Leaflet TECVAYLI 10mg / ml solution for injection
Indicated for: multiple myeloma
Route of administration: injectable
Substance: teclistamab (monoclonal antibody)
ATC: L01FX24 (Antineoplastic and immunomodulating agents | Monoclonal antibodies and antibody drug conjugates | Other monoclonal antibodies and antibody drug conjugates)
Risk of severe allergic reaction. Seek urgent medical help if serious symptoms occur.
This medicine is subject to additional monitoring.
Use during breastfeeding only on medical advice.
Use during pregnancy only on medical advice.
Teclistamab is a bispecific antibody used for the treatment of relapsed or refractory multiple myeloma. It works by binding T cells to myeloma cells, stimulating the immune system to destroy cancer cells.
The medication is administered via subcutaneous injection, as directed by a doctor. It is important for patients to be closely monitored to prevent severe adverse reactions, such as cytokine release syndrome.
Patients should be aware of potential side effects, such as fever, fatigue, or nausea. It is important to inform the doctor of any unusual symptoms.
Common side effects include fever, fatigue, nausea, and decreased blood cell counts. In rare cases, severe reactions such as cytokine release syndrome or serious infections may occur. Patients should be informed of these risks before starting treatment.
General data about TECVAYLI 10mg / ml
- Substance: teclistamab
- Date of latest medicines list: 01-06-2026
- Product code: W69547001
- Concentration: 10mg / ml
- Pharmaceutical form: solution for injection
- Quantity: 1
- Product type: Original
- Price: 5017.73 RON
- Prescription status: P-RF - Medicines dispensed with a medical prescription that is retained by the pharmacy and cannot be renewed.
Concentrations available for teclistamab
- 10mg/ml
- 90mg/ml
Leaflet TECVAYLI 10mg/ml
Contents of the package leaflet for the medicine TECVAYLI 10mg / ml solution for injection
1. NAME OF THE MEDICINAL PRODUCT
TECVAYLI 10 mg/mL solution for injection
TECVAYLI 90 mg/mL solution for injection
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
TECVAYLI 10 mg/mL solution for injection
One 3 mL vial contains 30 mg of teclistamab (10 mg/mL).
TECVAYLI 90 mg/mL solution for injection
One 1.7 mL vial contains 153 mg of teclistamab (90 mg/mL).
Teclistamab is a humanised immunoglobulin G4-proline, alanine, alanine (IgG4-PAA) bispecificantibody directed against the B cell maturation antigen (BCMA) and CD3 receptors, produced in amammalian cell line (Chinese hamster ovary [CHO]) using recombinant DNA technology.
Excipient with known effectEach 3 mL vial contains 1.2 mg (0.4 mg/mL) of polysorbate 20.
Each 1.7 mL vial contains 0.68 mg (0.4 mg/mL) of polysorbate 20.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Solution for injection (injection).
The solution is colourless to light yellow, with a pH of 5.2 and osmolarity of approximately296 mOsm/L (10 mg/mL solution for injection), and approximately 357 mOsm/L (90 mg/mL solutionfor injection).
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
TECVAYLI is indicated as monotherapy for the treatment of adult patients with relapsed andrefractory multiple myeloma, who have received at least three prior therapies, including animmunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody and have demonstrateddisease progression on the last therapy.
4.2 Posology and method of administration
Treatment with TECVAYLI should be initiated and supervised by physicians experienced in thetreatment of multiple myeloma.
TECVAYLI should be administered by a healthcare professional with adequately trained medicalpersonnel and appropriate medical equipment to manage severe reactions, including cytokine releasesyndrome (CRS) (see section 4.4).
PosologyPre-treatment medicinal products should be administered prior to each dose of TECVAYLI in thestep-up dosing schedule (see below).
TECVAYLI step-up dosing schedule should not be administered in patients with active infection (see
Table 3 and section 4.4).
Recommended dosing schedule
The recommended dosing schedule for TECVAYLI is provided in Table 1. The recommended dosesof TECVAYLI are 1.5 mg/kg by subcutaneous injection (SC) weekly, preceded by step-up doses of0.06 mg/kg and 0.3 mg/kg. In patients who have a complete response or better for a minimum of6 months, a reduced dosing frequency of 1.5 mg/kg SC every two weeks may be considered (seesection 5.1).
Treatment with TECVAYLI should be initiated according to the step-up dosing schedule in Table 1 toreduce the incidence and severity of cytokine release syndrome. Due to the risk of cytokine releasesyndrome, patients should be instructed to remain within proximity of a healthcare facility, andmonitored for signs and symptoms daily for 48 hours after administration of all doses within the
TECVAYLI step-up dosing schedule (see section 4.4).
Failure to follow the recommended doses or dosing schedule for initiation of therapy, or re-initiationof therapy after dose delays, may result in increased frequency and severity of adverse reactionsrelated to mechanism of action, particularly cytokine release syndrome (see section 4.4).
Table 1: TECVAYLI dosing schedule
Dosing schedule Day Dosea
All patients
Day 1 Step-up dose 1 0.06 mg/kg SC singledose
Step-up dosing Day 3c Step-up dose 2 0.3 mg/kg SC singlescheduleb dose
Day 5d First maintenance 1.5 mg/kg SC singledose dose
One week after first
Weekly dosing Subsequent 1.5 mg/kg SC onceb maintenance dose andschedule maintenance doses weeklyweekly thereaftere
Patients who have a complete response or better for a minimum of 6 months
Biweekly (everytwo weeks) dosing Consider reducing the dosing frequency to 1.5 mg/kg SC every two weeksscheduleba Dose is based on actual body weight and should be administered subcutaneously.b See Table 2 for recommendations on restarting TECVAYLI after dose delays.c Step-up dose 2 may be given between two to seven days after Step-up dose 1.d First maintenance dose may be given between two to seven days after Step-up dose 2. This is the first full maintenancedose (1.5 mg/kg).e Maintain a minimum of five days between weekly maintenance doses.
Refer to Tables 9, 10 and 11 to determine the dosage based on predetermined weight ranges (seesection 6.6).
Duration of treatmentPatients should be treated with TECVAYLI until disease progression or unacceptable toxicity.
Pre-treatment medicinal products
The following pre-treatment medicinal products must be administered 1 to 3 hours before each dose ofthe TECVAYLI step-up dosing schedule (see Table 1) to reduce the risk of cytokine release syndrome(see sections 4.4 and 4.8).
- Corticosteroid (oral or intravenous dexamethasone 16 mg)
- Antihistamine (oral or intravenous diphenhydramine 50 mg, or equivalent)
- Antipyretics (oral or intravenous acetaminophen 650 to 1 000 mg, or equivalent)
Administration of pre-treatment medicinal products may also be required prior to administration ofsubsequent doses of TECVAYLI for the following patients:
- Patients who repeat doses within the TECVAYLI step-up dosing schedule due to dose delays(Table 2), or
- Patients who experienced CRS following the previous dose (Table 3).
Prevention of herpes zoster reactivation
Prior to starting treatment with TECVAYLI, antiviral prophylaxis should be considered for theprevention of herpes zoster virus reactivation, per local institutional guidelines.
Restarting TECVAYLI after dose delay
If a dose of TECVAYLI is delayed, therapy should be restarted based on the recommendations listedin Table 2 and TECVAYLI resumed according to the dosing schedule (see Table 1). Pre-treatmentmedicinal products should be administered as indicated in Table 2. Patients should be monitoredaccordingly (see section 4.2).
Table 2: Recommendations for restarting therapy with TECVAYLI after dose delay
Last dose Duration of delay from Actionadministered the last doseadministered
More than 1 week (> Restart TECVAYLI step-up dosing schedule at
Step-up dose 17 days) Step-up dose 1 (0.06 mg/kg)a.
More than 1 week to less Repeat Step-up dose 2 (0.3 mg/kg)a andthan or equal to 4 weeks continue TECVAYLI step-up dosing schedule.
Step-up dose 2 (8 days to ≤ 28 days)
More than 4 weeks Restart TECVAYLI step-up dosing schedule at(>28 days) Step-up dose 1 (0.06 mg/kg)a.
More than 1 week to less Continue TECVAYLI at last maintenance dosethan or equal to 9 weeks and schedule (1.5 mg/kg once weekly or(8 days to ≤ 63 days) 1.5 mg/kg every two weeks).
More than 9 weeks to Restart TECVAYLI step-up dosing schedule at
Any maintenanceless than or equal to 16 Step-up dose 2 (0.3 mg/kg)a.
dosesweeks (64 days to ≤112 days)
More than 16 weeks Restart TECVAYLI step-up dosing schedule at(>112 days) Step-up dose 1 (0.06 mg/kg)a.a Pre-treatment medicinal products should be administered prior to TECVAYLI dose and patients monitoredaccordingly.
Dose modificationsTreatment with TECVAYLI should be initiated according to the step-up dosing schedule in Table 1.
Dose reductions of TECVAYLI are not recommended.
Dose delays may be required to manage toxicities related to TECVAYLI (see section 4.4).
Recommendations on restarting TECVAYLI after a dose delay are provided in Table 2.
Recommended actions after adverse reactions following administration of TECVAYLI are listed in
Table 3.
Table 3: Recommended actions taken after adverse reactions following administration of
TECVAYLI
Adverse reactions Grade Actions
Cytokine release Grade 1 - Withhold TECVAYLI untilsyndromea (see - Temperature ≥38 °Cb adverse reaction resolves.section 4.4) - See Table 4 for management ofcytokine release syndrome.
- Administer pre-treatmentmedicinal products prior tonext dose of TECVAYLI.
Grade 2 - Withhold TECVAYLI until
- Temperature ≥38 °Cb with either: adverse reaction resolves.
- Hypotension responsive to - See Table 4 for management offluids and not requiring cytokine release syndrome.vasopressors, or - Administer pre-treatment
- Oxygen requirement of low- medicinal products prior toflow nasal cannulac or blow-by next dose of TECVAYLI.
- Monitor patient daily for
Grade 3 (Duration: less than 48 hours) 48 hours following the next
- Temperature ≥38 °Cb with either: dose of TECVAYLI. Instruct
- Hypotension requiring one patients to remain withinvasopressor with or without proximity of a healthcarevasopressin, or facility during daily
- Oxygen requirement of high- monitoring.
flow nasal cannulac, facemask,non-rebreather mask, or Venturimask
Grade 3 (Recurrent or duration: more - Permanently discontinuethan 48 hours) therapy with TECVAYLI.
- Temperature ≥38 °Cb with either: - See Table 4 for management of
- Hypotension requiring one cytokine release syndrome.vasopressor with or withoutvasopressin, or
- Oxygen requirement of high-flow nasal cannulac, facemask,non-rebreather mask, or Venturimask.
Grade 4
- Temperature ≥38 °Cb with either:
- Hypotension requiring multiplevasopressors (excludingvasopressin), or
- Oxygen requirement of positivepressure (e.g., continuouspositive airway pressure[CPAP], bilevel positive airwaypressure [BiPAP], intubation,and mechanical ventilation).
Immune effector Grade 1 - Withhold TECVAYLI untilcell-associated adverse reaction resolves.neurotoxicity - See Table 5 for management ofsyndrome (ICANS)dimmune effector(see section 4.4) cell-associated neurotoxicitysyndrome.
Grade 2 - Withhold TECVAYLI until
Grade 3 (First occurrence) adverse reaction resolves.
- See Table 5 for management ofimmune effectorcell-associated neurotoxicitysyndrome.
- Monitor patient daily for48 hours following the nextdose of TECVAYLI. Instructpatients to remain withinproximity of a healthcarefacility during dailymonitoring.
Grade 3 (Recurrent) - Permanently discontinue
Grade 4 therapy with TECVAYLI.
- See Table 5 for management ofimmune effectorcell-associated neurotoxicitysyndrome.
Infections (see All Grades - Do not administer TECVAYLIsection 4.4) step-up dosing schedule inpatients with active infection.
TECVAYLI step-up dosingschedule may proceed uponresolution of active infection.
Grade 3 - Withhold subsequent
Grade 4 maintenance doses of
TECVAYLI (i.e., dosesadministered after TECVAYLIstep-up dosing schedule) untilinfection improves to Grade 2or better.
Haematologic Absolute neutrophil count less than - Withhold TECVAYLI untiltoxicities (see 0.5109/L absolute neutrophil count issections 4.4 and 4.8) 0.5109/L or higher.
Febrile neutropenia - Withhold TECVAYLI untilabsolute neutrophil count is1.0109/L or higher, and feverresolves.
Haemoglobin less than 8 g/dL - Withhold TECVAYLI untilhaemoglobin is 8 g/dL orhigher.
Platelet count less than 25 000/µL - Withhold TECVAYLI untilplatelet count is 25 000/µL or
Platelet count between 25 000/µL and higher and no evidence of50 000/µL with bleeding bleeding.
Other adverse Grade 3 - Withhold TECVAYLI untilreactions (see Grade 4 adverse reaction improves tosection 4.8)e Grade 2 or better.
a Based on American Society for Transplantation and Cellular Therapy (ASTCT) grading for CRS (Lee et al 2019).b Attributed to CRS. Fever may not always be present concurrently with hypotension or hypoxia as it may be masked byinterventions such as antipyretics or anticytokine therapy (e.g., tocilizumab or corticosteroids).c Low-flow nasal cannula is ≤6 L/min, and high-flow nasal cannula is >6 L/min.d Based on ASTCT grading for ICANS.e Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.03.
Special populationsPaediatric population
There is no relevant use of TECVAYLI in the paediatric population for the treatment of multiplemyeloma.
ElderlyNo dosage adjustment is necessary (see section 5.2).
Renal impairmentNo dosage adjustment is recommended for patients with mild or moderate renal impairment (seesection 5.2).
Hepatic impairmentNo dosage adjustment is recommended for patients with mild hepatic impairment (see section 5.2).
Method of administrationTECVAYLI is for subcutaneous injection only.
For instructions on handling 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
In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.
Cytokine release syndrome (CRS)Cytokine release syndrome, including life-threatening or fatal reactions, may occur in patientsreceiving TECVAYLI.
Clinical signs and symptoms of CRS may include but are not limited to fever, hypoxia, chills,hypotension, tachycardia, headache, and elevated liver enzymes. Potentially life-threateningcomplications of CRS may include cardiac dysfunction, adult respiratory distress syndrome,neurologic toxicity, renal and/or hepatic failure, and disseminated intravascular coagulation (DIC).
Treatment should be initiated with TECVAYLI according to the step-up dosing schedule to reducerisk of CRS. Pre-treatment medicinal products (corticosteroids, antihistamine and antipyretics) shouldbe administered prior to each dose of the TECVAYLI step-up dosing schedule to reduce risk of CRS(see section 4.2).
The following patients should be instructed to remain within proximity of a healthcare facility andmonitored daily for 48 hours:
- If the patient has received any dose within the TECVAYLI step-up dosing schedule (for CRS).
- If the patient has received TECVAYLI after experiencing Grade 2 or higher CRS.
Patients who experience CRS following their previous dose should be administered pre-treatmentmedicinal products prior to the next dose of TECVAYLI.
Patients should be counselled to seek medical attention should signs or symptoms of CRS occur. Atthe first sign of CRS, patients should be immediately evaluated for hospitalisation. Treatment withsupportive care, tocilizumab and/or corticosteroids should be instituted, based on severity as indicatedin Table 4 below. The use of myeloid growth factors, particularly granulocyte macrophage-colonystimulating factor (GM-CSF), has the potential to worsen CRS symptoms and should be avoidedduring CRS. Treatment with TECVAYLI should be withheld until CRS resolves as indicated in
Table 3 (see section 4.2).
Management of cytokine release syndrome
CRS should be identified based on clinical presentation. Patients should be evaluated and treated forother causes of fever, hypoxia, and hypotension.
If CRS is suspected, TECVAYLI should be withheld until the adverse reaction resolves (see Table 3).
CRS should be managed according to the recommendations in Table 4. Supportive care for CRS(including but not limited to anti-pyretic agents, intravenous fluid support, vasopressors, supplementaloxygen, etc.) should be administered as appropriate. Laboratory testing to monitor for disseminatedintravascular coagulation (DIC), haematology parameters, as well as pulmonary, cardiac, renal, andhepatic function should be considered.
Table 4: Recommendations for management of cytokine release syndrome withtocilizumab and corticosteroids
Gradee Presenting symptoms Tocilizumaba Corticosteroidsb
Grade 1 Temperature ≥38 °Cc May be considered Not applicable
Grade 2 Temperature ≥38 °Cc with Administer tocilizumabb If no improvement withineither: 8 mg/kg intravenously 24 hours of starting
- Hypotension responsive to over 1 hour (not to tocilizumab, administerfluids and not requiring exceed 800 mg). methylprednisolonevasopressors, or 1 mg/kg intravenously
- Oxygen requirement of Repeat tocilizumab every twice daily, orlow-flow nasal cannulad or 8 hours as needed, if not dexamethasone 10 mgblow-by responsive to intravenous intravenously everyfluids or increasing 6 hours.supplemental oxygen.
Continue corticosteroid
Limit to a maximum of use until the event is3 doses in a 24-hour Grade 1 or less, then taperperiod; maximum total of over 3 days.4 doses.
Grade 3 Temperature ≥38 °Cc with Administer tocilizumab If no improvement,either: 8 mg/kg intravenously administer
- Hypotension requiring one over 1 hour (not to methylprednisolonevasopressor with or exceed 800 mg). 1 mg/kg intravenouslywithout vasopressin, or twice daily, or
- Oxygen requirement of Repeat tocilizumab every dexamethasone 10 mghigh-flow nasal cannulad, 8 hours as needed, if not intravenously everyfacemask, non-rebreather responsive to intravenous 6 hours.
mask, or Venturi mask fluids or increasingsupplemental oxygen. Continue corticosteroiduse until the event is
Limit to a maximum of Grade 1 or less, then taper3 doses in a 24-hour over 3 days.period; maximum total of4 doses.
Grade 4 Temperature ≥38 °Cc with Administer tocilizumab As above, or administereither: 8 mg/kg intravenously methylprednisolone
- Hypotension requiring over 1 hour (not to 1 000 mg intravenouslymultiple vasopressors exceed 800 mg). per day for 3 days, per(excluding vasopressin), physician discretion.or Repeat tocilizumab every
- Oxygen requirement of 8 hours as needed if not If no improvement or ifpositive pressure (e.g., responsive to intravenous condition worsens,continuous positive airway fluids or increasing consider alternatepressure [CPAP], bilevel supplemental oxygen. immunosuppressants b.
positive airway pressure[BiPAP], intubation, and Limit to a maximum ofmechanical ventilation) 3 doses in a 24-hourperiod; maximum total of4 doses.
a Refer to tocilizumab prescribing information for details.b Treat unresponsive CRS per institutional guidelines.c Attributed to CRS. Fever may not always be present concurrently with hypotension or hypoxia as it may be masked byinterventions such as antipyretics or anticytokine therapy (e.g., tocilizumab or corticosteroids).d Low-flow nasal cannula is ≤6 L/min, and high-flow nasal cannula is >6 L/min.e Based on ASTCT grading for CRS (Lee et al 2019).
Neurologic toxicities, including ICANS
Serious, life-threatening or fatal neurologic toxicities, including Immune Effector Cell-Associated
Neurotoxicity Syndrome (ICANS) occurred following treatment with TECVAYLI.
Patients should be monitored for signs or symptoms of neurologic toxicities during treatment andtreated promptly.
Patients should be counselled to seek medical attention should signs or symptoms of neurologictoxicity occur. At the first sign of neurologic toxicity, including ICANS, patients should beimmediately evaluated and treated based on severity. Patients who experience Grade 2 or higher
ICANS or first occurrence of Grade 3 ICANS with the previous dose of TECVAYLI should beinstructed to remain within proximity of a healthcare facility and monitored for signs and symptomsdaily for 48 hours.
For ICANS and other neurologic toxicities, treatment with TECVAYLI should be withheld asindicated in Table 3 (see section 4.2).
Due to the potential for ICANS, patients should be advised not to drive or operate heavy machineryduring the TECVAYLI step-up dosing schedule and for 48 hours after completing the TECVAYLIstep-up dosing schedule and in the event of new onset of any neurological symptoms (see section 4.7).
Management of neurologic toxicities
At the first sign of neurologic toxicity, including ICANS, neurology evaluation should be considered.
Other causes of neurologic symptoms should be ruled out. TECVAYLI should be withheld untiladverse reaction resolves (see Table 3). Intensive care and supportive therapy should be provided forsevere or life-threatening neurologic toxicities. General management for neurologic toxicity (e.g.,
ICANS with or without concurrent CRS) is summarised in Table 5.
Table 5: Guidelines for management of immune effector cell-associated neurotoxicitysyndrome (ICANS)
Grade Presenting symptomsa Concurrent CRS No Concurrent CRS
Grade 1 ICE score 7-9b Management of CRS per Monitor neurologic
Table 4. symptoms and consider
Or, depressed level of neurology consultationconsciousnessc: awakens Monitor neurologic symptoms and evaluation, perspontaneously. and consider neurology physician discretion.
consultation and evaluation, perphysician discretion.
Consider non-sedating, anti-seizure medicinal products(e.g., levetiracetam) for seizure prophylaxis.
Grade 2 ICE score 3-6b Administer tocilizumab per Administer
Table 4 for management of dexamethasoned 10 mg
Or, depressed level of CRS. intravenously everyconsciousnessc: awakens If no improvement after starting 6 hours.to voice. tocilizumab, administerdexamethasoned 10 mg Continue dexamethasoneintravenously every 6 hours if use until resolution tonot already taking other Grade 1 or less, thencorticosteroids. Continue taper.dexamethasone use untilresolution to Grade 1 or less,then taper.
Consider non-sedating, anti-seizure medicinal products(e.g., levetiracetam) for seizure prophylaxis. Considerneurology consultation and other specialists for furtherevaluation, as needed.
Grade 3 ICE score 0-2b Administer tocilizumab per Administer
Table 4 for management of dexamethasoned 10 mg
Or, depressed level of CRS. intravenously everyconsciousnessc: awakens In addition, administer 6 hours.only to tactile stimulus, dexamethasoned 10 mgor intravenously with the first dose Continue dexamethasoneof tocilizumab, and repeat dose use until resolution toseizuresc, either: every 6 hours. Continue Grade 1 or less, then
- any clinical seizure, dexamethasone use until taper.
focal or generalised resolution to Grade 1 or less,that resolves rapidly, then taper.or Consider non-sedating, anti-seizure medicinal products
- non-convulsive (e.g., levetiracetam) for seizure prophylaxis. Considerseizures on neurology consultation and other specialists for furtherelectroencephalogra evaluation, as needed.m (EEG) that resolvewith intervention, orraised intracranialpressure: focal/localoedema onneuroimagingc.
Grade 4 ICE score 0b Administer tocilizumab per As above, or consider
Table 4 for management of administration of
Or, depressed level of CRS. methylprednisoloneconsciousnessc either: 1 000 mg per day
- patient is unarousable As above, or consider intravenously for 3 days;or requires vigorous administration of if improves, then manageor repetitive tactile methylprednisolone 1 000 mg as above.stimuli to arouse, or per day intravenously with first
- stupor or coma, or dose of tocilizumab, andcontinue methylprednisoloneseizuresc, either: 1 000 mg per day intravenously
- life-threatening for 2 or more days.
prolonged seizure Consider non-sedating, anti-seizure medicinal products(>5 minutes), or (e.g., levetiracetam) for seizure prophylaxis. Consider
- repetitive clinical or neurology consultation and other specialists for furtherelectrical seizures evaluation, as needed. In case of raised intracranialwithout return to pressure/cerebral oedema, refer to institutional guidelinesbaseline in between, for management.
ormotor findingsc:
- deep focal motorweakness such ashemiparesis orparaparesis, orraised intracranialpressure/cerebraloedemac, withsigns/symptoms such as:
- diffuse cerebraloedema onneuroimaging, or
- decerebrate ordecorticate posturing,or
- cranial nerve VIpalsy, or
- papilloedema, or
- cushing’s triada Management is determined by the most severe event, not attributable to any other cause.b 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 yourtongue” = 1 point); Writing (ability to write a standard sentence = 1 point; and Attention (count backwards from 100by ten = 1 point). If patient is unarousable and unable to perform ICE Assessment (Grade 4 ICANS) = 0 points.
c Attributable to no other cause.d All references to dexamethasone administration are dexamethasone or equivalent.
InfectionsSevere, life-threatening, or fatal infections have been reported in patients receiving TECVAYLI (seesection 4.8). New or reactivated viral infections occurred during therapy with TECVAYLI.
Patients should be monitored for signs and symptoms of infection prior to and during treatment with
TECVAYLI and treated appropriately. Prophylactic antimicrobials should be administered accordingto local institutional guidelines.
TECVAYLI step-up dosing schedule should not be administered in patients with active infection. Forsubsequent doses, TECVAYLI should be withheld as indicated in Table 3 (see section 4.2).
Progressive Multifocal Leukoencephalopathy (PML), which can be fatal, has also been reported inpatients receiving TECVAYLI. Patients should be monitored for any new onset of or changes inpre-existing neurological signs or symptoms. If PML is suspected, treatment with TECVAYLI shouldbe withheld and appropriate diagnostic testing initiated. If PML is confirmed, TECVAYLI must bediscontinued.
Hepatitis B virus reactivationHepatitis B virus reactivation can occur in patients treated with medicinal products directed against Bcells, and in some cases, may result in fulminant hepatitis, hepatic failure, and death.
Patients with evidence of positive HBV serology should be monitored for clinical and laboratory signsof HBV reactivation while receiving TECVAYLI, and for at least six months following the end of
TECVAYLI treatment.
In patients who develop reactivation of HBV while on TECVAYLI, treatment with TECVAYLIshould be withheld as indicated in Table 3 and manage per local institutional guidelines (seesection 4.2).
HypogammaglobulinaemiaHypogammaglobulinaemia has been reported in patients receiving TECVAYLI (see section 4.8).
Immunoglobulin levels should be monitored during treatment with TECVAYLI. Intravenous orsubcutaneous immunoglobulin therapy was used to treat hypogammaglobulinaemia in 39% of patients.
Patients should be treated according to local institutional guidelines, including infection precautions,antibiotic or antiviral prophylaxis, and administration of immunoglobulin replacement.
Vaccines
Immune response to vaccines may be reduced when taking TECVAYLI.
The safety of immunisation with live viral vaccines during or following TECVAYLI treatment has notbeen studied. Vaccination with live virus vaccines is not recommended for at least 4 weeks prior to thestart of treatment, during treatment and least 4 weeks after treatment.
NeutropeniaNeutropenia and febrile neutropenia have been reported in patients who received TECVAYLI (seesection 4.8).
Complete blood cell counts should be monitored at baseline and periodically during treatment.
Supportive care should be provided per local institutional guidelines.
Patients with neutropenia should be monitored for signs of infection.
Treatment with TECVAYLI should be withheld as indicated in Table 3 (see section 4.2).
ExcipientsSodium
This medicinal product contains less than 1 mmol (23 mg) sodium per dose, that is to say essentially‘sodium-free’.
Polysorbate
This medicinal product contains 0.4 mg of polysorbate 20 in each mL, which is equivalent to 1.2 mgper 3 mL vial and 0.68 mg per 1.7 mL vial. Polysorbates may cause hypersensitivity reactions.
4.5 Interaction with other medicinal products and other forms of interaction
No interaction studies have been performed with TECVAYLI.
The initial release of cytokines associated with the start of TECVAYLI treatment could suppress
CYP450 enzymes. The highest risk of interaction is expected to be from initiation of TECVAYLIstep-up schedule up to 7 days after the first maintenance dose or during a CRS event. During this timeperiod, toxicity or medicinal product concentrations (e.g., cyclosporine) should be monitored inpatients who are receiving concomitant CYP450 substrates with a narrow therapeutic index. The doseof the concomitant medicinal product should be adjusted as needed.
4.6 Fertility, pregnancy and lactation
Women of child-bearing potential/Contraception in males and females
Pregnancy status for females of child-bearing potential should be verified prior to starting treatmentwith TECVAYLI.
Women of child-bearing potential should use effective contraception during treatment and forfive months after the final dose of TECVAYLI. In clinical studies, male patients with a female partnerof child-bearing potential used effective contraception during treatment and for three months after thelast dose of teclistamab.
PregnancyThere are no available data on the use of teclistamab in pregnant women or animal data to assess therisk of teclistamab in pregnancy. Human IgG is known to cross the placenta after the first trimester ofpregnancy. Therefore, teclistamab, a humanised IgG4-based antibody, has the potential to betransmitted from the mother to the developing foetus. TECVAYLI is not recommended for womenwho are pregnant. TECVAYLI is associated with hypogammaglobulinaemia, therefore, assessment ofimmunoglobulin levels in newborns of mothers treated with TECVAYLI should be considered.
Breast-feedingIt is not known whether teclistamab is excreted in human or animal milk, affects breast-fed infants oraffects milk production. Because of the potential for serious adverse reactions in breast-fed infantsfrom TECVAYLI, patients should be advised not to breast-feed during treatment with TECVAYLIand for at least five months after the last dose.
FertilityThere are no data on the effect of teclistamab on fertility. Effects of teclistamab on male and femalefertility have not been evaluated in animal studies.
4.7 Effects on ability to drive and use machines
TECVAYLI has major influence on the ability to drive and use machines.
Due to the potential for ICANS, patients receiving TECVAYLI are at risk of depressed level ofconsciousness (see section 4.8). Patients should be instructed to avoid driving and operating heavy orpotentially dangerous machinery during and for 48 hours after completion of TECVAYLI step-updosing schedule and in the event of new onset of any neurological symptoms (Table 1) (see section 4.2and section 4.4).
4.8 Undesirable effects
The most frequent adverse reactions of any grade in patients were hypogammaglobulinaemia (75%),cytokine release syndrome (72%), neutropenia (71%), anaemia (55%), musculoskeletal pain (52%),fatigue (41%), thrombocytopenia (40%), injection site reaction (38%), upper respiratory tract infection(37%), lymphopenia (35%), diarrhoea (28%), pneumonia (28%), nausea (27%), pyrexia (27%),headache (24%), cough (24%), constipation (21%) and pain (21%).
Serious adverse reactions were reported in 65% patients who received TECVAYLI, includingpneumonia (16%), COVID-19 (15%), cytokine release syndrome (8%), sepsis (7%), pyrexia (5%),musculoskeletal pain (5%), acute kidney injury (4.8%), diarrhoea (3.0%), cellulitis (2.4%), hypoxia(2.4%), febrile neutropenia (2.4%), and encephalopathy (2.4%).
Tabulated list of adverse reactionsThe safety data of TECVAYLI was evaluated in MajesTEC-1, which included 165 adult patients withmultiple myeloma who received the recommended dosing regimen of TECVAYLI as monotherapy.
The median duration of TECVAYLI treatment was 8.5 (Range: 0.2 to 24.4) months.
Table 6 summarises adverse reactions reported in patients who received TECVAYLI. The safety dataof TECVAYLI was also evaluated in the all treated population (N=302) with no additional adversereactions identified.
Adverse reactions observed during clinical studies are listed below by frequency category. Frequencycategories are defined as follows: 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); very rare (<1/10 000) and not known (frequencycannot be estimated from the available data).
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Table 6: Adverse reactions in patients with multiple myeloma treated with TECVAYLI in
MajesTEC-1 at the recommended dose for monotherapy use
Frequency N=165(All n (%)
System Organ Class Adverse Reaction grades) Any Grade Grade 3 or 4
Infections and infestations Pneumonia1 Very 46 (28%) 32 (19%)common
Sepsis2 Common 13 (7.9%) 11 (6.7%)
COVID-193 Very 30 (18%) 20 (12%)common
Upper respiratory tract Very 61 (37%) 4 (2.4%)infection4 common
Cellulitis Common 7 (4.2%) 5 (3.0%)
Urinary tract infection5, 21 Very 23 (14%) 10 (6.1%)common
Progressive multifocal Uncommon 1 (0.6%) 1 (0.6%)leukoencephalopathy21
Blood and lymphatic system Neutropenia Very 117 (71%) 106 (64%)disorders common
Febrile neutropenia Common 6 (3.6%) 5 (3.0%)
Thrombocytopenia Very 66 (40%) 35 (21%)common
Lymphopenia Very 57 (35%) 54 (33%)common
Anaemia6 Very 90 (55%) 61 (37%)common
Leukopenia Very 29 (18%) 12 (7.3%)common
Hypofibrinogenaemia Common 16 (9.7%) 2 (1.2%)
Immune system disorders Cytokine release syndrome Very 119 (72%) 1 (0.6%)common
Hypogammaglobulinaemia7 Very 123 (75%) 3 (1.8%)common
Metabolism and nutrition Hyperamylasaemia Common 6 (3.6%) 4 (2.4%)disorders Hyperkalaemia Common 8 (4.8%) 2 (1.2%)
Hypercalcaemia Very 19 (12%) 5 (3.0%)common
Hyponatraemia Common 13 (7.9%) 8 (4.8%)
Hypokalaemia Very 23 (14%) 8 (4.8%)common
Hypocalcaemia Common 12 (7.3%) 0
Hypophosphataemia Very 20 (12%) 10 (6.1%)common
Hypoalbuminaemia Common 4 (2.4%) 1 (0.6%)
Hypomagnesaemia Very 22 (13%) 0common
Decreased appetite Very 20 (12%) 1 (0.6%)common
Hypoglycaemia21 Common 4 (2.4%) 0
Nervous system disorders Immune effector cell- Common 5 (3.0%) 0associated neurotoxicitysyndrome
Encephalopathy8 Common 16 (9.7%) 0
Neuropathy peripheral9 Very 26 (16%) 1 (0.6%)common
Headache Very 39 (24%) 1 (0.6%)common
Vascular disorders Haemorrhage10 Very 20 (12%) 5 (3.0%)common
Hypertension11 Very 21 (13%) 9 (5.5%)common
Hypotension21 Very 18 (11%) 4 (2.4%)common
Respiratory, thoracic and Hypoxia Common 16 (9.7%) 6 (3.6%)mediastinal disorders Dyspnoea12 Very 22 (13%) 3 (1.8%)common
Cough13 Very 39 (24%) 0common
Gastrointestinal disorders Diarrhoea Very 47 (28%) 6 (3.6%)common
Abdominal pain14, 21 Very 20 (12%) 2 (1.2%)common
Vomiting Very 21 (13%) 1 (0.6%)common
Nausea Very 45 (27%) 1 (0.6%)common
Constipation Very 34 (21%) 0common
Musculoskeletal and Musculoskeletal pain15 Very 85 (52%) 14 (8.5%)connective tissue disorders common
Muscle spasms21 Very 17 (10%) 0common
General disorders and Pyrexia Very 45 (27%) 1 (0.6%)administration site commonconditions Injection site reaction16 Very 62 (38%) 1 (0.6%)common
Pain17 Very 34 (21%) 3 (1.8%)common
Oedema18 Very 23 (14%) 0common
Fatigue19 Very 67 (41%) 5 (3.0%)common
Investigations Blood creatinine increased Common 9 (5.5%) 0
Transaminase elevation20 Common 16 (9.7%) 4 (2.4%)
Lipase increased Common 10 (6.1%) 2 (1.2%)
Blood alkaline phosphatase Very 18 (11%) 3 (1.8%)increased common
Gamma- Common 16 (9.7%) 5 (3.0%)glutamyltransferaseincreased
Activated partial Common 13 (7.9%) 2 (1.2%)thromboplastin timeprolonged
International normalised Common 10 (6.1%) 2 (1.2%)ratio increased
Adverse events are coded using MedDRA Version 24.0.
Note: The output includes the diagnosis of CRS and ICANS; the symptoms of CRS or ICANS are excluded.1 Pneumonia includes Enterobacter pneumonia, lower respiratory tract infection, lower respiratory tract infection viral,
Metapneumovirus pneumonia, Pneumocystis jirovecii pneumonia, pneumonia, Pneumonia adenoviral, Pneumoniabacterial, Pneumonia klebsiella, Pneumonia moraxella, Pneumonia pneumococcal, Pneumonia pseudomonal,
Pneumonia respiratory syncytial viral, Pneumonia staphylococcal and Pneumonia viral.
2 Sepsis includes bacteraemia, Meningococcal sepsis, neutropenic sepsis, Pseudomonal bacteraemia, Pseudomonalsepsis, sepsis and Staphylococcal bacteraemia.
3 COVID-19 includes asymptomatic COVID-19 and COVID-19.4 Upper respiratory tract infection includes bronchitis, nasopharyngitis, pharyngitis, respiratory tract infection,respiratory tract infection bacterial, rhinitis, rhinovirus infection, sinusitis, tracheitis, upper respiratory tract infectionand viral upper respiratory tract infection.
5 Urinary tract infection includes Cystitis, Cystitis escherichia, Cystitis klebsiella, Escherichia urinary tract infection,
Urinary tract infection and Urinary tract infection bacterial.
6 Anaemia includes anaemia, iron deficiency and iron deficiency anaemia.7 Hypogammaglobulinaemia includes patients with adverse events of hypogammaglobulinaemia, hypoglobulinaemia,immunoglobulins decreased, and/or patients with laboratory IgG levels below 500 mg/dL following treatment withteclistamab.
8 Encephalopathy includes confusional state, depressed level of consciousness, lethargy, memory impairment andsomnolence.
9 Neuropathy peripheral includes dysaesthesia, hypoaesthesia, hypoaesthesia oral, neuralgia, paraesthesia, paraesthesiaoral, peripheral sensory neuropathy and sciatica.
10 Haemorrhage includes conjunctival haemorrhage, epistaxis, haematoma, haematuria, haemoperitoneum, haemorrhoidalhaemorrhage, lower gastrointestinal haemorrhage, melaena, mouth haemorrhage and subdural haematoma.
11 Hypertension includes essential hypertension and hypertension.12 Dyspnoea includes acute respiratory failure, dyspnoea and dyspnoea exertional.13 Cough includes allergic cough, cough, productive cough and upper-airway cough syndrome.14 Abdominal pain includes Abdominal discomfort, Abdominal pain and Abdominal pain upper.15 Musculoskeletal pain includes arthralgia, back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain,myalgia, neck pain and pain in extremity.16 Injection site reaction includes injection site bruising, injection site cellulitis, injection site discomfort, injection siteerythema, injection site haematoma, injection site induration, injection site inflammation, injection site oedema,injection site pruritus, injection site rash, injection site reaction and injection site swelling.
17 Pain includes ear pain, flank pain, groin pain, non-cardiac chest pain, oropharyngeal pain, pain, pain in jaw, toothacheand tumour pain.
18 Oedema includes face oedema, fluid overload, oedema peripheral and peripheral swelling.19 Fatigue includes asthenia, fatigue and malaise.20 Transaminase elevation includes alanine aminotransferase increased and aspartate aminotransferase increased.21 New adverse reaction terms identified using long term follow-up from MajesTEC-1.
Description of selected adverse reactionsCytokine release syndrome
In MajesTEC-1 (N=165), CRS was reported in 72% of patients following treatment with TECVAYLI.
One-third (33%) of patients experienced more than one CRS event. Most patients experienced CRSfollowing Step-up Dose 1 (44%), Step-up Dose 2 (35%), or the initial maintenance dose (24%). Lessthan 3% of patients developed first occurrence of CRS following subsequent doses of TECVAYLI.
CRS events were Grade 1 (50%) and Grade 2 (21%) or Grade 3 (0.6%). The median time to onset of
CRS was 2 (Range: 1 to 6) days after the most recent dose, with a median duration of 2 (Range: 1 to 9)days.
The most frequent signs and symptoms associated with CRS were fever (72%), hypoxia (13%), chills(12%), hypotension (12%), sinus tachycardia (7%), headache (7%), and elevated liver enzymes(aspartate aminotransferase and alanine aminotransferase elevation) (3.6% each).
In MajesTEC-1, tocilizumab, corticosteroids and tocilizumab in combination with corticosteroids wereused to treat CRS in 32%, 11% and 3% of CRS events, respectively.
Neurologic toxicities, including ICANS
In MajesTEC-1 (N=165), neurologic toxicity events were reported in 15% of patients receiving
TECVAYLI. Neurologic toxicity events were Grade 1 (8.5%), Grade 2 (5.5%), or Grade 4 (<1%). Themost frequently reported neurologic toxicity event was headache (8%).
ICANS, including Grade 3 and higher, were reported in clinical trials and with post-marketingexperience. The most frequent clinical manifestation of ICANS were confusional state, decreased levelof consciousness, disorientation, dysgraphia, aphasia, apraxia, and somnolence. The onset ofneurologic toxicity can be concurrent with CRS, following resolution of CRS, or in the absence of
CRS. The observed time to onset of ICANS ranged from 0 to 21 days after the most recent dose.
ImmunogenicityPatients treated with subcutaneous teclistamab monotherapy (N=238) in MajesTEC-1 were evaluatedfor antibodies to teclistamab using an electrochemiluminescence-based immunoassay. One subject(0.4%) developed neutralising antibodies to teclistamab of low-titre.
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.
4.9 Overdose
Symptoms and signs
The maximum tolerated dose of teclistamab has not been determined. In clinical studies, doses of up to6 mg/kg have been administered.
TreatmentIn the event of an overdose, the patient should be monitored for any signs or symptoms of adversereactions, and appropriate symptomatic treatment should be instituted immediately.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Other monoclonal antibodies and antibody drug conjugates, ATC code:
L01FX24
Mechanism of actionTeclistamab is a full-size, IgG4-PAA bispecific antibody that targets the CD3 receptor expressed onthe surface of T cells and B cell maturation antigen (BCMA), which is expressed on the surface ofmalignant multiple myeloma B-lineage cells, as well as late-stage B cells and plasma cells. With itsdual binding sites, teclistamab is able to draw CD3+ T cells in close proximity to BCMA+ cells,resulting in T cell activation and subsequent lysis and death of BCMA+ cells, which is mediated bysecreted perforin and various granzymes stored in the secretory vesicles of cytotoxic T cells. Thiseffect occurs without regard to T cell receptor specificity or reliance on major histocompatibilitycomplex (MHC) Class 1 molecules on the surface of antigen presenting cells.
Pharmacodynamic effectsWithin the first month of treatment, activation of T-cells, redistribution of T-cells, reduction of B-cellsand induction of serum cytokines were observed.
Within one month of treatment with teclistamab, the majority of responders had reduction in soluble
BCMA, and a greater reduction in soluble BCMA was observed in subjects with deeper responses toteclistamab.
Clinical efficacy and safetyThe efficacy of TECVAYLI monotherapy was evaluated in patients with relapsed or refractorymultiple myeloma in a single-arm, open-label, multi-centre, Phase 1/2 study (MajesTEC-1). The studyincluded patients who had previously received at least three prior therapies, including a proteasomeinhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. The study excludedpatients who experienced stroke or seizure within the past 6 months, and patients with Eastern
Cooperative Oncology Group performance score (ECOG PS) ≥2, plasma cell leukaemia, known active
CNS involvement or exhibited clinical signs of meningeal involvement of multiple myeloma, or activeor documented history of autoimmune disease with the exception of vitiligo, Type 1 diabetes and priorautoimmune thyroiditis.
Patients received initial step-up doses of 0.06 mg/kg and 0.3 mg/kg of TECVAYLI administeredsubcutaneously, followed by the maintenance dose of TECVAYLI 1.5 mg/kg, administeredsubcutaneously once weekly thereafter, until disease progression or unacceptable toxicity. Patientswho had a complete response (CR) or better for a minimum of 6 months were eligible to reduce dosingfrequency to 1.5 mg/kg subcutaneously every two weeks until disease progression or unacceptabletoxicity (see section 4.2). The median duration between Step-up Dose 1 and Step-up Dose 2 was 2.9(Range: 2-7) days. The median duration between Step-up Dose 2 and the initial maintenance dose was3.1 (Range: 2-9) days. Patients were hospitalised for monitoring for at least 48 hours afteradministration of each dose of the TECVAYLI Step-up dosing schedule.
The efficacy population included 165 patients. The median age was 64 (Range: 33-84) years with 15%of subjects ≥75 years of age; 58% were male; 81% were White, 13% were Black, 2% were Asian. The
International Staging System (ISS) at study entry was 52% in Stage I, 35% in Stage II and 12% in
Stage III. High-risk cytogenetics (presence of del(17p), t(4;14) or t(14;16)) were present in 26% ofpatients. Seventeen percent of patients had extramedullary plasmacytomas.
The median time since initial diagnosis of multiple myeloma to enrolment was 6 (Range: 0.8-22.7)years. The median number of prior therapies was 5 (Range: 2-14), with 23% of patients who received3 prior therapies. Eighty-two percent of patients received prior autologous stem cell transplantation,and 4.8% of patients received prior allogeneic transplantation. Seventy-eight percent of patients weretriple-class refractory (refractory to proteasome inhibitor, an immunomodulatory agent and ananti-CD38 monoclonal antibody).
Efficacy results were based on overall response rate, as determined by the Independent Review
Committee (IRC) assessment, using International Myeloma Working Group (IMWG) 2016 criteria(see Table 7).
Table 7: Efficacy results for MajesTEC-1
All Treated (N=165)
Overall response rate (ORR: sCR, CR, VGPR, PR) n(%) 104 (63.0%)95% CI (%) (55.2%, 70.4%)
Stringent complete response (sCR) 54 (32.7%)
Complete response (CR) 11 (6.7%)
Very good partial response (VGPR) 32 (19.4%)
Partial response (PR) 7 (4.2%)
Duration of Response (DOR) (months)
Number of Responders 104
DOR (Months): Median (95% CI) 18.4 (14.9, NE)1
Time to First Response (months)
Number of responders 104
Median 1.2
Range (0.2; 5.5)
MRD negativity rate2 in all treated patients, n (%) [N=165] 44 (26.7%)95% CI (%) (20.1%, 34.1%)
MRD negativity rate2,3 in patients achieving CR or sCR, n (%) 30 (46.2%)[N=65]95% CI (%) (33.7%, 59.0%)1 NE=not estimable2 MRD-negativity rate is defined as the proportion of participants who achieved MRD negative status (at 10-5) at anytimepoint after initial dose, and prior to progressive disease (PD) or subsequent anti-myeloma therapy.3 Only MRD assessments (10-5 testing threshold) within 3 months of achieving CR/sCR untildeath/progression/subsequent therapy (exclusive) are considered.
Results of an updated efficacy analysis after a median follow-up of 30.6 months among responders(n=104) showed a higher proportion of patients with CR (7.3%) and sCR (38.8%) compared with theprimary analysis. MRD negativity rates also increased in all treated patients (29.1%) and in patientsachieving CR or sCR (51.3%). The median DOR was 24.0 (17.0, NE) months.
The median follow-up after schedule change was 12.6 (Range: 1.0 to 24.7) months in patients whoswitched to 1.5 mg/kg subcutaneously every two weeks.
Paediatric populationThe European Medicines Agency has waived the obligation to submit the results of studies with
TECVAYLI in all subsets of the paediatric population in multiple myeloma (see section 4.2 forinformation on paediatric use).
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 European Medicines Agency will review new information on this medicinal product at least everyyear and this SmPC will be updated as necessary.
5.2 Pharmacokinetic properties
Teclistamab exhibited approximately dose-proportional pharmacokinetics following subcutaneousadministration across a dose range of 0.08 mg/kg to 3 mg/kg (0.05 to 2.0 times the recommendeddose). Ninety percent of steady state exposure was achieved after 12 weekly maintenance doses. Themean accumulation ratio between the first and 13th weekly maintenance dose of teclistamab 1.5 mg/kgwas 4.2-fold for Cmax, 4.1-fold for Ctrough, and 5.3-fold for AUCtau.
The Cmax, Ctrough, and AUCtau of teclistamab are presented in Table 8.
Table 8: Pharmacokinetic parameters of teclistamab for the 13th recommended weeklymaintenance dose (1.5 mg/kg) in patients with relapsed or refractory multiplemyeloma in MajesTEC-1
Teclistamab
Pharmacokinetic Parameter Geometric Mean (CV%)
Cmax (µg/mL) 23.8 (55%)
Ctrough (µg/mL) 21.1 (63%)
AUCtau (µg·h/mL) 3 838 (57%)
Cmax = Maximum serum teclistamab concentration; Ctrough = Serum teclistamab concentration prior to next dose; CV =geometric coefficient of variation; AUCtau = Area under the concentration-time curve over the weekly dosing interval.
AbsorptionThe mean bioavailability of teclistamab was 72% when administered subcutaneously. The median(range) Tmax of teclistamab after the first and 13th weekly maintenance doses were 139 (19 to 168)hours and 72 (24 to 168) hours, respectively.
DistributionThe mean volume of distribution was 5.63 L (29% coefficient of variation (CV)).
EliminationTeclistamab clearance decreases over time, with a mean (CV%) maximal reduction from baseline tothe 13th weekly maintenance dose of 40.8% (56%). The geometric mean (CV%) clearance is0.472 L/day (64%) at the 13th weekly maintenance dose. Patients who discontinue teclistamab after the13th weekly maintenance dose are expected to have a 50% reduction from Cmax in teclistamabconcentration at a median (5th to 95th percentile) time of 15 (7 to 33) days after Tmax and a 97%reduction from Cmax in teclistamab concentration at a median time of 69 (32 to 163) days after Tmax.
Population pharmacokinetic analysis (based on MajesTEC-1) showed that soluble BCMA did notimpact teclistamab serum concentrations.
Special populationsThe pharmacokinetics of TECVAYLI in paediatric patients aged 17 years and younger have not beeninvestigated.
Results of population pharmacokinetic analyses indicate that age (24 to 84 years) and sex did notinfluence the pharmacokinetics of teclistamab.
Renal impairmentNo formal studies of TECVAYLI in patients with renal impairment have been conducted.
Results of population pharmacokinetic analyses indicate that mild renal impairment(60 mL/min/1.73 m2 ≤ estimated glomerular filtration rate (eGFR) <90 mL/min/1.73 m2) or moderaterenal impairment (30 mL/min/1.73 m2 ≤ eGFR <60 mL/min/1.73 m2) did not significantly influencethe pharmacokinetics of teclistamab. Limited data are available from patients with severe renalimpairment.
Hepatic impairmentNo formal studies of TECVAYLI in patients with hepatic impairment have been conducted.
Results of population pharmacokinetic analyses indicate that mild hepatic impairment (total bilirubin>1 to 1.5 times upper limit of normal (ULN) and any aspartate aminotransferase (AST), or totalbilirubin ≤ULN and AST>ULN) did not significantly influence the pharmacokinetics of teclistamab.
No data are available in patients with moderate and severe hepatic impairment.
5.3 Preclinical safety data
No animal studies have been performed to assess the carcinogenic or genotoxic potential ofteclistamab.
Reproductive toxicology and fertility
No animal studies have been conducted to evaluate the effects of teclistamab on reproduction andfoetal development. In the 5-week repeat-dose toxicity study in cynomolgus monkeys, there were nonotable effects in the male and female reproductive organs at doses up to 30 mg/kg/week(approximately 22 times the maximum recommended human dose, based on AUC exposure)intravenously for five weeks.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
EDTA disodium salt dihydrate
Glacial acetic acid
Polysorbate 20 (E432)
Sodium acetate trihydrate
Sucrose
Water for injections
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.
6.3 Shelf life
Unopened vial2 years
Prepared syringe
The prepared syringes should be administered immediately. If immediate administration is notpossible, in-use storage times of the prepared syringe should be no longer than 20 hours at 2 °C - 8 °Cor ambient temperature (15 °C - 30 °C). Discard after 20 hours if not used.
6.4 Special precautions for storage
Store in a refrigerator (2 °C - 8 °C).
Do not freeze.
Store in the original carton in order to protect from light.
6.5 Nature and contents of container
3 mL solution for injection in a Type 1 glass vial with an elastomeric closure, and aluminium seal witha flip-off button containing 30 mg of teclistamab (10 mg/mL).
Pack size of 1 vial.
1.7 mL solution for injection in a Type 1 glass vial with an elastomeric closure, and aluminium sealwith a flip-off button containing 153 mg of teclistamab (90 mg/mL).
Pack size of 1 vial.
6.6 Special precautions for disposal and other handling
It is very important that the instructions for preparation and administration provided in this section arestrictly followed to minimise potential dosing errors with TECVAYLI 10 mg/mL and TECVAYLI90 mg/mL vials.
TECVAYLI should be administered via subcutaneous injection only. Do not administer TECVAYLIintravenously.
TECVAYLI should be administered by a healthcare professional with adequately trained medicalpersonnel and appropriate medical equipment to manage severe reactions, including cytokine releasesyndrome (see section 4.4).
TECVAYLI 10 mg/mL and TECVAYLI 90 mg/mL vials are for single use only.
TECVAYLI vials of different concentrations should not be combined to achieve maintenance dose.
Aseptic technique should be used to prepare and administer TECVAYLI.
Any unused medicinal product or waste material should be disposed in accordance with localrequirements.
Preparation of TECVAYLI
- Verify the prescribed dose for each TECVAYLI injection. To minimise errors, use thefollowing tables to prepare TECVAYLI injection.
o Use Table 9 to determine the total dose, injection volume and number of vials required,based on patient’s actual body weight for Step-up dose 1 using TECVAYLI 10 mg/mLvial.
Table 9: Injection volumes of TECVAYLI (10 mg/mL) for Step-up dose 1 (0.06 mg/kg)
Body weight Total dose Volume of injection Number of vials(kg) (mg) (mL) (1 vial=3 mL)35-39 2.2 0.22 140-44 2.5 0.25 145-49 2.8 0.28 150-59 3.3 0.33 160-69 3.9 0.39 1
Step-Up dose 1 70-79 4.5 0.45 1(0.06 mg/kg) 80-89 5.1 0.51 190-99 5.7 0.57 1100-109 6.3 0.63 1110-119 6.9 0.69 1120-129 7.5 0.75 1130-139 8.1 0.81 1140-149 8.7 0.87 1150-160 9.3 0.93 1o Use Table 10 to determine the total dose, injection volume and number of vials requiredbased on patient’s actual body weight for Step-up dose 2 using TECVAYLI 10 mg/mLvial.
Table 10: Injection volumes of TECVAYLI (10 mg/mL) for Step-up dose 2 (0.3 mg/kg)
Body weight Total dose Volume of injection Number of vials(kg) (mg) (mL) (1 vial=3 mL)35-39 11 1.1 140-44 13 1.3 145-49 14 1.4 150-59 16 1.6 160-69 19 1.9 1
Step-up dose 2 70-79 22 2.2 1(0.3 mg/kg) 80-89 25 2.5 190-99 28 2.8 1100-109 31 3.1 2110-119 34 3.4 2120-129 37 3.7 2130-139 40 4.0 2140-149 43 4.3 2150-160 47 4.7 2o Use Table 11 to determine the total dose, injection volume and number of vials requiredbased on patient’s actual body weight for the maintenance dose using TECVAYLI90 mg/mL vial.
Table 11: Injection volumes of TECVAYLI (90 mg/mL) for maintenance dose (1.5 mg/kg)
Body weight Total dose Volume of injection Number of vials(kg) (mg) (mL) (1 vial=1.7 mL)35-39 56 0.62 140-44 63 0.70 145-49 70 0.78 150-59 82 0.91 160-69 99 1.1 1
Maintenance 70-79 108 1.2 1dose (1.5 mg/kg) 80-89 126 1.4 190-99 144 1.6 1100-109 153 1.7 1110-119 171 1.9 2120-129 189 2.1 2130-139 198 2.2 2140-149 216 2.4 2150-160 234 2.6 2
- Remove the appropriate TECVAYLI vial from refrigerated storage (2 °C - 8 °C) and equilibrateto ambient temperature (15 °C - 30 °C), as needed, for at least 15 minutes. Do not warm
TECVAYLI in any other way.
- Once equilibrated, gently swirl the vial for approximately 10 seconds to mix. Do not shake.
- Withdraw the required injection volume of TECVAYLI from the vial(s) into an appropriatelysized syringe using a transfer needle.o Each injection volume should not exceed 2.0 mL. Divide doses requiring greater than2.0 mL equally into multiple syringes.
- TECVAYLI is compatible with stainless steel injection needles and polypropylene andpolycarbonate syringe material.
- Replace the transfer needle with an appropriately sized needle for injection.
- Visually inspect TECVAYLI for particulate matter and discolouration prior to administration.
Do not use if the solution is discoloured, or cloudy, or if foreign particles are present.o TECVAYLI solution for injection is colourless to light yellow.
Administration of TECVAYLI
- Inject the required volume of TECVAYLI into the subcutaneous tissue of the abdomen(preferred injection site). Alternatively, TECVAYLI may be injected into the subcutaneoustissue at other sites (e.g., thigh). If multiple injections are required, TECVAYLI injectionsshould be at least 2 cm apart.
- Do not inject into tattoos or scars or areas where the skin is red, bruised, tender, hard or notintact.
10. DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines
Agency https://www.ema.europa.eu.