TEPKINLY Concentrate for solution for injection Ref.[51282] Active ingredients: Epcoritamab

Traceability

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

Cytokine release syndrome (CRS)

CRS, which may be life-threatening or fatal, occurred in patients receiving epcoritamab. The most common signs and symptoms of CRS include pyrexia, hypotension and hypoxia. Other signs and symptoms 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 tocilizumab and/or corticosteroids as appropriate (see section 4.2, Table 4). Patients should be counselled on the signs and symptoms associated with CRS and patients should be instructed to contact their healthcare professional 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 the severity of CRS (see section 4.2).

Patients with DLBCL should be hospitalised for 24 hours after administration of the Cycle 1 Day 15 dose 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 manifest as aphasia, altered level of consciousness, impairment of cognitive skills, motor weakness, seizures, and cerebral oedema.

The majority of cases of ICANS occurred within Cycle 1 of epcoritamab treatment, however some occurred 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-seizure medicinal products should be instituted as appropriate (see section 4.2, Table 5). Patients should be counselled on the signs and symptoms of ICANS and that the onset of events may be delayed. Patients should be instructed to contact their healthcare professional and seek immediate medical attention should signs 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 15 dose of 48 mg to monitor for signs and symptoms of ICANS.

Serious infections

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

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

As appropriate, prophylactic antimicrobials should be administered prior to and during treatment with epcoritamab (see section 4.2). Patients should be monitored for signs and symptoms of infection, before and 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.

Tumour lysis syndrome (TLS)

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

Tumour flare

Tumour flare has been reported in patients treated with epcoritamab (see section 4.8). Manifestations could 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 a heightened risk of compromise and morbidity due to mass effect secondary to tumour flare in patients with bulky tumours located in close proximity to airways and/or a vital organ. Patients treated with epcoritamab 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 and patients with CD20-negative FL may have less benefit compared to patients with CD20-positive DLBCL and patients with CD20-positive FL, respectively. The potential risks and benefits associated with treatment of patients with CD20-negative DLBCL and FL with epcoritamab should be considered.

Patient card

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

Immunisation

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

Excipients with known effect

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. Polysorbate 80 may cause allergic reactions.

No interaction studies have been performed.

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

Women of childbearing potential / Contraception in females

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

Pregnancy

Based on its mechanism of action, epcoritamab may cause foetal harm, including B-cell lymphocytopenia 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 not been conducted with epcoritamab. IgG1 antibodies, such as epcoritamab, can cross the placenta resulting in 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 using contraception.

Breast-feeding

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 lactational transfer. Breast-feeding should be discontinued during treatment with epcoritamab and for at least 4 months after the last dose.

Fertility

No fertility studies have been conducted with epcoritamab (see section 5.3). The effect of epcoritamab on male 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, cycling or using heavy or potentially dangerous machines.

Summary of the safety profile

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

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 adverse reaction (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 of epcoritamab 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 dose delays (≥3%) were viral infections (17%), CRS (11%), neutropenia (5.2%), pneumonia (4.7%), upper respiratory tract infection (4.2%), and pyrexia (3.7%).

Tabulated list of adverse reactions

Adverse reactions for epcoritamab from clinical studies (Table 7) are listed by MedDRA system organ class 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 treated with epcoritamab in GCT3013-01 study:

Adverse reactions were graded using NCI CTCAE version 5.0
^a Viral 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 infection
^b Pneumonia includes COVID-19 pneumonia and pneumonia
^c Upper respiratory tract infection includes laryngitis, pharyngitis, respiratory syncytial virus infection, rhinitis, rhinovirus infection, and upper respiratory tract infection
^d Fungal infection includes candida infection, oesophageal candidiasis, oral candidiasis and oropharyngeal candidiasis
^e Sepsis includes bacteraemia, sepsis, and septic shock
^f Neutropenia includes neutropenia and neutrophil count decreased
^g Anaemia includes anaemia and serum ferritin decreased
^h Thrombocytopenia includes platelet count decreased and thrombocytopenia
ⁱ Lymphopenia includes lymphocyte count decreased and lymphopenia
^j Events graded using American Society for Transplantation and Cellular Therapy (ASTCT) consensus criteria
^k Clinical Tumour Lysis Syndrome was graded based on Cairo-Bishop
^l Cardiac arrhythmias include bradycardia, sinus bradycardia, sinus tachycardia, supraventricular tachycardia, and tachycardia
^m Abdominal pain includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, and abdominal tenderness
ⁿ Rash includes rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular, and rash vesicular
° Musculoskeletal 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 pain pInjection 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 site pain, injection site pruritus, injection site rash, injection site reaction, injection site swelling, and injection site urticaria.
^q Fatigue includes asthenia, fatigue, and lethargy
^r Pyrexia includes body temperature increased and pyrexia
^s Oedema includes face oedema, generalised oedema, oedema, oedema peripheral, peripheral swelling, swelling, and swelling face
^t Blood sodium decreased includes blood sodium decreased and hyponatraemia

Description of selected adverse reactions

Cytokine release syndrome

2-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-cell lymphoma and follicular lymphoma treated with epcoritamab at the 2-step step-up dose schedule. The incidence 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 dose was 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 included pyrexia 99%, hypotension 32% and hypoxia 16%. Other signs and symptoms of CRS in ≥3% of patients included 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 concurrent with CRS in 4.1% of patients with CRS. See section 4.2 and 4.4 for monitoring and management guidance.

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 at the 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% of patients. 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 the intermediate 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 the most recent administered epcoritamab dose was 59 hours (range: 1 to 8 days). The median time to onset after the first full dose was 61 hours (range: 1 to 8 days). CRS resolved in 100% of patients and the median duration 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 and symptoms 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 supportive care. 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%.

Serious infections

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 tract infection (1.8%), bacteraemia (1.2%), and septic shock (1.2%). The median time to onset of first serious infection 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.

Follicular lymphoma

In study GCT3013-01, serious infections of any grade occurred in 32% (68/215) of patients with follicular 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%), and Pneumocystis jirovecii pneumonia (1.4%). The median time to onset of first serious infection from the start of epcoritamab treatment (Cycle 1 Day 1) was 81 days (range: 1 to 636 days), with median duration of 18 days (range: 4 to 249 days). Grade 5 events of infection occurred in 8 (3.7%) patients, 6 (2.8%) of which were attributed to COVID-19 or COVID-19 pneumonia.

Neutropenia

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 was 65 days (range: 2 to 750 days), with median duration of 15 days (range: 2 to 415 days). Of the 105 patients who had neutropenia/neutrophil count decreased events, 61% received G-CSF to treat the events.

Tumour lysis syndrome

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).

Tumour flare

In study GCT3013-01, tumour flare occurred in 1.6% (6/382) of patients, all of which were grade 2. The median time to onset was 19.5 days (range 9 to 34 days), and median duration was 9 days (range 1 to 50 days).

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 listed in Appendix V.

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