Posology : מינונים

4.2    Posology and method of administration

Treatment with TALVEY should be initiated and supervised by physicians experienced in the treatment of multiple myeloma.
TALVEY should be administered by a healthcare professional with adequately-trained medical personnel and appropriate medical equipment to manage severe reactions, including cytokine release syndrome (CRS) and neurologic toxicity, including immune effector cell-associated neurotoxicity syndrome (ICANS).

Posology

Pre-treatment medicinal products should be administered prior to each dose of TALVEY during the step-up phase (see below).
TALVEY should be administered subcutaneously on a weekly or biweekly (every 2 weeks) dosing schedule according to Table 1. Patients who receive talquetamab according to the 0.4 mg/kg body weight weekly dosing schedule and have attained an adequate clinical response that is confirmed in at least two consecutive disease assessments can be considered for switch to the 0.8 mg/kg body weight biweekly dosing schedule.

Table 1:    Recommended TALVEY dose
Dosing
Phase                                            Day                                   TALVEY dosea schedule
Day 1                                        0.01 mg/kg
Weekly dosing          Step-up phase                       Day 3b                                        0.06 mg/kg schedule                                                 Day 5b                                         0.4 mg/kg Treatment phase               Once a week thereafterc                               0.4 mg/kg 
Day 1                                         0.01 mg/kg
Biweekly (every                                                Day 3b                                        0.06 mg/kg Step-up phase
2 weeks) dosing                                                Day 5b                                         0.4 mg/kg schedule                                                    Day 7b                                         0.8 mg/kg Treatment phase           Once every 2 weeks thereafterc                            0.8 mg/kg a
Based on actual body weight and administered subcutaneously.
b
Dose may be administered between 2 to 4 days after the previous dose and may be given up to 7 days after the previous dose to allow for resolution of adverse reactions.
c
Maintain a minimum of 6 days between weekly doses and a minimum of 12 days between biweekly (every 2 weeks) doses.


Patients should be instructed to remain within proximity of a healthcare facility and monitored for 48 hours after administration of all doses within the TALVEY step-up phase for signs and symptoms of CRS and ICANS (see section 4.4).

Duration of treatment
Patients should be treated with TALVEY until disease progression or unacceptable toxicity.

Pre-treatment
The following pre-treatment medicinal products must be administered 1 to 3 hours before each dose of TALVEY during the step-up phase to reduce the risk of CRS (see section 4.4).

•           Corticosteroid (oral or intravenous dexamethasone 16 mg or equivalent)
•           Antihistamine (oral or intravenous diphenhydramine 50 mg or equivalent)
•           Antipyretics (oral or intravenous paracetamol 650 mg to 1 000 mg or equivalent) 
Pre-treatment medicinal products should be administered prior to subsequent doses for patients who repeat doses within the TALVEY step-up phase due to dose delays (see Table 2) or for patients who experienced CRS (see Table 3).

Prevention of infection
Prior to starting treatment with TALVEY, prophylaxis should be considered for the prevention of infections, per local institutional guidelines.
Dose delays

If a dose of TALVEY is delayed, therapy should be restarted based on recommendations in Table 2, and weekly or biweekly dosing should be resumed accordingly (see Posology above). Pre-treatment medicinal products should be administered prior to restarting TALVEY, and patients should be monitored accordingly.

Table 2:    Recommendations for restarting TALVEY after dose delay
Last dose             Time from last dose     TALVEY recommendation*
Dosing schedule   administered          administered
0.01 mg/kg            More than 7 days        Restart at 0.01 mg/kg
8 to 28 days            Repeat 0.06 mg/kg
0.06 mg/kg
Weekly                                  More than 28 days       Restart at 0.01 mg/kg dosing schedule                         8 to 35 days            Repeat 0.4 mg/kg 0.4 mg/kg             36 to 56 days           Restart at 0.06 mg/kg
More than 56 days       Restart at 0.01 mg/kg

0.01 mg/kg                 More than 7 days                 Restart at 0.01 mg/kg 8 to 28 days                     Repeat 0.06 mg/kg
0.06 mg/kg
More than 28 days                Restart at 0.01 mg/kg
Biweekly                                              8 to 35 days                     Repeat 0.4 mg/kg (every 2 weeks)            0.4 mg/kg                  36 to 56 days                    Restart at 0.06 mg/kg dosing schedule                                       More than 56 days                Restart at 0.01 mg/kg 14 to 35 days                    Repeat 0.8 mg/kg
0.8 mg/kg                  36 to 56 days                    Restart at 0.4 mg/kg More than 56 days                Restart at 0.01 mg/kg
*   Administer pretreatment medicinal products prior to restarting TALVEY. After restarting TALVEY, resume weekly or biweekly (every 2 weeks) dosing accordingly (see section 4.2).


Dose modifications for adverse reactions
Dose delays may be required to manage toxicities related to TALVEY (see section 4.4). See Table 2 for recommendations on restarting TALVEY after a dose delay.

See Tables 3 and 4 for recommended actions for the management of CRS and ICANS. See Table 6 for recommended dose modifications for other adverse reactions.

Cytokine release syndrome (CRS)
CRS should be identified based on clinical presentation (see section 4.4). Other causes of fever, hypoxia, and hypotension should be evaluated and treated. If CRS is suspected, TALVEY should be withheld until CRS resolves and should be managed according to the recommendations in Table 3.
Supportive therapy for CRS should be administered, which may include intensive care for severe or life-threatening CRS. Laboratory testing should be considered to monitor for disseminated intravascular coagulation (DIC), haematology parameters, as well as pulmonary, cardiac, renal, and hepatic function.

Table 3:     Recommendations for management of CRS
CRS Gradea                 TALVEY actions          Tocilizumabb                                        Corticosteroidsc Grade 1                Withhold TALVEY until May be considered.                                    Not applicable CRS resolves.
Temperature ≥ 38°Cd
Administer pre-treatment medicinal product prior to next dose of
TALVEY.


Grade 2                          Withhold TALVEY until               Administer tocilizumabc          If no improvement CRS resolves.                       8 mg/kg intravenously            within 24 hours of Temperature ≥ 38°Cd                                                  over 1 hour (not to              starting tocilizumab, with either:                     Administer pre-treatment            exceed 800 mg).                  administer medicinal products prior                                             methylprednisolone • Hypotension                    to next dose of                     Repeat tocilizumab every         1 mg/kg intravenously responsive to fluids           TALVEY.                             8 hours as needed, if not        twice daily, or and not requiring                                                  responsive to intravenous        dexamethasone 10 mg vasopressors, or               Monitor patient for                 fluids or increasing             intravenously every 48 hours following the              supplemental oxygen.             6 hours.
• Oxygen requirement             next dose of TALVEY.
of low-flow nasal              Instruct patients to                Limit to a maximum of            Continue corticosteroid cannulae or blow-by.           remain within proximity             3 doses in a 24-hour             use until the event is of a healthcare facility            period; maximum total of         Grade 1 or less, then during monitoring.                  4 doses.                         taper over 3 days.
Grade 3                          Duration < 48 hours                 Administer tocilizumab           If no improvement, 8 mg/kg intravenously            administer
Temperature ≥ 38°Cd              Per Grade 2.                        over 1 hour (not to              methylprednisolone with either:                                                         exceed 800 mg).                  1 mg/kg intravenously Recurrent or                                                         twice daily or • Hypotension                    Duration ≥ 48 hours                 Repeat tocilizumab every         dexamethasone requiring one                                                      8 hours as needed, if not        (e.g., 10 mg vasopressor, with or           Permanently discontinue             responsive to intravenous        intravenously every without vasopressin,           TALVEY.                             fluids or increasing             6 hours).
or                                                                 supplemental oxygen.
Continue corticosteroid
• Oxygen requirement                                                 Limit to a maximum of            use until the event is of high-flow nasal                                                 3 doses in a 24-hour             Grade 1 or less, then cannulae, facemask,                                                period; maximum total of         taper over 3 days.
non-rebreather mask,                                               4 doses.
or Venturi mask
Grade 4                          Permanently discontinue             Administer tocilizumab           As above or administer TALVEY.                             8 mg/kg intravenously            methylprednisolone Temperature ≥ 38°Cd                                                  over 1 hour (not to              1 000 mg intravenously with either:                                                         exceed 800 mg).                  per day for 3 days, per physician discretion.
• Hypotension                                                        Repeat tocilizumab every requiring multiple                                                 8 hours as needed, if not        If no improvement or if vasopressors                                                       responsive to intravenous        condition worsens, (excluding                                                         fluids or increasing             consider alternate vasopressin), or                                                   supplemental oxygen.             immunosuppressants.c 
• oxygen requirement                                                 Limit to a maximum of of positive pressure                                               3 doses in a 24-hour (e.g., continuous                                                  period; maximum total of positive airway                                                    4 doses.
pressure [CPAP],
bilevel positive airway pressure
[BiPAP], intubation,
and mechanical ventilation) a
Based on ASTCT grading for CRS (Lee et al 2019).
b
Refer to tocilizumab prescribing information for details.
c
Treat unresponsive CRS per institutional guidelines.
d
Attributed to CRS. Fever may not always be present concurrently with hypotension or hypoxia as it may be masked by interventions such as antipyretics or anticytokine therapy (e.g., tocilizumab or corticosteroids).
e
Low-flow nasal cannula is ≤ 6 L/min, and high-flow nasal cannula is > 6 L/min.



Neurologic toxicity, including ICANS
At the first sign of neurologic toxicity, including ICANS, TALVEY should be withheld and neurology evaluation should be considered. Other causes of neurologic symptoms should be ruled out.
Supportive therapy should be provided, which may include intensive care, for severe or life-threatening ICANS (see section 4.4). Management recommendations for ICANS are summarised in Table 4.

Table 4:  Recommendations for management of ICANS
ICANS Gradea, b                   Concurrent CRS                                   No concurrent CRS Grade 1                   Management of CRS per Table 3.                     Monitor neurologic symptoms and consider neurology
ICEc score 7-9                     Monitor neurologic symptoms and           consultation and evaluation, per consider neurology consultation and       physician discretion.
or depressed level of              evaluation, per physician discretion.
consciousnessd: awakens            Withhold TALVEY until ICANS resolves.
spontaneously.
Consider non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis.
Grade 2                            Administer tocilizumab per Table 3 for Administer dexamethasonee management of CRS.                       10 mg intravenously every
ICEc score 3-6                                                              6 hours. Continue If no improvement after starting         dexamethasone use until or depressed level of              tocilizumab, administer                  resolution to Grade 1 or less, consciousnessd: awakens to         dexamethasonee 10 mg intravenously       then taper.
voice.                             every 6 hours if not already taking other corticosteroids. Continue dexamethasone use until resolution to
Grade 1 or less, then taper.
Withhold TALVEY until ICANS resolves.

Consider non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis. Consider neurology consultation and other specialists for further evaluation, as needed.

Monitor patient for 48 hours following the next dose of TALVEY. Instruct patients to remain within proximity of a healthcare facility during monitoring.
Grade 3                            Administer tocilizumab per Table 3 for Administer dexamethasonee management of CRS.                        10 mg intravenously every
ICEc score 0-2                                                               6 hours. Continue (If ICE score is 0, but the        Administer dexamethasonee 10 mg           dexamethasone use until patient is arousable (e.g.,        intravenously with the first dose of      resolution to Grade 1 or less, awake with global aphasia) and     tocilizumab and repeat dose every         then taper.
able to perform assessment)        6 hours. Continue dexamethasone use until resolution to Grade 1 or less, then taper.



or depressed level of               Consider non-sedating, anti-seizure medicines (e.g., levetiracetam) for consciousnessd: awakens only        seizure prophylaxis. Consider neurology consultation and other specialists to tactile stimulus,                for further evaluation, as needed.
 or seizuresd, either:               First Occurrence:
• any clinical seizure, focal       Withhold TALVEY until ICANS resolves.
or generalised, that resolves rapidly, or                     Monitor patient for 48 hours following the next dose of TALVEY. Instruct • non-convulsive seizures on        patients to remain within proximity of a healthcare facility during electroencephalogram            monitoring.
(EEG) that resolve with intervention,                   Recurrent:
Permanently discontinue TALVEY.
or raised intracranial pressure: focal/local oedema on neuroimagingd.
Grade 4                             Administer tocilizumab per Table 3 for      Administer dexamethasonee management of CRS.                          10 mg intravenously and repeat ICEc score 0                                                                    dose every 6 hours. Continue (Patient is unarousable and         Administer dexamethasonee 10 mg             dexamethasone use until unable to perform ICE               intravenously and repeat dose every         resolution to Grade 1 or less, assessment)                         6 hours. Continue dexamethasone use         then taper.
until resolution to Grade 1 or less, then or depressed level of               taper.                                      Alternatively, consider consciousnessd either:                                                          administration of • patient is unarousable or         Alternatively, consider administration      methylprednisolone 1 000 mg requires vigorous or            of methylprednisolone 1 000 mg per          per day intravenously for 3 days; repetitive tactile stimuli to   day intravenously with first dose of        if improves, then manage as arouse, or                      tocilizumab, and continue                   above.
• stupor or coma,                   methylprednisolone 1 000 mg per day intravenously for 2 or more days.
or seizuresd, either:               Permanently discontinue TALVEY.
• life-threatening prolonged seizure (> 5 minutes), or       Consider non-sedating, anti-seizure medicines (e.g., levetiracetam) for • repetitive clinical or            seizure prophylaxis. Consider neurology consultation and other specialists electrical seizures without     for further evaluation, as needed.
return to baseline in between,                        In case of raised intracranial pressure/cerebral oedema, refer to local institutional guidelines for management.
or motor findingsd:
• deep focal motor weakness such as hemiparesis or paraparesis,
 or raised intracranial pressure/cerebral oedemad,
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
Management is determined by the most severe event, not attributable to any other cause.
b
ASTCT 2019 grading for ICANS.
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
Attributable to no other cause.
e
All references to dexamethasone administration are dexamethasone or equivalent 

Table 5:    Recommendations for management of neurologic toxicity (excluding ICANS) Adverse Reaction        Severitya                                Actions Neurologic       Grade 1               • Withhold TALVEY until neurologic toxicity Toxicitya                                  symptoms resolve or stabilise.b (excluding       Grade 2               • Withhold TALVEY until neurologic toxicity ICANS)           Grade 3 (First            symptoms improve to Grade 1 or less.b occurrence)           • Provide supportive therapy.
Grade 3 (Recurrent)   • Permanently discontinue TALVEY.
Grade 4               • Provide supportive therapy, which may include intensive care.
a
Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03.
b
See Table 2 for recommendations on restarting TALVEY after dose delays.


Other adverse reactions
The recommended dose modifications for other adverse reactions are provided in Table 6.
Table 6:       Recommended dose modifications for other adverse reactions Adverse reaction             Severity                           Dose modification Serious infections         All Grades              • Do not administer TALVEY step-up dosing (see section 4.4)                                     schedule in patients with active infection.
• Withhold TALVEY in the step-up phase until infection resolves.
Grade 3-4               • Withhold TALVEY during the treatment phase until infection improves to Grade 2 or better.
Cytopenias                 Absolute neutrophil     • Withhold TALVEY until absolute neutrophil (see section 4.4)          count less than            count is 0.5 × 109/L or higher.
0.5 × 10 /L
9

Febrile neutropenia     • Withhold TALVEY until absolute neutrophil count is 1.0 × 109/L or higher and fever resolves.
Haemoglobin less        • Withhold TALVEY until haemoglobin is 8 g/dL or than 8 g/dL                higher.

Platelet count less              • Withhold TALVEY until platelet count is than 25 000/µL                     25 000/µL or higher and no evidence of bleeding.

Platelet count between 25 000/µL and 50 000/µL with bleeding

Oral toxicity, including              Toxicity not                     Interrupt TALVEY until stabilisation or improvement, weight loss                           responding to                    and consider restarting on modified schedule as (see section 4.4)                     supportive care                  follows: • If current dose is 0.4 mg/kg every week, change to
0.4 mg/kg every two weeks
• If current dose is 0.8 mg/kg every two weeks,
change to 0.8 mg/kg every four weeks
Skin reactions, including             Grade 3-4                        • Withhold TALVEY until adverse reaction nail disorders                                                             improves to Grade 1 or baseline.
(see section 4.4)
Other non-haematologic              Grade 3-4                      • Withhold TALVEY until adverse reaction adverse reactionsa                                                   improves to Grade 1 or baseline.
(see section 4.8) a
Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.03.


Special populations
Paediatric population
There is no relevant use of TALVEY in the paediatric population in the treatment of multiple myeloma.

Elderly
No dose adjustment is required (see section 5.2).

Renal impairment
No dose adjustment is recommended for patients with mild or moderate renal impairment (see section 5.2).

Hepatic impairment
No dose adjustment is recommended for patients with mild hepatic impairment (see section 5.2).
Limited or no data are available in patients with moderate and severe hepatic impairment.

Method of administration
TALVEY is for subcutaneous use.

The required volume of TALVEY should be injected into the subcutaneous tissue of the abdomen (preferred injection site). Alternatively, TALVEY may be injected into the subcutaneous tissue at other sites (e.g., thigh). If multiple injections are required, TALVEY injections should be at least 2 cm apart.

TALVEY must not be injected into tattoos or scars or areas where the skin is red, bruised, tender, hard or not intact.

For instructions on handling of the medicinal product before administration, see section 6.6.