Tepkinly 48 mg solution for injection
Summary of Product Characteristics Updated 28-Oct-2024 | AbbVie Ltd
This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.
1. Name of the medicinal product
Tepkinly 48 mg solution for injection
2. Qualitative and quantitative composition
Each 0.8 ml single use vial contains 48 mg of epcoritamab at a concentration of 60 mg/ml.
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.
Excipient with known effect
Each vial of Tepkinly contains 21.9 mg of sorbitol. For the full list of excipients, see section 6.1.
3. Pharmaceutical form
Solution for injection (injection)
Colourless to slightly yellow solution, pH 5.5 and osmolarity of approximately 211 mOsm/kg.
4. Clinical particulars
4.1 Therapeutic indications
Tepkinly (epcoritamab), as monotherapy, is indicated for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after two or more lines of systemic therapy.
4.2 Posology and method of administration
Tepkinly must only be administered under the supervisions of a healthcare professional qualified in the use of anti-cancer therapies with access to appropriate medical support to manage severe reactions such as cytokine release syndrome (CRS) (see section 4.4).
Posology
Recommended pre-medication and dose schedule
Details on recommended premedication for cytokine release syndrome (CRS) are shown in Table 1.
Table 1 - Epcoritamab premedication and CRS prophylaxis
| Cycle | Patient requiring premedication | Premedication | Corticosteroid prophylaxis |
| Cycle 1 | All patients | 30-120 minutes prior to each weekly administration of epcoritamab • Prednisolone (100 mg oral or IV) or dexamethasone (15 mg oral or intravenous) or equivalent • Diphenhydramine (50 mg oral or IV) or equivalent • Paracetamol (1000 mg oral) | Prednisolone (100 mg oral or IV) or equivalent for three consecutive days following each weekly administration of epcoritamab in Cycle 1 |
| Cycle 2 and beyond | Patients who experienced Grade 2 or 3a CRS with previous dose | 30-120 minutes prior to next administration of epcoritamab after a grade 2 or 3a CRS event • Prednisolone (100 mg oral or IV) or • Dexamethasone (15 mg oral or intravenous) or equivalent | Prednisolone (100 mg oral or IV) or equivalent for three consecutive days following the next administration of epcoritamab until epcoritamab is given without subsequent CRS of Grade 2 or higher |
| a Patients will be permanently discontinued from epcoritamab after a Grade 4 CRS event. | |||
Administer Tepkinly according to the dosing schedule in 28-day cycles outlined in Table 2.
Tepkinly is for subcutaneous (SC) injection only.
Table 2 - Dosing schedule
| Dosing schedule | Cycle of treatment | Days | Epcoritamab dose (mg)a |
| Weekly | Cycle 1 | 1 | 0.16 mg (Priming dose) |
| 8 | 0.8 mg (Intermediate dose) | ||
| 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 mg |
| a0.16 mg is a priming dose, 0.8 mg is an intermediate dose and 48 mg is a full dose. | |||
Tepkinly should be administered until disease progression or unacceptable toxicity. Atypical responses (i.e. an initial transient increase in tumour size or small new lesions within the first few months followed by tumour shrinkage) have been observed. It is recommended to continue treatment for clinically stable patients with initial evidence of disease progression until disease progression is confirmed.
Tepkinly should be administered to well hydrated patients.
Prophylaxis against Pneumocystis jirovecii pneumonia (PCP) and herpes virus infections is strongly recommended especially during concurrent use of steroids.
Patients at an increased risk for clinical tumour lysis syndrome (CTLS) are recommended to receive hydration and prophylactic treatment with a uric acid lowering agent.
Monitor patients for potential CRS and/or immune effector cell-associated neurotoxicity syndrome (ICANS) following epcoritamab administration (see section 4.4).
Missed or delayed dose
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 treatment cycle (subsequent to the cycle during which the dose was delayed).
Dosage modifications and management of adverse reactions
Cytokine release syndrome (CRS)
Patients treated with epcoritamab may develop CRS.
Evaluate for and treat other causes of fever, hypoxia, and hypotension. If CRS is suspected, manage according to the recommendations in Table 3. Patients who experience CRS should be monitored more frequently during next scheduled epcoritamab administration.
Table 3 - CRS grading and management guidance
| Grade1 | Recommended therapy | Epcoritamab dose modification |
| Grade 1 • Fever (temperature ≥ 38° C) without hypotension or hypoxia | Provide supportive care such as antipyretics and intravenous hydration. Anticytokine therapy: Consider anti-cytokine therapy in certain cases, e.g., advanced age, high tumour burden, circulating tumour cells, fever refractory to antipyretics. Tocilizumab 8 mg/kg IV over 1 hour (not to exceed 800 mg per dose). Repeat tocilizumab after at least 8 hours as needed. Maximum of 2 doses in a 24-hour period. In case of concurrent ICANS choose alternative to tocilizumab. See Table 4. Corticosteroids In case of concurrent ICANS, initiation of corticosteroids is highly recommended. Consider dexamethasone 10-20 mg per day (or equivalent). | Hold epcoritamab until resolution of CRS event. |
| Grade 2a • Fever (temperature ≥ 38° C) AND/OR • Hypotension not requiring vasopressors. AND/OR • Hypoxia requiring low-flow (≤ 6 l/minute) nasal cannula or blow-by | Provide supportive care such as antipyretics and intravenous hydration Anticytokine therapy: Tocilizumab 8 mg/kg IV over 1 hour (not to exceed 800 mg per dose). Repeat tocilizumab after at least 8 hours as needed. Maximum of 2 doses in a 24-hour period. If CRS is refractory to initial anti-cytokine therapy, initiate/increase dose of corticosteroid therapy and consider alternative anti-cytokine therapy. In case of concurrent ICANS choose alternative to tocilizumab. See Table 4. Corticosteroids: In case of concurrent ICANS, initiation of corticosteroids is highly recommended. Consider dexamethasone 10-20 mg per day (or equivalent). | Hold epcoritamab until resolution of CRS event. |
| Grade 3a • Fever (temperature ≥ 38° C) AND/OR • Hypotension requiring 1 vasopressor with or without vasopressin. AND/OR • Hypoxia requiring high-flow (>6 l/minute) nasal cannula, facemask, non-rebreather mask, or venturi mask | Provide supportive care such as antipyretics and intravenous hydration Anticytokine therapy Tocilizumab 8 mg/kg IV over 1 hour (not to exceed 800 mg per dose). Repeat tocilizumab after at least 8 hours as needed. Maximum of 2 doses in a 24-hour period. If CRS is refractory to initial anti-cytokine therapy, initiate/increase dose of corticosteroid therapy and consider alternative anti-cytokine therapy. In case of concurrent ICANS choose alternative to tocilizumab. See Table 4. Corticosteroids: Dexamethasone (e.g., 10-20 mg IV every 6 hours). If no response, initiate methylprednisolone 1000 mg/day. | Hold epcoritamab until resolution of CRS event. In the event of Grade 3 CRS lasting longer than 72 hours, epcoritamab should be discontinued
If more than 2 separate events of Grade 3 CRS, even if each event resolved to Grade 2 within 72 hours, epcoritamab should be discontinued. |
| Grade 4 • Fever (temperature ≥ 38° C) AND/OR Hypotension requiring ≥ 2 vasopressors (excluding vasopressin) AND/OR • Hypoxia requiring positive pressure ventilation (e.g., CPAP, BiPAP, intubation and mechanical ventilation) | Provide supportive care such as antipyretics and intravenous hydration Anticytokine therapy Tocilizumab 8 mg/kg IV over 1 hour (not to exceed 800 mg per dose). Repeat tocilizumab after at least 8 hours as needed. Maximum of 2 doses in a 24-hour period. If CRS is refractory to initial anti-cytokine therapy, initiate/increase dose of corticosteroid therapy and consider alternative anti-cytokine therapy. In case of concurrent ICANS choose alternative to tocilizumab. See Table 4. Corticosteroids Dexamethasone (e.g., 10-20 mg IV every 6 hours). If no response, initiate methylprednisolone 1000 mg/day. | Permanently discontinue epcoritamab |
| 1 CRS graded according to ASTCT (American Society for Transplant and Cellular Therapy) consensus criteria (Lee et al., 2019) a If Grade 2 or 3 CRS occurs with the second full dose or beyond, administer CRS prophylaxis with each subsequent dose until epcoritamab dose is given without subsequent CRS (of any grade). | ||
Immune effector cell associated neurotoxicity syndrome (ICANS)
Monitor patients for signs and symptoms of ICANS. Rule out other causes of neurologic symptoms. If ICANS is suspected, manage according to the recommendations in Table 4.
Table 4 - ICANS grading and management guidance
| Grade1 | Recommended therapy | Epcoritamab dose modification |
| Grade 1b ICE score c 7-9 b or, depressed level of consciousnessb: awakens spontaneously. | Dexamethasone, 10 mg IV every 12 hours Consider non-sedating anti-seizure medication (e.g., levetiracetam) until resolution of ICANS No concurrent CRS: • Anti-cytokine therapy not recommended For ICANS with concurrent CRS: • Treatment with dexamethasoned • Choose immunosuppressant alternativese to tocilizumab, if possible | Hold epcoritamab until resolution of event. |
| Grade 2b ICE scorec 3-6 or, depressed level of consciousnessb: awakens to voice. | Dexamethasone at 10-20 mg IV every 12 hours Consider non-sedating anti-seizure medication (e.g., levetiracetam) until resolution of ICANS. No concurrent CRS: • Anti-cytokine therapy not recommended For ICANS with concurrent CRS: • Treatment with dexamethasoned • Choose immunosuppressant alternativese to tocilizumab, if possible | Hold epcoritamab until resolution of event. |
| Grade 3b ICE scorec 0-2 or, depressed level of consciousnessb: awakens only to tactile stimulus, or seizuresb, either: • any clinical seizure, focal or generalized that resolves rapidly, or • non-convulsive seizures on electroencephalogram (EEG) that resolve with intervention, or raised intracranial pressure: focal/local oedemab on neuroimagingc. | Dexamethasone 10-20 mg IV every 6 hours. • If no response, initiate methylprednisolone 1000 mg/day. Consider non-sedating anti-seizure medication (e.g., levetiracetam) until resolution of ICANS. No concurrent CRS: • Anti-cytokine therapy not recommended For ICANS with concurrent CRS: • Treatment with dexamethasone o If no response, initiate methylprednisolone 1000 mg/day • Choose immunosuppressant alternativese to tocilizumab, if possible | First episode: delay epcoritamab until full resolution of event. Second episode: permanently discontinue epcoritamab. |
| Grade 4b ICE scorec, b 0 Or, depressed level of consciousnessb either: • patient is unarousable or requires vigorous or repetitive tactile stimuli to arouse, or • stupor or coma, or seizuresb, either: • life-threatening prolonged seizure (>5 minutes), or • repetitive clinical or electrical seizures without return to baseline in between, or motor findingsb: • deep focal motor weakness such as hemiparesis or paraparesis, or raised intracranial pressure / cerebral oedemab, with signs/symptoms such as: • diffuse cerebral oedema on neuroimaging, or • decerebrate or decorticate posturing, or • cranial nerve VI palsy, or • papilloedema, or • cushing's triad | Dexamethasone 10-20 mg IV every 6 hours. • If no response, initiate methylprednisolone 1000 mg/day. Consider non-sedating anti-seizure medication (e.g., levetiracetam) until resolution of ICANS. No concurrent CRS: • Anti-cytokine therapy not recommended For ICANS with concurrent CRS: • Treatment with dexamethasone o If no response, initiate methylprednisolone 1000 mg/day • Choose immunosuppressant alternativese to tocilizumab, if possible | Permanently discontinue epcoritamab. |
| a ICANS graded according to ASTCT ICANS Consensus Grading (Lee et al., 2019) bICANS grade is determined by the most severe event (ICE score, level of consciousness, seizures, motor findings, raised ICP/cerebral edema) not attributable to any other cause c If 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 to clock, pen, button = 3 points); Following Commands (e.g., “ show me 2 fingers” or “ close your eyes and stick out your tongue” = 1 point); Writing (ability to write a standard sentence = 1 point; and Attention (count backwards from 100 by ten = 1 point). If patient is unarousable and unable to perform ICE Assessment (Grade 4 ICANS) = 0 points. d Dexamethasone should be administered at 10 mg intravenously every 12 hours e Riegler L et al. (2019) | ||
Table 5: Recommended Dosage Modifications for Other Adverse Reactions
| Adverse Reaction1 | Severity1 | Action |
| Infections (see section 4.4) | Grades 1-4 | Withhold epcoritamab in patients with active infection, until the infection resolves |
| Febrile neutropenia | Absolute neutrophil count less than 0.5 x 109/L | Withhold epcoritamab until absolute neutrophil count is 0.5 x 109/L or higher |
| Thrombocytopenia (see section 4.8) | Platelet count less than 50 x 109/L | Withhold epcoritamab until platelet count is 50 x 109/L or higher |
| Other Adverse Reactions (see section 4.8) | Grade 3 or higher | Withhold epcoritamab until the toxicity resolves to Grade 1 or baseline |
| 1 Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.0. | ||
Special populations
Renal impairment
No formal studies of Tepkinly in patients with renal impairment have been conducted. Based on population pharmacokinetic (PK) analyses, no dosage adjustment is necessary for patients with mild or moderate renal impairment. No data are available in patients with severe renal impairment (see section 5.2).
Hepatic impairment
No formal studies of Tepkinly in patients with hepatic impairment have been conducted. Based on population pharmacokinetic (PK) analyses, no dosage adjustment is necessary for patients with mild hepatic impairment. Data are limited in patients with moderate hepatic impairment and no data are available in patients with severe hepatic impairment (see section 5.2).
Paediatric population
The safety and efficacy of Tepkinly in children aged less than 18 years of age have not yet been established. No data are available.
Elderly
No dose adjustment is necessary in patients ≥ 65 years.
Method of administration
Tepkinly should be administered by subcutaneous injection, preferably in the lower part of abdomen or the thigh. Change of injection site from left to right side or vice versa is recommended 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.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
4.4 Special warnings and precautions for use
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)
Cytokine release syndrome, which may be life-threatening or fatal, occurred in patients receiving epcoritamab (see section 4.8). The most common signs and symptoms of CRS include pyrexia, hypotension and hypoxia. Other signs and symptoms of CRS 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. Patients 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. At the first signs or symptoms of CRS, institute treatment of supportive care with tocilizumab and/or corticosteroids as appropriate (see section 4.2, Table 3). Counsel patients on the signs and symptoms associated with CRS and instruct patients 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).
Immune effector cell-associated neurotoxicity syndrome (ICANS)
ICANS, including a fatal event, have occurred in patients receiving epcoritamab (see section 4.8). 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 the Cycle 1 of epcoritamab treatment, however some occurred with delayed onset.
Patients should be monitored for signs and symptoms of ICANS following epcoritamab administration. Patients 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. At the first signs or symptoms of ICANS institute treatment with corticosteroids and non-sedating-anti-seizure medications as appropriate (see section 4.2). Counsel patients on the signs and symptoms of ICANS and that the onset of events may be delayed. Instruct patients to contact their healthcare professional and seek immediate medical attention should signs or symptoms occur at any time. Delay or discontinue epcoritamab as recommended (see section 4.2).
Serious infections
Serious or fatal infections were observed in patients treated with epcoritamab in clinical studies (see section 4.8).
Epcoritamab must not be administered in patients with active infections. As appropriate, administer prophylactic antimicrobials prior to and during treatment with epcoritamab (see section 4.2). Caution should be exercised when considering the use of epcoritamab in patients with a history of recurring or chronic infections, with underlying conditions that may predispose to infections or who have had significant prior immunosuppressive treatment. Patients should be monitored for signs and symptoms of infection before and after epcoritamab, 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.
Immunisation
Live and/or live-attenuated vaccines should not be given during treatment with epcoritamab. 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.
4.5 Interaction with other medicinal products and other forms of interaction
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 (see section 5.2).
4.6 Fertility, pregnancy and lactation
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.
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.
Verify pregnancy status in females of reproductive potential prior to initiating epcoritamab treatment.
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.
4.7 Effects on ability to drive and use machines
Epcoritamab has minor influence on the ability to drive and use machines. Due to the potential for neurological events, such as ICANS, patients who experience neurological signs and symptoms should be advised not to drive, cycle or use tools or potentially dangerous machines until symptoms resolve.
4.8 Undesirable effects
Summary of the safety profile
The safety of epcoritamab was evaluated in a non-randomised, single-arm study in 167 patients with relapsed or refractory LBCL 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 3.7 months (range: 0 to 25 months).
The most common adverse reactions (≥ 20%) were CRS (50.9%), fatigue (30.5%), neutropenia (30.5%), injection site reactions (29.9%), pyrexia (23.4%), abdominal pain (23.4%), nausea (21.6%), and diarrhoea (21.0%). The most common Grade 3-4 adverse reactions (≥ 2%) were neutropenia (23.4%), anaemia (10.2%), thrombocytopenia (7.2%), pneumonia (6.0%), fatigue (3.0%), CRS (3.0%), febrile neutropenia (2.4%), oedema (2.4%) and hypophosphataemia (2.4%).
Serious adverse reactions occurred in 43.7% of patients. The most common serious adverse reactions (≥ 2%) were CRS (31.1%), pneumonia (7.2%), upper respiratory tract infections (2.4%), febrile neutropenia (2.4%), ICANS (2.4%), and pyrexia (2.4%). Four patients (2.4%) experienced a fatal adverse reaction (ICANS in 1 (0.6%) patient and pneumonia in 3 (1.8%) patients).
Adverse reactions that led to discontinuation occurred in 4.8% of patients. Discontinuation of epcoritamab due to pneumonia occurred in 6 (3.6%) patients and CRS, ICANS or fatigue occurred in 1 (0.6%) patient each.
Dose delays due to adverse reactions occurred in 23.4% of patients. Adverse reactions leading to dose delays (≥ 3% of patients) were CRS (7.2%), neutropenia (4.8%), pyrexia (3.0%), and thrombocytopenia (3.0%).
Tabulated list of adverse reactions
Adverse reactions for epcoritamab from clinical studies (Table 6) 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).
Table 6 Adverse reactions reported in patients with relapsed or refractory LBCL treated with epcoritamab in EPCORE NHL-1 study
| System organ class / preferred term or adverse reaction | All grades | Grade 3-4 |
| Infections and infestations | ||
| Pneumoniaa | Very common | Common |
| Upper respiratory tract infectionb | Common | Common |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||
| Tumour flare | Common | |
| Blood and lymphatic system disorders | ||
| Neutropeniac | Very common | Very common |
| Anaemiad | Very common | Very common |
| Thrombocytopeniae | Very common | Common |
| Febrile neutropenia | Common | Common |
| Immune system disorders | ||
| Cytokine release syndromef | Very common | Common |
| Metabolism and nutrition disorders | ||
| Hypophosphatemia | Common | Common |
| Hypokalemia | Common | Uncommon |
| Hypomagnesemia | Common | |
| Tumour lysis syndromeg | Common | Common |
| Nervous system disorders | ||
| Headache | Very common | Uncommon |
| Immune effector cell-associated neurotoxicity syndromef | Common | |
| Gastrointestinal disorders | ||
| Abdominal painh | Very common | Common |
| Nausea | Very common | Common |
| Diarrhoea | Very common | |
| Vomiting | Very common | Uncommon |
| Skin and subcutaneous tissue disorders | ||
| Rashi | Common | |
| Pruritus | Common | |
| General disorders and administration site conditions | ||
| Fatiguej | Very common | Common |
| Injection site reactionsk | Very common | |
| Pyrexial | Very common | Uncommon |
| Oedemam | Very common | Common |
| Investigations | ||
| Alanine aminotransferase increased | Common | Uncommon |
| Aspartate aminotransferase increased | Common | Common |
| Alkaline phosphatase increased | Common | |
| a Pneumonia includes COVID-19 pneumonia and pneumonia b Upper respiratory tract infection includes laryngitis, pharyngitis, respiratory syncytial virus infection, rhinitis, rhinovirus infection, and upper respiratory tract infection c Neutropenia includes neutropenia and neutrophil count decreased d Anaemia includes anaemia and serum ferritin decreased e Thrombocytopenia includes platelet count decreased and thrombocytopenia f CRS and ICANS events were graded based on American Society for Transplantation and Cellular Therapy (ASTCT) criteria g Tumour Lysis Syndrome was graded based on Cairo-Bishop h Abdominal pain includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, and abdominal tenderness i Rash includes rash, rash erythematous, rash maculo-papular, and rash pustular j Fatigue includes asthenia, fatigue, and lethargy k Injection site reactions include injection site bruising, injection site erythema, injection site hypertrophy, injection site inflammation, injection site mass, injection site pain, injection site pruritus, injection site rash, injection site reaction, injection site swelling, and injection site urticaria l Pyrexia includes body temperature increased and pyrexia m Oedema includes face oedema, generalized oedema, oedema, oedema peripheral, and peripheral swelling Note: Events were graded using NCI CTCAE version 5.0 | ||
Description of selected adverse reactions
Cytokine release syndrome
CRS of any grade occurred in 51% (85/167) of patients treated with epcoritamab. The incidence of Grade 1 was 31%, Grade 2 was 17%, and Grade 3 occurred in 3.0% of patients. Recurrent CRS occurred in 33% of patients with CRS. CRS of any grade occurred in 6.6% of patients after the priming dose (Cycle 1 Day 1); 13% after the intermediate dose (Cycle 1 Day 8); 44% after the first full dose (Cycle 1 Day 15); 4.6% after the second full dose (Cycle 1 Day 22); and 2.8% 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 11 days). The median time to onset after the first full dose was 20.2 hours (range: 0.2 days to 7 days). CRS resolved in 98% of events, and the median duration of CRS events was 2 days (range 1 to 27 days).
Dose delays due to CRS occurred in 7.2% of patients. Treatment was discontinued in 0.6% of patients due to CRS.
Of the 85 patients that experienced CRS, the most common signs and symptoms of CRS included pyrexia (99%), hypotension (31%), and hypoxia (19%). Other signs and symptoms of CRS in greater than two patients included chills (11%), tachycardia (including sinus tachycardia (9%)), dyspnoea (3.5%) and headache (3.5%). Tocilizumab was used to manage CRS event in 16% of patients and corticosteroids were used in 11% of patients. Out of the 32 events treated with tocilizumab, 88% responded within four (4) days of treatment.
Hospitalizations due to CRS occurred in 28% of patients and the median time to CRS resolution in those who were hospitalized was 1 day (range <1 to 26 days).
Immune effector cell associated neurotoxicity syndrome
ICANS occurred in 6.0% of patients treated with epcoritamab; 4.2% experienced Grade 1 and 1.2% experienced Grade 2. One patient (0.6%) 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 16.5 days (range: 8 to 141 days). ICANS resolved in 90% (9/10) of patients with supportive care. The median time to resolution of ICANS was 5 days (range: 1 to 9 days).
Dose delays due to ICANS occurred in 1.8% of patients. Treatment was discontinued in 0.6% of patients due to ICANS.
Serious infections
Serious infections of any grade occurred in 25% of patients treated with epcoritamab. The most frequent serious infections were COVID-19 (6.6%), COVID-19 pneumonia (4.2%), pneumonia (3.6%), sepsis (2.4%), cellulitis (1.8%), upper respiratory tract infection (1.8%), bacteraemia (1.2%), septic shock (1.2%), and progressive multifocal leukoencephalopathy (1.2%). The median time to onset of first serious infection was 56 days (range: 4 to 631 days), with median duration of 15 days (range: 4 to 125 days). Grade 5 events (fatal serious) of infections occurred in 7 (4.2%) patients.
Dose delays due to serious infections occurred in 15% of patients. Treatment was discontinued in 6.0% of patients due to serious infections (see Section 4.4).
Immunogenicity
Epcoritamab has the potential to induce anti-product antibodies (ADA). The incidence of antibodies to epcoritamab was low and all the patients who were positive had low titres (≥ 1 in 0.6% (1/158)). Due to the low number of patients with ADAs, a meaningful analysis of the impact of ADAs on safety is limited (see section 5.2).
Neutropenia
Neutropenia of any grade occurred in 31% of patients, including 23% Grade 3-4 events. The median time to onset of first neutropenia/neutrophil count decreased event was 65 days (range: 1 to 750 days), with median duration of 15 days (range: 2 to 155 days). Of the 51 patients who had neutropenia/neutrophil count decreased events, 51% received G-CSF to treat the events. Dose delays due to neutropenia occurred in 8 (4.8%) patients and there were no dose discontinuations due to neutropenia.
Tumour Lysis Syndrome
TLS occurred in 1.8% of patients. There was one patient who experienced onset on Day 14 with resolution on Day 17. Two additional patients experienced onset on Day 8 and Day 33 and both events were ongoing at the time of death; the deaths were due to disease progression.
Tumour Flare
Tumour flare occurred in 3.0% of patients, all of which were grade 2. The median time to onset was 17 days (range 9 to 34 days), and median duration was 15.5 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 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
In the event of overdose, monitor the patient for any signs or symptoms of adverse reactions and administer appropriate supportive treatment.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic agents, Other Antineoplastic agents, ATC code: L01FX27
Mechanism of action
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. CD20 is expressed on most human B-cell lymphomas and leukaemias and on B cells in peripheral blood, but not hematopoietic stem cells or plasma cells. The activity of epcoritamab is dependent upon simultaneous engagement of CD20-expressing cancer cells and CD3-expressing endogenous T cells by epcoritamab that induces specific T-cell activation and T-cell-mediated killing of CD20-expressing cells, as epcoritamab does not have direct immune effector mechanisms.
Epcoritamab Fc region is silenced for direct immune effector mechanisms, such as antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cellular cytotoxicity (CDC), and antibody-dependent cellular phagocytosis (ADCP).
Pharmacodynamic effects
Epcoritamab induced depletion of circulating B-cells (defined as CD19 B-cell counts < 10 cell/µ l in subjects who have detectable B cells at treatment initiation) after the first full dose (48 mg) which was sustained while patients remained on treatment. Subsequent treatment with epcoritamab induced expansion and activation of circulating T-cells from baseline.
Following subcutaneous administration of epcoritamab, transient and modest elevations of circulating levels of selected 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. Levels returned to baseline prior to the subsequent full dose.
Clinical efficacy and safety
Study EPCORE NHL-1 (GCT3013-01) was an open-label, multi-cohort, multicentre, single-arm trial that evaluated epcoritamab as monotherapy in patients with relapsed or refractory large B-cell lymphoma (LBCL) after two or more lines of systemic therapy. The study included patients with CD20 positive LBCL based on any representative pathology report, patients who had failed prior autologous 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 monoclonal antibody-containing therapy. The study excluded patients with CNS (central nervous system) involvement of lymphoma, seizure disorder requiring therapy, allogeneic HSCT or solid organ transplant, chronic ongoing infectious diseases, any patients with known impaired T-cell immunity, a creatinine clearance of less than 45 ml/min, alanine aminotransferase >3 times the upper limit of normal and clinically significant cardiac disease, including cardiac ejection fraction less than 45%.
Efficacy was evaluated in 139 patients with DLBCL within Study EPCORE NHL-1. Patients received epcoritamab subcutaneously (SC) in cycles of 4 weeks, i.e., 28 days. Epcoritamab was administered as a monotherapy 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 7.
Table 7 - Demographics and baseline characteristics of patients with DLBCL in EPCORE NHL-1 study
| Characteristics | (N=139) |
| Age |
|
| Median, years (min, max) | 66 (22, 83) |
| Males, n (%) | 85 (61) |
| Race n, % |
|
| White, | 84 (60) |
| Black, or African American | 0 |
| Asian | 27 (19) |
| Other | 5 (4) |
| Not Reported | 23 (17) |
| ECOG performance status; % |
|
| 0 | 67 (48) |
| 1 | 67 (48) |
| 2 | 5 (4) |
| Number of prior lines of anti-lymphoma therapy, % |
|
| Median (min, max) | 3 (2, 11) |
| 2 | 41 (30) |
| 3 | 47 (34) |
| ≥ 4 | 51 (37) |
| DLBCL Disease history; % |
|
| De Novo DLBCL | 97 (70) |
| DLBCL transformed from indolent lymphoma | 40 (29) |
| FISH Analysis Per Central lab, N=88 |
|
| Double-hit/Triple-hit lymphoma, (%) | 12 (14) |
| Prior therapy; (%) |
|
| Prior CAR-T | 53 (38) |
| Prior autologous HSCT | 26 (19) |
| Primary refractory diseasea | 82 (59) |
| Refractory to ≥ 2 consecutive lines of prior anti-lymphoma therapyb | 104 (75) |
| 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 they are refractory to frontline antilymphoma therapy. bA patient is considered to be refractory if they experience disease progression or stable disease as best response or disease progression within 6 months after therapy completion. | |
Efficacy was established based on overall response rate (ORR) determined by Lugano criteria (2014) as assessed by Independent Review Committee (IRC). The median follow-up time was 15.7 months (range: 0.3 to 23.5 months).
In this study, 7.9% (11/139) of patients had initial progressive disease (PD) by Lugano or indeterminate response (IR) by LYRIC and later obtained a partial response (PR) or complete response (CR).
Table 8 - Efficacy results in study EPCORE NHL-1 in patients with DLBCL
| Endpoint IRC assessment | Epcoritamab (N=139) |
| ORRa, n (%) | 86 (62) |
| (95% CI) | (53.3, 70) |
| CR, n (%) | 54 (39) |
| (95% CI) | (30.7, 47.5) |
| PR n (%) | 32 (23%) |
| (95% CI) | (16.3, 30.9) |
| DORb | |
| Median (95% CI), months | 15.6 (9.7, NR) |
| DOCRb | |
| Median (95% CI), months | NR (14.3, NR) |
| TTR, median (range), months | 1.4 (1.0, 8.4) |
| CI = confidence interval; CR = complete response; DOR = duration of response; IRC = independent review committee; ORR = overall response rate; PR = partial response; TTR = time to response a ORR = CR+PR; Determined by Lugano criteria (2014) as assessed by independent review committee (IRC) b Included patients with initial PD by Lugano or IR by LYRIC (pseudo-progression) who later obtained PR/CR. | |
The median time to CR was 2.6 months (range: 1.2 to 10.2 months).
Median DOR (CR and PR) in patients who achieved a CR was 17.3 months (95% CI:15.6, NR) compared to a median DOR of 2.1 months (95% CI; 1.4, 3.1) in those who achieved a partial response.
Response durations were longer in patients who achieved CR, as compared to patients with a best response of partial response (PR).
Immunogenicity
In the EPCORE NHL-1 clinical study, 4 of 158 (2.5%) patients who were treated with epcoritamab at the full dose of 48 mg and evaluable for the presence of anti-drug antibodies (ADA) tested positive for anti-epcoritamab antibodies on treatment (two at cycle 2 day 22, one at cycle 1 day 22, and one at cycle 2 day 1) with titres of 1:320 or less. There was no evidence of an altered pharmacokinetic profile with anti-epcoritamab binding antibody development based on a population PK analysis. There are insufficient data to evaluate the effect of ADA on the safety or efficacy of epcoritamab.
Paediatric population
The Medicines and Healthcare products Regulatory Agency has deferred the obligation to submit the results of studies with epcoritamab in one or more subsets of the paediatric population in the treatment of mature B-cell malignancies, as per paediatric investigation plan (PIP) decision, for the granted indication (see section 4.2 for information on paediatric use).
Conditional approval
This medicinal product has been authorised under a so-called 'conditional approval' scheme. This means that further evidence on this medicinal product is awaited. The Medicines and Healthcare products Regulatory Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary.
5.2 Pharmacokinetic properties
The population pharmacokinetics following subcutaneous administration of epcoritamab was described by a two-compartment model with first order subcutaneous absorption and target-mediated drug elimination. The moderate to high pharmacokinetic variability for epcoritamab was observed and characterised by inter-individual variability (IIV) ranging from 25.7% to 137.5% coefficient of variation (CV) for epcoritamab PK parameters.
Following the recommended SC dose 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 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 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.
Absorption
The peak concentrations occurred around 3-4 days (Tmax) in patients with LBCL receiving the 48 mg full dose.
Distribution
The geometric mean (% CV) central volume of distribution is 8.27 l (27.5%) based on population PK modelling.
Biotransformation
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.
Elimination
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. The population PK model-derived geometric mean half-life of full dose epcoritamab (48 mg) ranged from 22 to 25 days based on frequency of dosing.
Special populations
No clinically important effects on the pharmacokinetics of epcoritamab were observed based on age (20 to 89 years), sex, or race/ethnicity (white, Asian, and other), mild to moderate renal impairment (CLcr ≥ 30 ml/min to CLcr < 90 ml/min), and mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin 1 to 1.5 times ULN and any AST) after accounting for differences in bodyweight. No patients with severe to 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 (total bilirubin >1.5 to 3 times ULN and any AST, N=1). Therefore, the pharmacokinetics of epcoritamab is unknown in these populations.
In patients who received the recommended dosage of epcoritamab, Cycle 1 median average concentration was 13% lower in the higher body weight (BW) group (85 to 144 kg) and 37% higher in the lower BW group (39 to 65 kg) compared to patients with BW of 65 to less than 85 kg.
Paediatric
The pharmacokinetics of epcoritamab in paediatric patients has not been established.
5.3 Preclinical safety data
Carcinogenicity
Carcinogenicity studies have not been conducted with epcoritamab.
Mutagenicity
Mutagenicity studies have not been conducted with epcoritamab.
Impairment of fertility
Animal fertility studies have not been conducted with epcoritamab, however, epcoritamab did not cause toxicological changes in the reproductive organs of male or female cynomolgus monkeys at doses up to 1 mg/kg/week in intravenous general toxicity study of 5-week duration.
Animal pharmacology and/or toxicology
Effects generally consistent with the pharmacologic mechanism of action of epcoritamab were observed in cynomolgus monkeys. These findings included dose-related adverse clinical signs (including vomiting, decreased activity, and mortality at high doses) and cytokine release, reversible hematologic alterations, reversible B-cell depletion in peripheral blood, and reversible decreased lymphoid cellularity in secondary lymphoid tissues.
6. Pharmaceutical particulars
6.1 List of excipients
Sodium acetate trihydrate
Acetic acid
Sorbitol (E420)
Polysorbate 80
Water for injections
6.2 Incompatibilities
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.
6.3 Shelf life
Unopened vial
2 years
Diluted epcoritamab
Chemical and physical in-use stability has been demonstrated for 24 hours at 2 ° C to 8 ° C including up to 12 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 longer than 24 hours at 2 ° C to 8 ° C, unless preparation has taken place in controlled and validated aseptic conditions.
Minimise exposure to daylight. Allow epcoritamab solution to equilibrate to room temperature before administration. Discard unused epcoritamab solution beyond the allowable storage time.
6.4 Special precautions for storage
Store and transport refrigerated (2° C to 8° C).
Keep the vial in the outer carton in order to protect from light.
Do not freeze. Do not shake.
For storage conditions after reconstitution/first opening of the medicinal product, see section 6.3.
6.5 Nature and contents of container
Type I glass vial with a bromobutyl rubber stopper coated with fluoropolymer at the contact site and an aluminium seal with a plastic orange flip off cap, containing 48 mg per 0.8 ml solution for injection.
Each carton contains one vial.
6.6 Special precautions for disposal and other handling
Tepkinly 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 dosing schedule in Section 4.2.
Epcoritamab should be inspected visually for particulate matter and discolouration prior to administration. The solution for injection should be a colourless to slightly yellow solution. Do not use if solution is discoloured, or cloudy, or if 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 to administration.
Epcoritamab has to be prepared using aseptic technique.
Filtration is not required. However, if filtered, do not use filters made of nylon.
| 1) Prepare epcoritamab vial a) 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 invert, 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 the prepared epcoritamab, see section 6.3. |
| 4) Discard the vial containing unused epcoritamab in accordance with local requirements. |
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. Marketing authorisation holder
AbbVie Ltd
Maidenhead
SL6 4UB
United Kingdom
8. Marketing authorisation number(s)
PLGB 41042/0093
9. Date of first authorisation/renewal of the authorisation
Date of first authorisation: 20 October 2023
Date of latest renewal: 22 August 2024
10. Date of revision of the text
23 October 2024
AbbVie House, Vanwall Business Park, Vanwall Road, Maidenhead, Berkshire, SL6 4UB, UK
www.abbviemedinfo.com
+44 (0)1628 561 092
+44 (0)1628 561 092
www.abbvie.co.uk