Posology : מינונים

4.2   Posology and method of administration

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.

Posology

Recommended pre-medication and dose schedule
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         Days                     Epcoritamab dose (mg)a 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 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-   Pre-medication                   Administration medication
Cycle 1              All patients             Prednisolone (100 mg oral or       •    30-120 minutes prior to intravenous) or dexamethasone           each weekly
(15 mg oral or intravenous) or          administration of equivalent                              epcoritamab
•    And for three consecutive days following each weekly administration of epcoritamab in Cycle 1

•   Diphenhydramine               •    30-120 minutes prior to
(50 mg oral or                     each weekly intravenous) or                    administration of equivalent                         epcoritamab
•   Paracetamol
(650 to 1,000 mg oral)

Cycle 2 and              Patients who              Prednisolone (100 mg oral or        •    30-120 minutes prior to beyond                   experienced Grade 2 or    intravenous) or                          next administration of 3a CRS with previous      dexamethasone (15 mg oral                epcoritamab after a grade dose                      or intravenous) or                       2 or 3a CRS event equivalent                          •    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).

Dose 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
Gradea                              Recommended therapy                         Epcoritamab dose modification Grade 1                             Provide supportive care such as             Hold epcoritamab until resolution • Fever (temperature ≥ 38 °C)       antipyretics and                            of CRS event 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
Grade 2                             Provide supportive care such as             Hold epcoritamab until resolution • Fever (temperature ≥ 38 °C)       antipyretics and                            of CRS event intravenous hydration and
Dexamethasoneb should be considered
• Hypotension not requiring vasopressors                        Anti-cytokine therapy,
tocilizumabd, is recommended and/or
If CRS is refractory to dexamethasone and
• Hypoxia requiring low-flow        tocilizumab: oxygene by nasal cannula or blow-       •     Alternative by                                           immunosuppressantsg and methylprednisolone
1,000 mg/day intravenously should be administered until clinical improvement

For CRS with concurrent ICANS refer to
Table 4
Grade 3                             Provide supportive care such as             Hold epcoritamab until resolution • Fever (temperature ≥ 38 °C)       antipyretics and                            of CRS event intravenous hydration and                                                                             In the event of Grade 3 CRS Dexamethasonec should be administered       lasting longer than 72 hours, • Hypotension requiring a                                                       epcoritamab should be vasopressor with or without         Anti-cytokine therapy,                      discontinued vasopressin                         tocilizumabd, is recommended
If more than 2 separate events of and/or                              If CRS is refractory to dexamethasone and   Grade 3 CRS, even if each event tocilizumab:                                resolved to Grade 2 within Gradea                              Recommended therapy                           Epcoritamab dose modification • Hypoxia requiring high-flow            •    Alternative                         72 hours, epcoritamab should be oxygenf by nasal cannula,                    immunosuppressantsg and              discontinued facemask, non-rebreather mask,               methylprednisolone or venturi mask                              1,000 mg/day intravenously should be administered until clinical improvement


For CRS with concurrent ICANS refer to
Table 4
Grade 4                             Provide supportive care such as               Permanently discontinue • Fever (temperature ≥ 38 °C)       antipyretics and                              epcoritamab intravenous hydration and
Dexamethasonec should be administered
• Hypotension requiring
≥ 2 vasopressors (excluding         Anti-cytokine therapy,
vasopressin)                        tocilizumabd, is recommended
 and/or                              If CRS is refractory to dexamethasone and tocilizumab:
• Hypoxia requiring positive             •   Alternative pressure ventilation (e.g., CPAP,            immunosuppressantsg and
BiPAP, intubation and mechanical             methylprednisolone ventilation)                                 1,000 mg/day intravenously should be administered until clinical improvement

For CRS with concurrent ICANS refer to
Table 4
 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)

Immune effector cell-associated neurotoxicity syndrome (ICANS)

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                                  Treatment with dexamethasoned                                  Hold epcoritamab ICE scorec 7-9 b                                                                                         until resolution of or, depressed level of                    Consider non-sedating anti-seizure medicinal products (e.g.,   event consciousnessb: awakens levetiracetam) until resolution of ICANS spontaneously

No concurrent CRS:
•   Anti-cytokine therapy not recommended

For ICANS with concurrent CRS:
•   Treatment with dexamethasoned
•   Choose immunosuppressant alternativese to tocilizumab, if possible

Grade 2b                                  Treatment with dexamethasonef                                  Hold epcoritamab ICE scorec 3-6                                                                                           until resolution of or, depressed level of                    Consider non-sedating anti-seizure medicinal products (e.g.,   event consciousnessb: awakens levetiracetam) until resolution of ICANS to voice

No concurrent CRS:
•   Anti-cytokine therapy not recommended

For ICANS with concurrent CRS:
•   Treatment with dexamethasoned
•   Choose immunosuppressant alternativese to tocilizumab, if possible

Grade 3b                                  Treatment with dexamethasoneg                                  Permanently ICE scorec 0-2                                •   If no response, initiate methylprednisolone            discontinue or, depressed level of                            1,000 mg/day                                           epcoritamab consciousnessb: awakens only to tactile stimulus,                 Consider non-sedating anti-seizure medicinal products (e.g., or                                        levetiracetam) until resolution of ICANS  seizuresb, either:                        No concurrent CRS:
• any clinical seizure, focal or              •   Anti-cytokine therapy not recommended generalised that resolves rapidly,
or                                        For ICANS with concurrent CRS: • non-convulsive seizures on
•   Treatment with dexamethasone electroencephalogram (EEG) that resolve with intervention, or               o If no response, initiate raised intracranial                                       methylprednisolone 1,000 mg/day pressure: focal/local                         •   Choose immunosuppressant alternativese to oedemab on                                        tocilizumab, if possible neuroimagingc


Gradea                                   Recommended therapy                                              Epcoritamab dose modification
Grade 4b                                 Treatment with dexamethasoneg                                    Permanently ICE scorec, b 0                               •   If no response, initiate methylprednisolone             discontinue 1,000 mg/day                                            epcoritamab or, depressed level of consciousnessb either:
Consider non-sedating anti-seizure medicinal products (e.g.,
•   patient is unarousable or requires vigorous or repetitive      levetiracetam) until resolution of ICANS tactile stimuli to arouse, or
•   stupor or coma, or                   No concurrent CRS:
•   Anti-cytokine therapy not recommended b seizures , either:
•   life-threatening prolonged           For ICANS with concurrent CRS: seizure (> 5 minutes), or                • Treatment with dexamethasone •   repetitive clinical or electrical                o If no response, initiate methylprednisolone 1,000 mg/day seizures without return to
• Choose immunosuppressant alternativese to baseline in between,
tocilizumab, if possible 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
 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              Absolute neutrophil count  • Withhold epcoritamab until neutropenia (see section 4.8)       less than 0.5 x 109/L          absolute neutrophil count is 0.5 x 109/L or higher
Thrombocytopenia (see section       Platelet count             • Withhold epcoritamab until 9
4.8)                                less than 50 x 10 /L           platelet count is 50 x 109/L or higher
Other adverse reactions (see        Grade 3 or higher          • Withhold epcoritamab until the section 4.8)                                                       toxicity resolves to Grade 1 or baseline
1
Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 5.0.

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).

Special populations

Renal impairment
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).

Hepatic impairment

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).


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

Method of administration

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 or preparation of the medicinal product before administration, see section 6.6.