4.1. Therapeutic indications

TECVAYLI is indicated as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, who have received at least three prior therapies, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody and have demonstrated disease progression on the last therapy.

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. In patients who have a complete response or better for a minimum of 6 months, a reduced dosing frequency of 1.5 mg/kg SC every two weeks may be considered (see section 5.1).

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

All patients

Step-up dosing scheduleb

Day 1

Step‑up dose 1

0.06 mg/kg SC single dose

Day 3c

Step‑up dose 2

0.3 mg/kg SC single dose

Day 5d

First maintenance dose

1.5 mg/kg SC single dose

Weekly dosing scheduleb

One week after first maintenance dose and weekly thereaftere

Subsequent maintenance doses

1.5 mg/kg SC once weekly

Patients who have a complete response or better for a minimum of 6 months

Biweekly (every two weeks) dosing scheduleb

Consider reducing the dosing frequency to 1.5 mg/kg SC every two weeks

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.

Refer to Tables 9, 10 and 11 to determine the dosage based on predetermined weight ranges (see section 6.6).

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 administered

Duration of delay from the last dose administered

Action

Step-up dose 1

More than 1 week (> 7 days)

Restart TECVAYLI step-up dosing schedule at Step-up dose 1 (0.06 mg/kg)a.

Step-up dose 2

More than 1 week to less than or equal to 4 weeks (8 days to ≤ 28 days)

Repeat Step-up dose 2 (0.3 mg/kg)a and continue TECVAYLI step-up dosing schedule.

More than 4 weeks (>28 days)

Restart TECVAYLI step-up dosing schedule at Step-up dose 1 (0.06 mg/kg)a.

Any maintenance doses

More than 1 week to less than or equal to 9 weeks (8 days to ≤ 63 days)

Continue TECVAYLI at last maintenance dose and schedule(1.5 mg/kg once weekly or 1.5 mg/kg every two weeks).

More than 9 weeks to less than or equal to 16 weeks (64 days to ≤ 112 days)

Restart TECVAYLI step-up dosing schedule at Step-up dose 2 (0.3 mg/kg)a.

More than 16 weeks (>112 days)

Restart TECVAYLI step-up dosing schedule at 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 syndromea (see section 4.4)

Grade 1

• Temperature ≥38°Cb

• Withhold TECVAYLI until adverse reaction resolves.

• See Table 4 for management of cytokine release syndrome.

• Administer pre‑treatment medicinal products prior to next dose of TECVAYLI.

Grade 2

• Temperature ≥38°Cb with either:

• Hypotension responsive to fluids and not requiring vasopressors, or

• Oxygen requirement of low-flow nasal cannulac or blow-by

Grade 3 (Duration: less than 48 hours)

• Temperature ≥38°Cb with either:

• Hypotension requiring one vasopressor with or without vasopressin, or

• Oxygen requirement of high-flow nasal cannulac, facemask, non-rebreather mask, or Venturi mask

• Withhold TECVAYLI until adverse reaction resolves.

• See Table 4 for management of cytokine release syndrome.

• Administer pre‑treatment medicinal products prior to next dose of TECVAYLI.

• 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 or duration: more than 48 hours)

• Temperature ≥38°Cb with either:

• Hypotension requiring one 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).

• Permanently discontinue therapy with TECVAYLI.

• See Table 4 for management of cytokine release syndrome.

Immune effector cell‑associated neurotoxicity syndrome (ICANS)d (see section 4.4)

Grade 1

• Withhold TECVAYLI until adverse reaction resolves.

• See Table 5 for management of immune effector cell‑associated neurotoxicity syndrome.

Grade 2

Grade 3 (First occurrence)

• Withhold TECVAYLI until 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)

Grade 4

• Permanently discontinue therapy with TECVAYLI.

• See Table 5 for management of immune effector cell‑associated neurotoxicity syndrome.

Infections (see section 4.4)

All Grades

• Do not administer TECVAYLI step-up dosing schedule in patients with active infection. TECVAYLI step‑up dosing schedule may proceed upon resolution of active infection.

Grade 3

Grade 4

• Withhold subsequent maintenance doses of TECVAYLI (i.e., doses administered after TECVAYLI step-up dosing schedule) until infection improves to Grade 2 or better.

Haematologic toxicities (see sections 4.4 and 4.8)

Absolute neutrophil count less than 0.5 x 109/L

• Withhold TECVAYLI until absolute neutrophil count is 0.5 x 109/L or higher.

Febrile neutropenia

• Withhold TECVAYLI until absolute neutrophil count is 1.0 x 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

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

• Withhold TECVAYLI until platelet count is 25 000/µL or higher and no evidence of bleeding.

Other adverse reactions (see section 4.8)e

Grade 3

Grade 4

• Withhold TECVAYLI until adverse reaction improves to 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.

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

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Cytokine release syndrome (CRS)

Cytokine release syndrome, including life-threatening or fatal reactions, may occur in patients receiving 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-threatening complications 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 reduce risk of CRS. Pre‑treatment medicinal products (corticosteroids, antihistamine and antipyretics) should be 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 and monitored 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‑treatment medicinal products prior to the next dose of TECVAYLI.

Patients should be counselled to seek medical attention should signs or symptoms of CRS occur. At the first sign of CRS, patients should be immediately evaluated for hospitalisation. Treatment with supportive care, tocilizumab and/or corticosteroids should be instituted, based on severity as indicated in Table 4 below. The use of myeloid growth factors, particularly granulocyte macrophage-colony stimulating factor (GM-CSF), has the potential to worsen CRS symptoms and should be avoided during 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 for other 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, supplemental oxygen, etc.) should be administered as appropriate. Laboratory testing to monitor for disseminated intravascular coagulation (DIC), haematology parameters, as well as pulmonary, cardiac, renal, and hepatic function should be considered.

Table 4: Recommendations for management of cytokine release syndrome with tocilizumab and corticosteroids

Gradee

Presenting symptoms

Tocilizumaba

Corticosteroidsb

Grade 1

Temperature ≥38°Cc

May be considered

Not applicable

Grade 2

Temperature ≥38°Cc with either:

• Hypotension responsive to fluids and not requiring vasopressors, or

• Oxygen requirement of low-flow nasal cannulad or blow-by

Administer tocilizumabb 8 mg/kg intravenously over 1 hour (not to exceed 800 mg).

Repeat tocilizumab every 8 hours as needed, if not responsive to intravenous fluids or increasing supplemental oxygen.

Limit to a maximum of 3 doses in a 24‑hour period; maximum total of 4 doses.

If no improvement within 24 hours of starting tocilizumab, administer methylprednisolone 1 mg/kg intravenously twice daily, or dexamethasone 10 mg intravenously every 6 hours.

Continue corticosteroid use until the event is Grade 1 or less, then taper over 3 days.

Grade 3

Temperature ≥38°Cc with either:

• Hypotension requiring one vasopressor with or without vasopressin, or

• Oxygen requirement of high-flow nasal cannulad, facemask, non-rebreather mask, or Venturi mask

Administer tocilizumab 8 mg/kg intravenously over 1 hour (not to exceed 800 mg).

Repeat tocilizumab every 8 hours as needed, if not responsive to intravenous fluids or increasing supplemental oxygen.

Limit to a maximum of 3 doses in a 24‑hour period; maximum total of 4 doses.

If no improvement, administer methylprednisolone 1 mg/kg intravenously twice daily, or dexamethasone 10 mg intravenously every 6 hours.

Continue corticosteroid use until the event is Grade 1 or less, then taper over 3 days.

Grade 4

Temperature ≥38°Cc 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)

Administer tocilizumab 8 mg/kg intravenously over 1 hour (not to exceed 800 mg).

Repeat tocilizumab every 8 hours as needed if not responsive to intravenous fluids or increasing supplemental oxygen.

Limit to a maximum of 3 doses in a 24‑hour period; maximum total of 4 doses.

As above, or administer methylprednisolone 1 000 mg intravenously per day for 3 days, per physician discretion.

If no improvement or if condition worsens, consider alternate immunosuppressants b.

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 by interventions 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 and treated promptly.

Patients should be counselled to seek medical attention should signs or symptoms of neurologic toxicity occur. At the first sign of neurologic toxicity, including ICANS, patients should be immediately 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 be instructed to remain within proximity of a healthcare facility and monitored for signs and symptoms daily for 48 hours.

For ICANS and other neurologic toxicities, treatment with TECVAYLI should be withheld as indicated in Table 3 (see section 4.2).

Due to the potential for ICANS, patients should be advised not to drive or operate heavy machinery during the TECVAYLI step-up dosing schedule and for 48 hours after completing the TECVAYLI step-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 until adverse reaction resolves (see Table 3). Intensive care and supportive therapy should be provided for severe 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 neurotoxicity syndrome (ICANS)

Grade

Presenting symptomsa

Concurrent CRS

No Concurrent CRS

Grade 1

ICE score 7-9b

Or, depressed level of consciousnessc: awakens spontaneously.

Management of CRS per Table 4.

Monitor neurologic symptoms and consider neurology consultation and evaluation, per physician discretion.

Monitor neurologic symptoms and consider neurology consultation and evaluation, per physician discretion.

Consider non-sedating, anti-seizure medicinal products (e.g., levetiracetam) for seizure prophylaxis.

Grade 2

ICE score 3-6b

Or, depressed level of consciousnessc: awakens to voice.

Administer tocilizumab per Table 4 for management of CRS.

If no improvement after starting tocilizumab, administer dexamethasoned 10 mg intravenously every 6 hours if not already taking other corticosteroids. Continue dexamethasone use until resolution to Grade 1 or less, then taper.

Administer dexamethasoned 10 mg intravenously every 6 hours.

Continue dexamethasone use until resolution to Grade 1 or less, then taper.

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

Grade 3

ICE score 0-2b

Or, depressed level of consciousnessc: awakens only to tactile stimulus, or

seizuresc, either:

• any clinical seizure, focal or generalised that resolves rapidly, or

• non-convulsive seizures on electroencephalogram (EEG) that resolve with intervention, or

raised intracranial pressure: focal/local oedema on neuroimagingc.

Administer tocilizumab per Table 4 for management of CRS.

In addition, administer dexamethasoned 10 mg intravenously with the first dose of tocilizumab, and repeat dose every 6 hours. Continue dexamethasone use until resolution to Grade 1 or less, then taper.

Administer dexamethasoned 10 mg intravenously every 6 hours.

Continue dexamethasone use until resolution to Grade 1 or less, then taper.

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

Grade 4

ICE score 0b

Or, depressed level of consciousnessc either:

• patient is unarousable or requires vigorous or repetitive tactile stimuli to arouse, or

• stupor or coma, or

seizuresc, either:

• life-threatening prolonged seizure (>5 minutes), or

• repetitive clinical or electrical seizures without return to baseline in between, or

motor findingsc:

• deep focal motor weakness such as hemiparesis or paraparesis, or

raised intracranial pressure / cerebral oedemac, 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

Administer tocilizumab per Table 4 for management of CRS.

As above, or consider administration of methylprednisolone 1 000 mg per day intravenously with first dose of tocilizumab, and continue methylprednisolone 1 000 mg per day intravenously for 2 or more days.

As above, or consider administration of methylprednisolone 1 000 mg per day intravenously for 3 days; if improves, then manage as above.

Consider non-sedating, anti-seizure medicinal products (e.g., levetiracetam) for seizure prophylaxis. Consider neurology consultation and other specialists for further evaluation, as needed. In case of raised intracranial pressure/cerebral oedema, refer to institutional guidelines for management.

a 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 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.

c Attributable to no other cause.

d All references to dexamethasone administration are dexamethasone or equivalent.

Infections

Severe, life-threatening, or fatal infections have been reported in patients receiving TECVAYLI (see section 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 according to local institutional guidelines.

TECVAYLI step-up dosing schedule should not be administered in patients with active infection. For subsequent 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 in patients receiving TECVAYLI. Patients should be monitored for any new onset of or changes in pre‑existing neurological signs or symptoms. If PML is suspected, treatment with TECVAYLI should be withheld and appropriate diagnostic testing initiated. If PML is confirmed, TECVAYLI must be discontinued.

Hepatitis B virus reactivation

Hepatitis B virus reactivation can occur in patients treated with medicinal products directed against B cells, 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 signs of 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 TECVAYLI should be withheld as indicated in Table 3 and manage per local institutional guidelines (see section 4.2).

Hypogammaglobulinaemia

Hypogammaglobulinaemia has been reported in patients receiving TECVAYLI (see section 4.8).

Immunoglobulin levels should be monitored during treatment with TECVAYLI. Intravenous or subcutaneous 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 not been studied. Vaccination with live virus vaccines is not recommended for at least 4 weeks prior to the start of treatment, during treatment and least 4 weeks after treatment.

Neutropenia

Neutropenia and febrile neutropenia have been reported in patients who received TECVAYLI (see section 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).

Tumour flare

Tumour flare has been reported in patients receiving TECVAYLI (see section 4.8). Manifestations included localised pain and symptoms of nerve and spinal compression due to transient tumour enlargement. Tumour flare does not imply treatment failure or tumour progression. Monitoring and evaluation of tumour flare is recommended in patients treated with TECVAYLI and should be managed as clinically indicated.

Excipients

Sodium

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 mg per 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 TECVAYLI step-up schedule up to 7 days after the first maintenance dose or during a CRS event. During this time period, toxicity or medicinal product concentrations (e.g., cyclosporine) should be monitored in patients who are receiving concomitant CYP450 substrates with a narrow therapeutic index. The dose of 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 treatment with TECVAYLI.

Women of child-bearing potential should use effective contraception during treatment and for five months after the final dose of TECVAYLI. In clinical studies, male patients with a female partner of child-bearing potential used effective contraception during treatment and for three months after the last dose of teclistamab.

Pregnancy

There are no available data on the use of teclistamab in pregnant women or animal data to assess the risk of teclistamab in pregnancy. Human IgG is known to cross the placenta after the first trimester of pregnancy. Therefore, teclistamab, a humanised IgG4-based antibody, has the potential to be transmitted from the mother to the developing foetus. TECVAYLI is not recommended for women who are pregnant. TECVAYLI is associated with hypogammaglobulinaemia, therefore, assessment of immunoglobulin levels in newborns of mothers treated with TECVAYLI should be considered.

Breast-feeding

It is not known whether teclistamab is excreted in human or animal milk, affects breast‑fed infants or affects milk production. Because of the potential for serious adverse reactions in breast‑fed infants from TECVAYLI, patients should be advised not to breast‑feed during treatment with TECVAYLI and for at least five months after the last dose.

Fertility

There are no data on the effect of teclistamab on fertility. Effects of teclistamab on male and female fertility 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 of consciousness (see section 4.8). Patients should be instructed to avoid driving and operating heavy or potentially dangerous machinery during and for 48 hours after completion of TECVAYLI step-up dosing schedule and in the event of new onset of any neurological symptoms (Table 1) (see section 4.2 and 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, including pneumonia (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 reactions

The safety data of TECVAYLI was evaluated in MajesTEC-1, which included 165 adult patients with multiple 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 data of TECVAYLI was also evaluated in the all treated population (N=302) with no additional adverse reactions identified.

Adverse reactions observed during clinical studies are listed below by frequency category. Frequency categories 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 (frequency cannot 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

System Organ Class

Adverse Reaction

Frequency

(All grades)

N=165

n (%)

Any Grade

Grade 3 or 4

Infections and infestations

Pneumonia1

Very common

46 (28%)

32 (19%)

Sepsis2

Common

13 (7.9%)

11 (6.7%)

COVID-193

Very common

30 (18%)

20 (12%)

Upper respiratory tract infection4

Very common

61 (37%)

4 (2.4%)

Cellulitis

Common

7 (4.2%)

5 (3.0%)

Urinary tract infection5, 21

Very common

23 (14%)

10 (6.1%)

Progressive multifocal leukoencephalopathy21

Uncommon

1 (0.6%)

1 (0.6%)

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Tumour flare22

Not known

Blood and lymphatic system disorders

Neutropenia

Very common

117 (71%)

106 (64%)

Febrile neutropenia

Common

6 (3.6%)

5 (3.0%)

Thrombocytopenia

Very common

66 (40%)

35 (21%)

Lymphopenia

Very common

57 (35%)

54 (33%)

Anaemia6

Very common

90 (55%)

61 (37%)

Leukopenia

Very common

29 (18%)

12 (7.3%)

Hypofibrinogenaemia

Common

16 (9.7%)

2 (1.2%)

Immune system disorders

Cytokine release syndrome

Very common

119 (72%)

1 (0.6%)

Hypogammaglobulinaemia7

Very common

123 (75%)

3 (1.8%)

Metabolism and nutrition disorders

Hyperamylasaemia

Common

6 (3.6%)

4 (2.4%)

Hyperkalaemia

Common

8 (4.8%)

2 (1.2%)

Hypercalcaemia

Very common

19 (12%)

5 (3.0%)

Hyponatraemia

Common

13 (7.9%)

8 (4.8%)

Hypokalaemia

Very common

23 (14%)

8 (4.8%)

Hypocalcaemia

Common

12 (7.3%)

0

Hypophosphataemia

Very common

20 (12%)

10 (6.1%)

Hypoalbuminaemia

Common

4 (2.4%)

1 (0.6%)

Hypomagnesaemia

Very common

22 (13%)

0

Decreased appetite

Very common

20 (12%)

1 (0.6%)

Hypoglycaemia21

Common

4 (2.4%)

0

Nervous system disorders

Immune effector cell-associated neurotoxicity syndrome

Common

5 (3.0%)

0

Encephalopathy8

Common

16 (9.7%)

0

Neuropathy peripheral9

Very common

26 (16%)

1 (0.6%)

Headache

Very common

39 (24%)

1 (0.6%)

Vascular disorders

Haemorrhage10

Very common

20 (12%)

5 (3.0%)

Hypertension11

Very common

21 (13%)

9 (5.5%)

Hypotension21

Very common

18 (11%)

4 (2.4%)

Respiratory, thoracic and mediastinal disorders

Hypoxia

Common

16 (9.7%)

6 (3.6%)

Dyspnoea12

Very common

22 (13%)

3 (1.8%)

Cough13

Very common

39 (24%)

0

Gastrointestinal disorders

Diarrhoea

Very common

47 (28%)

6 (3.6%)

Abdominal pain14, 21

Very common

20 (12%)

2 (1.2%)

Vomiting

Very common

21 (13%)

1 (0.6%)

Nausea

Very common

45 (27%)

1 (0.6%)

Constipation

Very common

34 (21%)

0

Musculoskeletal and connective tissue disorders

Musculoskeletal pain15

Very common

85 (52%)

14 (8.5%)

Muscle spasms21

Very common

17 (10%)

0

General disorders and administration site conditions

Pyrexia

Very common

45 (27%)

1 (0.6%)

Injection site reaction16

Very common

62 (38%)

1 (0.6%)

Pain17

Very common

34 (21%)

3 (1.8%)

Oedema18

Very common

23 (14%)

0

Fatigue19

Very common

67 (41%)

5 (3.0%)

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 increased

Very common

18 (11%)

3 (1.8%)

Gamma-glutamyltransferase increased

Common

16 (9.7%)

5 (3.0%)

Activated partial thromboplastin time prolonged

Common

13 (7.9%)

2 (1.2%)

International normalised ratio increased

Common

10 (6.1%)

2 (1.2%)

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, Pneumonia bacterial, 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, Pseudomonal sepsis, 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 infection and 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 with teclistamab.

8 Encephalopathy includes confusional state, depressed level of consciousness, lethargy, memory impairment and somnolence.

9 Neuropathy peripheral includes dysaesthesia, hypoaesthesia, hypoaesthesia oral, neuralgia, paraesthesia, paraesthesia oral, peripheral sensory neuropathy and sciatica.

10 Haemorrhage includes conjunctival haemorrhage, epistaxis, haematoma, haematuria, haemoperitoneum, haemorrhoidal haemorrhage, 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 site erythema, 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, toothache and 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.

22 Based on post-marketing experience.

Description of selected adverse reactions

Cytokine 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 CRS following Step-up Dose 1 (44%), Step-up Dose 2 (35%), or the initial maintenance dose (24%). Less than 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 were used 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%). The most frequently reported neurologic toxicity event was headache (8%).

ICANS, including Grade 3 and higher, were reported in clinical trials and with post‑marketing experience. The most frequent clinical manifestation of ICANS were confusional state, decreased level of consciousness, disorientation, dysgraphia, aphasia, apraxia, and somnolence. The onset of neurologic 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.

Immunogenicity

Patients treated with subcutaneous teclistamab monotherapy (N=238) in MajesTEC-1 were evaluated for antibodies to teclistamab using an electrochemiluminescence-based immunoassay. One subject (0.4%) developed neutralising antibodies to teclistamab of low-titre.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: https://yellowcard.mhra.gov.uk/ or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Symptoms and signs

The maximum tolerated dose of teclistamab has not been determined. In clinical studies, doses of up to 6 mg/kg have been administered.

Treatment

In the event of an overdose, the patient should be monitored for any signs or symptoms of adverse reactions, and appropriate symptomatic treatment should be instituted immediately.