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. This indication is approved under accelerated approval based on response rate [see CLINICAL STUDIES (14)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

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).

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).

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.

Special populations

Paediatric population

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

Elderly (65 years of age and older)

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.

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.

Neurologic toxicities, including ICANS

Serious or life-threatening 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.

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. Progressive multifocal leukoencephalopathy (PML) has also 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).

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).

Excipients

This medicinal product contains less than 1 mmol (23 mg) sodium per dose, that is to say essentially ‘sodium-free’.

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.

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.

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).

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.

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 national reporting system listed in Appendix V.

To report any side effect(s):

Saudi Arabia:

·       The National Pharmacovigilance Centre (NPC):

- SFDA Call Center: 19999

- E-mail: npc.drug@sfda.gov.sa

- Website: https://ade.sfda.gov.sa/

Other GCC States:

-        Please contact the relevant competent authority.

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.

Pharmacotherapeutic group: Other monoclonal antibodies and antibody drug conjugates, ATC code: L01FX24

Mechanism of action

Teclistamab is a full-size, IgG4-PAA bispecific antibody that targets the CD3 receptor expressed on the surface of T cells and B cell maturation antigen (BCMA), which is expressed on the surface of malignant multiple myeloma B-lineage cells, as well as late-stage B cells and plasma cells. With its dual 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 by secreted perforin and various granzymes stored in the secretory vesicles of cytotoxic T cells. This effect occurs without regard to T cell receptor specificity or reliance on major histocompatibility complex (MHC) Class 1 molecules on the surface of antigen presenting cells.

Pharmacodynamic effects

Within the first month of treatment, activation of T-cells, redistribution of T-cells, reduction of B-cells and 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 to teclistamab.

Clinical efficacy and safety

The efficacy of TECVAYLI monotherapy was evaluated in patients with relapsed or refractory multiple myeloma in a single-arm, open-label, multi-centre, Phase 1/2 study (MajesTEC-1). The study included patients who had previously received at least three prior therapies, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. The study excluded patients 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 active or documented history of autoimmune disease with the exception of vitiligo, Type 1 diabetes and prior autoimmune thyroiditis.

Patients received initial step-up doses of 0.06 mg/kg and 0.3 mg/kg of TECVAYLI administered subcutaneously, followed by the maintenance dose of TECVAYLI 1.5 mg/kg, administered subcutaneously once weekly thereafter, until disease progression or unacceptable toxicity. Patients who had a complete response (CR) or better for a minimum of 6 months were eligible to reduce dosing frequency to 1.5 mg/kg subcutaneously every two weeks until disease progression or unacceptable toxicity (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 was 3.1 (Range: 2-9) days. Patients were hospitalised for monitoring for at least 48 hours after administration 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% of patients. 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 received 3 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 were triple-class refractory (refractory to proteasome inhibitor, an immunomodulatory agent and an anti‑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).

The median follow-up after schedule change was 12.6 (Range: 1.0 to 24.7) months in patients who switched to 1.5 mg/kg subcutaneously every two weeks.

Paediatric population

The 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 for information 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 every year and this SmPC will be updated as necessary.

Teclistamab exhibited approximately dose-proportional pharmacokinetics following subcutaneous administration across a dose range of 0.08 mg/kg to 3 mg/kg (0.05 to 2.0 times the recommended dose). Ninety percent of steady state exposure was achieved after 12 weekly maintenance doses. The mean accumulation ratio between the first and 13^th weekly maintenance dose of teclistamab 1.5 mg/kg was 4.2-fold for C_max, 4.1-fold for C_trough, and 5.3-fold for AUC_tau.

The C_max, C_trough, and AUC_tau of teclistamab are presented in Table 8.

Absorption

The mean bioavailability of teclistamab was 72% when administered subcutaneously. The median (range) T_max of teclistamab after the first and 13^th weekly maintenance doses were 139 (19 to 168) hours and 72 (24 to 168) hours, respectively.

Distribution

The mean volume of distribution was 5.63 L (29% coefficient of variation (CV)).

Elimination

Teclistamab clearance decreases over time, with a mean (CV%) maximal reduction from baseline to the 13^th weekly maintenance dose of 40.8% (56%). The geometric mean (CV%) clearance is 0.472 L/day (64%) at the 13^th weekly maintenance dose. Patients who discontinue teclistamab after the 13^th weekly maintenance dose are expected to have a 50% reduction from C_max in teclistamab concentration at a median (5^th to 95^th percentile) time of 15 (7 to 33) days after T_max and a 97% reduction from C_max in teclistamab concentration at a median time of 69 (32 to 163) days after T_max.

Population pharmacokinetic analysis (based on MajesTEC-1) showed that soluble BCMA did not impact teclistamab serum concentrations.

Special populations

The pharmacokinetics of TECVAYLI in paediatric patients aged 17 years and younger have not been investigated.

Results of population pharmacokinetic analyses indicate that age (24 to 84 years) and sex did not influence the pharmacokinetics of teclistamab.

Renal impairment

No 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 moderate renal impairment (30 mL/min/1.73 m² ≤ eGFR <60 mL/min/1.73 m²) did not significantly influence the pharmacokinetics of teclistamab. Limited data are available from patients with severe renal impairment.

Hepatic impairment

No 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 total bilirubin ≤ULN and AST>ULN) did not significantly influence the pharmacokinetics of teclistamab. No data are available in patients with moderate and severe hepatic impairment.

Carcinogenicity and mutagenicity

No animal studies have been performed to assess the carcinogenic or genotoxic potential of teclistamab.

Reproductive toxicology and fertility

No animal studies have been conducted to evaluate the effects of teclistamab on reproduction and foetal development. In the 5-week repeat-dose toxicity study in cynomolgus monkeys, there were no notable 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.

EDTA disodium salt dihydrate

Glacial acetic acid

Polysorbate 20 (E432)

Sodium acetate trihydrate

Sucrose

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Store in a refrigerator (2 °C ‑ 8 °C).

Do not freeze.

Store in the original carton in order to protect from light.

3 mL solution for injection in a Type 1 glass vial with an elastomeric closure, and aluminium seal with a 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 seal with a flip‑off button containing 153 mg of teclistamab (90 mg/mL).

Pack size of 1 vial.

It is very important that the instructions for preparation and administration provided in this section are strictly followed to minimise potential dosing errors with TECVAYLI 10 mg/mL and TECVAYLI 90 mg/mL vials.

TECVAYLI should be administered via subcutaneous injection only. Do not administer TECVAYLI intravenously.

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 (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 local requirements.

Preparation of TECVAYLI

·             Verify the prescribed dose for each TECVAYLI injection. To minimise errors, use the following 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/mL vial.

o      Use Table 10 to determine the total dose, injection volume and number of vials required based on patient’s actual body weight for Step-up dose 2 using TECVAYLI 10 mg/mL vial.

o      Use Table 11 to determine the total dose, injection volume and number of vials required based on patient’s actual body weight for the maintenance dose using TECVAYLI 90 mg/mL vial.

·             Remove the appropriate TECVAYLI vial from refrigerated storage (2 °C – 8 °C) and equilibrate to 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 appropriately sized syringe using a transfer needle.

o      Each injection volume should not exceed 2.0 mL. Divide doses requiring greater than 2.0 mL equally into multiple syringes.

·             TECVAYLI is compatible with stainless steel injection needles and polypropylene and polycarbonate 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 subcutaneous tissue at other sites (e.g., thigh). If multiple injections are required, TECVAYLI injections should be at least 2 cm apart.

·             Do not inject into tattoos or scars or areas where the skin is red, bruised, tender, hard or not intact.