted indication (see section4.2 for information on paediatric use).

This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. This meansthat further evidence on this medicinal product is awaited. The European Medicines Agency will reviewnew information on this medicinal product at least every year and this SmPC will be updated asnecessary.

The population pharmacokinetics following subcutaneous administration of epcoritamab was describedby a two-compartment model with first order subcutaneous absorption and target-mediated drugelimination. The moderate to high pharmacokinetic variability for epcoritamab was observed andcharacterised by inter-individual variability (IIV) ranging from 25.7% to 137.5% coefficient of variation(CV) for epcoritamab PK parameters.

In patients with LBCL in study GCT3013-01, based on individually estimated exposures usingpopulation pharmacokinetic modelling, following the recommended 2-step step-up dose schedule SCdose of epcoritamab 48 mg, the geometric mean (% CV) Cmax of epcoritamab is 10.8 mcg/ml (41.7%)and AUC0-7d is 68.9 day*mcg/ml (45.1%) at the end of the weekly dosing schedule. The Ctrough at Week12 is 8.4 (53.3%) mcg/ml. The geometric mean (% CV) Cmax of epcoritamab is 7.52 mcg/ml (41.1%) and

AUC0-14d is 82.6 day*mcg/ml (49.3%) at the end of q2w schedule. The Ctrough for q2W schedule is4.1 (73.9%) mcg/ml. The geometric mean (% CV) Cmax of epcoritamab is 4.76 mcg/ml (51.6%) and

AUC0-28d is 74.3 day*mcg/ml (69.5%) at steady state during the q4w schedule. The Ctrough for q4Wschedule is 1.2 (130%) mcg/ml.

Exposure parameters of epcoritamab in patients with FL were consistent with the exposure parametersseen in the patients with LBCL. Epcoritamab exposures are similar between FL subjects who receivedthe 3-step step-up dose schedule and 2-step step-up dose schedule except for transiently lower troughconcentrations, as expected, at Cycle 1 Day 15 after the second intermediate dose (3 mg) with 3-stepstep-up dose schedule compared first full 48 mg dose with 2-step step-up dose schedule.

The peak concentrations occurred around 3-4 days (Tmax) in patients with LBCL receiving the 48 mg fulldose.

The geometric mean (% CV) central volume of distribution is 8.27 l (27.5%) and apparent steady-statevolume of distribution is 25.6 l (81.8%) based on population PK modelling.

The metabolic pathway of epcoritamab has not been directly studied. Like other protein therapeutics,epcoritamab is expected to be degraded into small peptides and amino acids via catabolic pathways.

Epcoritamab is expected to undergo saturable target mediated clearance. The geometric mean (% CV)clearance (l/day) is 0.441 (27.8%). The half-life of epcoritamab is concentration dependent. Thepopulation PK model-derived geometric mean half-life of full dose epcoritamab (48 mg) ranged from 22to 25 days based on frequency of dosing.

No clinically important effects on the pharmacokinetics of epcoritamab (Cycle 1 AUC withinapproximately 36%) were observed based on age (20 to 89 years), sex, or race/ethnicity (white, Asian,and other), mild to moderate renal impairment creatinine clearance (CLcr ≥ 30 ml/min to CLcr< 90 ml/min), and mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin 1to 1.5 times ULN and any AST) after accounting for differences in bodyweight. No patients with severeto end-stage renal disease (CLcr < 30 ml/min) or severe hepatic impairment (total bilirubin > 3 times

ULN and any AST) have been studied. There is very limited data in moderate hepatic impairment (totalbilirubin > 1.5 to 3 times ULN and any AST, N=1). Therefore, the pharmacokinetics of epcoritamab isunknown in these populations.

Like other therapeutic proteins, body weight (39 to 172 kg) has a statistically significant effect on thepharmacokinetics of epcoritamab. Based on exposure-response analysis and clinical data, considering theexposures in patients at either low body weight (e.g., 46 kg) or high body weight (e.g., 105 kg) andacross body weight categories (< 65 kg, 65-< 85, ≥ 85), the effect on exposures is not clinically relevant.

The pharmacokinetics of epcoritamab in paediatric patients has not been established.

Animal pharmacology and/or toxicology

No reproductive or developmental toxicity studies in animals have been conducted with epcoritamab.

Effects generally consistent with the pharmacologic mechanism of action of epcoritamab were observedin cynomolgus monkeys. These findings included dose-related adverse clinical signs (includingvomiting, decreased activity, and mortality at high doses) and cytokine release, reversible hematologicalterations, reversible B-cell depletion in peripheral blood, and reversible decreased lymphoid cellularityin secondary lymphoid tissues.

Mutagenicity studies have not been conducted with epcoritamab.

Carcinogenicity studies have not been conducted with epcoritamab.

Animal fertility studies have not been conducted with epcoritamab, however, epcoritamab did not causetoxicological changes in the reproductive organs of male or female cynomolgus monkeys at doses up to1 mg/kg/week in intravenous general toxicity study of 5-week duration. The AUC exposures (time-averaged over 7 days) at the high dose in cynomolgus monkeys were similar to those in patients (AUC0-7d) receiving the recommended dose.

Sodium acetate trihydrate

Acetic acid

Sorbitol (E420)

Polysorbate 80

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts and/or diluents except those listed in section 6.6.

Unopened vial2 years.

Prepared epcoritamab

Chemical and physical in-use stability has been demonstrated for 24 hours at 2 °C to 8 °C including up to12 hours at room temperature (20-25 °C).

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

Minimise exposure to daylight. Allow epcoritamab solution to equilibrate to room temperature beforeadministration. Discard unused epcoritamab solution beyond the allowable storage time.

Store and transport refrigerated (2 °C to 8 °C).

Do not freeze.

Keep the vial in the outer carton in order to protect from light.

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

Type I glass vial with a bromobutyl rubber stopper coated with fluoropolymer at the contact site andaluminium seal with a plastic orange flip off cap, containing 48 mg per 0.8 ml solution for injection.

Each carton contains one vial.

Epcoritamab must be prepared and administered by a healthcare provider as a subcutaneous injection.

Each vial of epcoritamab is intended for single use only.

Each vial contains an overfill that allows withdrawal of the labelled amount.

The administration of epcoritamab takes place over the course of 28-day cycles, following the dosingschedule in section 4.2.

Epcoritamab should be inspected visually for particulate matter and discolouration prior toadministration. The solution for injection should be a colourless to slightly yellow solution. Do not use ifthe solution is discoloured, or cloudy, or if foreign particles are present.

48 mg full dose preparation instructions - No dilution required

Tepkinly 48 mg vial is supplied as ready-to-use solution that does not need dilution prior toadministration.

Epcoritamab has to be prepared using aseptic technique. Filtration of the solution is not required.

1) Prepare epcoritamab viala) Retrieve one 48 mg epcoritamab vial with the orange cap from the refrigerator.

b) Allow the vial to come to room temperature for no more than 1 hour.

c) Gently swirl the epcoritamab vial.

DO NOT vortex or vigorously shake the vial.

2) Withdraw dose

Withdraw 0.8 ml of epcoritamab into a syringe.

3) Label syringe

Label the syringe with the product name, dose strength (48 mg), date and the time of day. For storage of theprepared epcoritamab, see section 6.3.

4) Discard the vial and any unused portion of epcoritamab in accordance with local requirements.

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

AbbVie Deutschland GmbH & Co. KG

Knollstrasse67061 Ludwigshafen

Germany

EU/1/23/1759/002

Date of first authorisation: 22 September 2023

Date of latest renewal: 17 July 2024

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

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