Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: AbbVie Deutschland GmbH & Co. KG, Knollstrasse, 67061 Ludwigshafen, Germany
Tepkinly 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.
Tepkinly must only be administered under the supervision of a healthcare professional qualified in the use of anti-cancer therapy. At least 1 dose of tocilizumab for use in the event of CRS should be available prior to epcoritamab administration for Cycle 1. Access to an additional dose of tocilizumab within 8 hours of use of the previous tocilizumab dose should be available.
Tepkinly should be administered according to the following dosing schedule in 28-day cycles which is outlined in Table 1.
Table 1. Dosing schedule:
| Dosing schedule | Cycle of treatment | Days | Epcoritamab dose (mg)a |
|---|---|---|---|
| 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 | mg |
a 0.16 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.
Details on recommended pre-medication for cytokine release syndrome (CRS) are shown in Table 2.
Table 2. Epcoritamab pre-medication:
| Cycle | Patient requiring pre-medication | Pre-medication | Administration |
|---|---|---|---|
| Cycle 1 | All patients | Prednisolone (100 mg oral or intravenous) or dexamethasone (15 mg oral or intravenous) or equivalent | • 30-120 minutes prior to each weekly administration of epcoritamab • And for three consecutive days following each weekly administration of epcoritamab in Cycle 1 |
| • Diphenhydramine (50 mg oral or intravenous) or equivalent • Paracetamol (650 to 1 000 mg oral) | • 30-120 minutes prior to each weekly administration of epcoritamab | ||
| Cycle 2 and beyond | Patients who experienced Grade 2 or 3a CRS with previous dose | Prednisolone (100 mg oral or intravenous) or dexamethasone (15 mg oral or intravenous) or equivalent | • 30-120 minutes prior to next administration of epcoritamab after a grade 2 or 3a CRS event • And 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.
Prophylaxis against Pneumocystis jirovecii pneumonia (PCP) and herpes virus infections is strongly recommended especially during concurrent use of steroids.
Tepkinly should be administered to adequately hydrated patients. 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.
Patients should be monitored for signs and symptoms of CRS and/or immune effector cell-associated neurotoxicity syndrome (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 CRS and/or ICANS. 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 (see section 4.4).
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:
| Gradea | Recommended therapy | Epcoritamab dose modification |
|---|---|---|
| Grade 1 • Fever (temperature ≥38°C) | Provide supportive care such as antipyretics and intravenous hydration Dexamethasoneb may be initiated In cases of advanced age, high tumour burden, circulating tumour cells, fever refractory to antipyretics • Anti-cytokine therapy, tocilizumabd, should be considered For CRS with concurrent ICANS refer to Table 4 | Hold epcoritamab until resolution of CRS event |
| Grade 2 • Fever (temperature ≥38°C) and • Hypotension not requiring vasopressors and/or • Hypoxia requiring low-flow oxygene by nasal cannula or blow-by | Provide supportive care such as antipyretics and intravenous hydration Dexamethasoneb should be considered Anti-cytokine therapy, tocilizumabd, is recommended If CRS is refractory to dexamethasone and tocilizumab: • Alternative immunosuppressantsg and methylprednisolone 1 000 mg/day intravenously should be administered until clinical improvement For CRS with concurrent ICANS refer to Table 4 | Hold epcoritamab until resolution of CRS event |
| Grade 3 • Fever (temperature ≥38°C) and • Hypotension requiring a vasopressor with or without vasopressin and/or • Hypoxia requiring high-flow oxygenf by nasal cannula, facemask, non-rebreather mask, or venturi mask | Provide supportive care such as antipyretics and intravenous hydration Dexamethasonec should be administered Anti-cytokine therapy, tocilizumabd, is recommended If CRS is refractory to dexamethasone and tocilizumab: • Alternative immunosuppressantsg and methylprednisolone 1 000 mg/day intravenously should be administered until clinical improvement For CRS with concurrent ICANS refer to Table 4 | 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 • 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 Dexamethasonec should be administered Anti-cytokine therapy, tocilizumabd, is recommended If CRS is refractory to dexamethasone and tocilizumab: Alternative immunosuppressantsg and methylprednisolone 1 000 mg/day intravenously should be administered until clinical improvement For CRS with concurrent ICANS refer to Table 4 | Permanently discontinue epcoritamab |
a CRS graded according to ASTCT consensus criteria
b Dexamethasone should be administered at 10-20 mg per day (or equivalent)
c Dexamethasone should be administered at 10-20 mg intravenously every 6 hours
d Tocilizumab 8 mg/kg intravenously 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
e Low-flow oxygen is defined as oxygen delivered at <6 L/minute
f High-flow oxygen is defined as oxygen delivered at ≥6 L/minute
g Riegler L et al. (2019)
Patients should be monitored for signs and symptoms of ICANS. Other causes of neurologic symptoms should be ruled out. If ICANS is suspected, manage according to the recommendations in Table 4.
Table 4. ICANS grading and management guidance:
| Gradea | Recommended therapy | Epcoritamab dose modification |
|---|---|---|
| Grade 1b ICE scorec 7-9b or, depressed level of consciousnessb: awakens spontaneously | Treatment with dexamethasoned Consider non-sedating anti-seizure medicinal products (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 | Treatment with dexamethasonef Consider non-sedating anti-seizure medicinal products (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 generalised that resolves rapidly, or • non-convulsive seizures on electroencephalogram (EEG) that resolve with intervention, or raised intracranial pressure: focal/local oedemab on neuroimagingc | Treatment with dexamethasoneg • If no response, initiate methylprednisolone 1 000 mg/day Consider non-sedating anti-seizure medicinal products (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 1 000 mg/day • Choose immunosuppressant alternativese to tocilizumab, if possible | 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 | Treatment with dexamethasoneg • If no response, initiate methylprednisolone 1 000 mg/day Consider non-sedating anti-seizure medicinal products (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 1 000 mg/day • Choose immunosuppressant alternativese to tocilizumab, if possible | Permanently discontinue epcoritamab |
a ICANS graded according to ASTCT ICANS Consensus Grading
b ICANS grade is determined by the most severe event (ICE score, level of consciousness, seizures, motor findings, raised ICP/cerebral oedema) 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)
f Dexamethasone 10-20 mg intravenously every 12 hours
g Dexamethasone 10-20 mg intravenously every 6 hours
Table 5. Recommended dose 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 • For Grade 4, consider permanent discontinuation of Tepkinly |
| Neutropenia or febrile neutropenia (see section 4.8) | Absolute neutrophil count less than 0.5 × 109/L | • Withhold epcoritamab until absolute neutrophil count is 0.5 × 109/L or higher |
| Thrombocytopenia (see section 4.8) | Platelet count less than 50 × 109/L | • Withhold epcoritamab until platelet count is 50 × 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.
A re-priming Cycle (identical to Cycle 1 with standard CRS prophylaxis) is required:
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).
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. No dose 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. Epcoritamab has not been studied in patients with severe hepatic impairment (defined as total bilirubin >3 times ULN and any AST) and data are limited in patients with moderate hepatic impairment (defined as total bilirubin >1.5 to 3 times ULN and any AST). No dose recommendations can be made for patients with moderate 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 been established. No data are available.
Tepkinly is for subcutaneous use. It should be administered by subcutaneous injection only, preferably in the lower part of the 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 dilution of the medicinal product before administration, see section 6.6.
In the event of overdose, monitor the patient for any signs or symptoms of adverse reactions and administer appropriate supportive treatment.
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 dilution 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.
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 dilution of the medicinal product, see section 6.3.
Type I glass vial with a bromobutyl rubber stopper coated with fluoropolymer at the contact site and aluminium seal with a plastic light blue flip off cap, containing 4 mg per 0.8 ml concentrate for 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 dosing schedule in section 4.2.
Epcoritamab should be inspected visually for particulate matter and discolouration prior to administration. The concentrate should be a colourless to slightly yellow solution. Do not use if the solution is discoloured, or cloudy, or if foreign particles are present.
Epcoritamab has to be prepared using aseptic technique. Filtration of the diluted solution is not required.
0.16 mg priming dose preparation instructions – 2 dilutions required
Use an appropriately sized, syringe, vial, and needle for each transfer step.
1) Prepare epcoritamab vial
DO NOT vortex or vigorously shake the vial.
2) Perform first dilution
3) Perform second dilution
4) Withdraw dose
Withdraw 1 ml of the diluted epcoritamab from the dilution B vial into a syringe. The dilution B vial is no longer needed and should be discarded.
5) Label syringe
Label the syringe with the product name, dose strength (0.16 mg), date and the time of day. For storage of the diluted epcoritamab, see section 6.3.
6) Discard the vial and any unused portion of epcoritamab in accordance with local requirements.
0.8 mg intermediate dose preparation instructions – 1 dilution required
Use an appropriately sized syringe, vial and needle for each transfer step.
1) Prepare epcoritamab vial
DO NOT vortex or vigorously shake the vial.
2) Perform dilution
3) Withdraw dose
Withdraw 1 ml of the diluted epcoritamab from the dilution A vial into a syringe. The dilution A vial is no longer needed and should be discarded.
4) Label syringe
Label the syringe with the product name, dose strength (0.8 mg), date and the time of day. For storage of the diluted epcoritamab, see section 6.3.
5) 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 local requirements.
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