Posology : מינונים

4.2    Posology and method of administration

Treatment with TECVAYLI should be initiated and supervised by physicians experienced in the treatment of multiple myeloma.


TECVAYLI 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) (see section 4.4).

Posology

Pre-treatment medicinal products should be administered prior to each dose of TECVAYLI in the step-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 doses of TECVAYLI are 1.5 mg/kg by subcutaneous injection (SC) weekly, preceded by step-up doses of 0.06 mg/kg and 0.3 mg/kg.

Treatment with TECVAYLI should be initiated according to the step-up dosing schedule in Table 1 to reduce the incidence and severity of cytokine release syndrome. Due to the risk of cytokine release syndrome, patients should be instructed to remain within proximity of a healthcare facility, and monitored 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-initiation of therapy after dose delays, may result in increased frequency and severity of adverse reactions related to mechanism of action, particularly cytokine release syndrome (see section 4.4).

Table 1:   TECVAYLI dosing schedule
Dosing schedule            Day                                                    Dosea Day 1                                  Step-up dose 1      0.06 mg/kg single dose Step-up dosing           Day 3c                                 Step-up dose 2      0.3 mg/kg single dose scheduleb            Day 5d                                 First maintenance    1.5 mg/kg single dose dose
One week after first
Weekly dosing                                                    Subsequent maintenance dose and                                         1.5 mg/kg once weekly scheduleb                                                    maintenance doses weekly thereaftere a
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 maintenance dose (1.5 mg/kg).e        Maintain a minimum of five days between weekly maintenance doses.

Duration of treatment

Patients 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 of the 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 of subsequent 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 the prevention 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 listed in Table 2 and TECVAYLI resumed according to the dosing schedule (see Table 1). Pre-treatment medicinal products should be administered as indicated in Table 2. Patients should be monitored accordingly (see section 4.2).

Table 2:   Recommendations for restarting therapy with TECVAYLI after dose delay Last dose     Duration of delay from                        Action administered         the last dose administered
Restart TECVAYLI step-up dosing schedule at
Step-up dose 1      More than 7 days
Step-up dose 1 (0.06 mg/kg)a.
Repeat Step-up dose 2 (0.3 mg/kg)a and
8 days to 28 days continue TECVAYLI step-up dosing schedule.
Step-up dose 2
Restart TECVAYLI step-up dosing schedule at
More than 28 days
Step-up dose 1 (0.06 mg/kg)a.
Continue TECVAYLI dosing schedule at
8 days to 28 days
Any maintenance                             maintenance dose (1.5 mg/kg)a.
doses                                 Restart TECVAYLI step-up dosing schedule at More than 28 days
Step-up dose 1 (0.06 mg/kg)a.
a
Pre-treatment medicinal products should be administered prior to TECVAYLI dose and patients monitored accordingly.

Dose modifications

Treatment 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 until syndromea (see       • Temperature ≥38 °Cb                     adverse reaction resolves.
section 4.4)                                                • See Table 4 for management of cytokine release syndrome.
• Administer pre-treatment medicinal products prior to next dose of TECVAYLI.
Grade 2                                • Withhold TECVAYLI until
• Temperature ≥38 °Cb with either:        adverse reaction resolves.
• Hypotension responsive to         • See Table 4 for management of fluids and not requiring            cytokine release syndrome.
vasopressors, or                 • Administer pre-treatment
• Oxygen requirement of low-           medicinal products prior to flow 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 within vasopressor with or without         proximity of a healthcare vasopressin, or                     facility during daily
• Oxygen requirement of high-          monitoring.
flow nasal cannulac, facemask,
non-rebreather mask, or Venturi mask
Grade 3 (Recurrent or duration: more • Permanently discontinue than 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 without vasopressin, or
• Oxygen requirement of high- flow nasal cannulac, facemask,
non-rebreather mask, or Venturi mask.

Grade 4
• Temperature ≥38 °Cb with either:
• Hypotension requiring multiple vasopressors (excluding vasopressin), or
• Oxygen requirement of positive pressure (e.g., continuous positive airway pressure
[CPAP], bilevel positive airway pressure [BiPAP], intubation,
and mechanical ventilation).


Immune effector             Grade 1                                • Withhold TECVAYLI until cell-associated                                                      adverse reaction resolves.
neurotoxicity                                                      • See Table 5 for management of syndrome (ICANS)d                                                    immune effector (see section 4.4)                                                    cell-associated neurotoxicity syndrome.
Grade 2                                • Withhold TECVAYLI until
Grade 3 (First occurrence)               adverse reaction resolves.
• See Table 5 for management of immune effector cell-associated neurotoxicity syndrome.
• Monitor patient daily for
48 hours following the next dose of TECVAYLI. Instruct patients to remain within proximity of a healthcare facility during daily monitoring.
Grade 3 (Recurrent)                    • Permanently discontinue
Grade 4                                  therapy with TECVAYLI.
• See Table 5 for management of immune effector cell-associated neurotoxicity syndrome.
Infections (see             All Grades                             • Do not administer TECVAYLI section 4.4)                                                         step-up dosing schedule in patients with active infection.
TECVAYLI step-up dosing schedule may proceed upon resolution of active infection.
Grade 3                                • Withhold subsequent
Grade 4                                  maintenance doses of
TECVAYLI (i.e., doses administered after TECVAYLI step-up dosing schedule) until infection improves to Grade 2 or better.
Haematologic                Absolute neutrophil count less than    • Withhold TECVAYLI until toxicities (see             0.5109/L                                absolute neutrophil count is sections 4.4 and 4.8)                                                0.5109/L or higher.
Febrile neutropenia                    • Withhold TECVAYLI until absolute neutrophil count is
1.0109/L or higher, and fever resolves.
Haemoglobin less than 8 g/dL           • Withhold TECVAYLI until haemoglobin is 8 g/dL or higher.
Platelet count less than 25 000/µL     • Withhold TECVAYLI until platelet count is 25 000/µL or
Platelet count between 25 000/µL and     higher and no evidence of
50 000/µL with bleeding                  bleeding.
Other adverse               Grade 3                                • Withhold TECVAYLI until reactions (see              Grade 4                                  adverse reaction improves to section 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 by interventions 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 populations

Paediatric population
There is no relevant use of TECVAYLI in the paediatric population for the treatment of multiple myeloma.

Elderly

No dosage adjustment is necessary (see section 5.2).
Renal impairment

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

Hepatic impairment

No dosage adjustment is recommended for patients with mild hepatic impairment (see section 5.2).
Method of administration

TECVAYLI is for subcutaneous injection only.

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