TALVEY Solution for injection Ref.[51257] Active ingredients: Talquetamab

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)

CRS, including life-threatening or fatal reactions, may occur in patients receiving TALVEY (see section 4.8). Clinical signs and symptoms of CRS may include but are not limited to pyrexia, hypotension, chills, hypoxia, headache, tachycardia and elevated transaminases. Potentially life-threatening complications of CRS may include cardiac dysfunction, acute respiratory distress syndrome, neurologic toxicity, renal and/or hepatic failure, and disseminated intravascular coagulation (DIC).

TALVEY therapy should be initiated with step-up phase dosing and pre-treatment medicinal products (corticosteroids, antihistamine, and antipyretics) should be administered prior to each dose of TALVEY during the step-up phase to reduce the risk of CRS. Patients should be monitored following administration accordingly. In patients who experience CRS following their previous dose, pre-treatment medicinal products should be administered prior to the next TALVEY dose (see section 4.2).

Subjects who experienced Grade 3 or higher CRS with any previous T cell redirection therapy were excluded from clinical studies. It cannot be excluded that prior severe CRS with chimeric antigen receptor (CAR) T-cell therapy or other T-cell engagers might impact on the safety of TALVEY. The potential benefits of treatment should be carefully weighed against the risk of neurologic events, and heightened caution should be exercised when administering TALVEY to these patients.

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 and treatment with supportive care, tocilizumab and/or corticosteroids, should be instituted based on severity. The use of myeloid growth factors, particularly granulocyte macrophage-colony stimulating factor (GM-CSF), should be avoided during CRS. TALVEY should be withheld until CRS resolves (see section 4.2).

Neurologic toxicity, including ICANS

Serious or life-threatening neurologic toxicities, including ICANS have occurred following treatment with TALVEY (see section 4.8).

ICANS, including fatal reactions, have occurred following treatment with TALVEY. The onset of ICANS can be concurrent with CRS, following resolution of CRS, or in the absence of CRS. Clinical signs and symptoms of ICANS may include but are not limited to confusional state, depressed level of consciousness, disorientation, somnolence, lethargy, and bradyphrenia.

Patients should be monitored for signs and symptoms of neurologic toxicities and treated promptly. Patients should be counselled to seek medical attention should signs or symptoms of neurologic toxicities including ICANS occur. At the first sign of neurologic toxicities including ICANS, the patient should be immediately evaluated and supportive care should be provided based on severity. Patients who experience Grade 2 or higher ICANS should be instructed to remain within proximity of a healthcare facility and monitored for signs and symptoms for 48 hours following the next dose of TALVEY.

For ICANS and other neurologic toxicities, TALVEY should be withheld or discontinued based on severity and management recommendations should be followed as indicated in Table 4 (see section 4.2).

There are no data on use of talquetamab in patients with CNS involvement of myeloma or other clinically relevant CNS pathologies as a result of their exclusion from the study due to the potential risk of ICANS.

Due to the potential for ICANS, patients should be instructed to avoid driving or operating machines during the step-up phase and for 48 hours after completion of the step-up phase, and in the event of new onset of any neurological symptoms, until symptoms resolve (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. TALVEY should be withheld until adverse reaction resolves (see Table 4). Intensive care and supportive therapy should be provided for severe or life-threatening neurologic toxicities.

Oral toxicity

Oral toxicities, including dysgeusia, dry mouth, dysphagia, and stomatitis occur very commonly following treatment with TALVEY (see section 4.8).

Patients should be monitored for signs and symptoms of oral toxicity. Patients should be counselled to seek medical attention should signs or symptoms of oral toxicity occur, and supportive care should be provided. Supportive care may include saliva stimulating agents, steroid mouth wash, or consultation with a nutritionist. TALVEY should be interrupted or less frequent dosing should be considered (see section 4.2).

Over time, notable weight loss may occur (see section 4.8). Weight change should be monitored regularly during therapy. Clinically significant weight loss should be further evaluated. TALVEY should be interrupted or less frequent dosing should be considered (see section 4.2).

Serious infections

Serious infections, including life-threatening or fatal infections, have been reported in patients receiving TALVEY (see section 4.8). Patients should be monitored for signs and symptoms of infection prior to and during treatment with TALVEY and treated appropriately. Prophylactic antimicrobials should be administered according to local guidelines. TALVEY should not be administered in patients with active serious infection. TALVEY should be withheld as indicated (see section 4.2). Patients should be instructed to seek medical advice if signs or symptoms suggestive of an infection occur.

Hypogammaglobulinaemia

Hypogammaglobulinaemia has been reported in patients receiving TALVEY (see section 4.8). Immunoglobulin levels should be monitored during treatment with TALVEY. Intravenous or subcutaneous immunoglobulin therapy was used to treat hypogammaglobulinaemia patients. Patients should be treated according to local institutional guidelines, including infection precautions, antibiotic or antiviral prophylaxis, and administration of immunoglobulin replacement.

Cytopenias

Treatment-emergent Grade 3 or 4 neutropenia, febrile neutropenia and thrombocytopenia have been observed in patients who received TALVEY. A majority of cytopenias occurred during the first 8 to 10 weeks. Complete blood 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. TALVEY should be withheld as warranted (see section 4.2).

Skin reactions

TALVEY can cause skin reactions including rash, maculo-papular rash, erythema, erythematous rash, as well as nail disorders (see section 4.8). Skin reactions including rash progression should be monitored for early intervention and treatment with corticosteroids. For Grade 3 or higher, or worsening Grade 1 or 2 rashes, oral steroids should also be administered. For non-rash skin reactions dose modification may be considered (see Table 6). For skin reactions and nail disorders, TALVEY should be withheld based on severity and institutional guidelines should be followed (see section 4.2).

Vaccines

Immune response to vaccines may be reduced when taking TALVEY. The safety of immunisation with live viral vaccines during or following TALVEY 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 at least 4 weeks after treatment. For unexpected exposure during pregnancy, see section 4.6.

Women of child-bearing potential/contraception

Pregnancy status of females of child-bearing potential should be verified prior to initiating treatment with TALVEY. Females of reproductive potential should use effective contraception during treatment and for 3 months after the last dose of TALVEY (see section 4.6).

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.

Talquetamab causes release of cytokines (see section 5.1) that may suppress activity of cytochrome P450 (CYP) enzymes, potentially resulting in increased exposure of CYP substrates. The highest risk of drug-drug interaction is expected to occur from initiation of talquetamab step-up phase up to 9 days after the first treatment dose and during and after CRS (see section 4.4). Monitor for toxicity or concentrations of medicinal products that are CYP (e.g., CYP2C9, CYP2C19, CYP3A4/5, CYP2D6) substrates where minimal concentration changes may lead to serious adverse reactions. The dose of concomitant CYP (e.g., CYP2C9, CYP2C19, CYP3A4/5, CYP2D6) substrate drugs should be adjusted as needed.

Women of childbearing potential/Contraception in females

Pregnancy status of females of child-bearing potential should be verified prior to initiating treatment with TALVEY.

Females of reproductive potential should use effective contraception during treatment and for 3 months after the last dose of TALVEY.

Pregnancy

There are no available data on the use of TALVEY in pregnant women or animal data to assess the risk of TALVEY in pregnancy. Human IgG is known to cross the placenta after the first trimester of pregnancy. Therefore, talquetamab has the potential to be transmitted from the mother to the developing foetus. The effects of TALVEY on the developing foetus are unknown. TALVEY is not recommended for women who are pregnant or for women of childbearing potential not using contraception.

If TALVEY is taken during pregnancy, a reduced immune response to vaccines may be expected in newborns. Consequently, newborn vaccinations with live vaccines such as BCG vaccine should be postponed until 4 weeks.

Breast-feeding

It is not known whether talquetamab is excreted in human milk. Because the potential for serious adverse reactions in breast-fed infants is unknown for TALVEY, patients should not breast-feed during treatment with TALVEY and for at least 3 months after the last dose.

Fertility

There are no data on the effect of talquetamab on fertility. Effects of talquetamab on male and female fertility have not been evaluated in animal studies.

TALVEY has major influence on the ability to drive and use machines.

Due to the potential for ICANS, patients receiving TALVEY are at risk of depressed level of consciousness (see section 4.4). Patients should be instructed to avoid driving or operating machines during the step-up phase and for 48 hours after completion of the step-up phase (see section 4.2), and in the event of new onset of any neurological symptoms, until symptoms resolve.

Summary of the safety profile

The most frequent adverse reactions were CRS (77%), dysgeusia (72%), hypogammaglobulinaemia (67%), nail disorder (56%), musculoskeletal pain (48%), anaemia (47%), skin disorder (43%), fatigue (43%), weight decreased (40%), rash (39%), dry mouth (36%), neutropenia (35%), pyrexia (33%), xerosis (32%), thrombocytopenia (30%), upper respiratory tract infection (29%), lymphopenia (27%), dysphagia (24%), diarrhoea (25%), pruritus (23%), cough (23%), pain (22%), decreased appetite (22%) and headache (20%).

Serious adverse reactions reported in patients included CRS (13%), pyrexia (5%), ICANS (3.8%), sepsis (3.8%), COVID-19 (3.2%), bacterial infection (2.4%), pneumonia (2.4%), viral infection (2.4%), neutropenia (2.1%) and pain (2.1%).

The most frequent adverse reactions leading to treatment discontinuation were ICANS (1.1%) and weight decreased (0.9%).

Tabulated list of adverse reactions

The safety of TALVEY was evaluated in 339 adult patients with relapsed or refractory multiple myeloma, including patients treated with TALVEY at the recommended dosing regimen with or without prior T cell redirection therapy in MonumenTAL-1. The median duration of treatment was 7.4 (range: 0.0 to 32.9) months.

Table 7 summarises adverse reactions reported in patients who received TALVEY. The safety data of TALVEY was also evaluated in the All Treated population (N=501) 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 (≥1/1000 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 7. Adverse reactions in patients with multiple myeloma treated with TALVEY in MonumenTAL-1 (N=339):

Adverse reactions are coded using MedDRA Version 24.0.
^‡ Per CTCAE v4.03, maximum toxicity grade for dysgeusia is 2 and maximum toxicity grade for dry mouth is 3.
^* Grouped term
^# Contains fatal outcome(s)
¹ Haemorrhage includes: Conjunctival haemorrhage, Epistaxis, Haematoma, Haematuria, Lower gastrointestinal haemorrhage, Periorbital haemorrhage, Petechiae, Rectal haemorrhage, Subdural haematoma and Vaginal haemorrhage.
² Hypogammaglobulinaemia includes: hypogammaglobulinaemia and/or subjects with laboratory IgG levels below 500 mg/dL following treatment with talquetamab.
³ Encephalopathy includes: agitation, amnesia, aphasia, bradyphrenia, confusional state, delirium, disorientation, encephalopathy, hallucination, lethargy, memory impairment, restlessness, sleep disorder and somnolence.
⁴ Motor dysfunction includes: dysgraphia, dysphonia, gait disturbance, muscle spasms, muscular weakness and tremor.
⁵ Sensory neuropathy includes: dysaesthesia, hypoaesthesia, hypoaesthesia oral, neuralgia, peripheral sensory neuropathy, sciatica and vestibular neuronitis.
⁶ Dyspnoea includes: acute respiratory failure, dyspnoea, dyspnoea exertional, respiratory failure and tachypnoea.
⁷ Dysgeusia includes: ageusia, dysgeusia, hypogeusia and taste disorder.
⁸ Stomatitis includes: cheilitis, glossitis, glossodynia, mouth ulceration, oral discomfort, oral mucosal erythema, oral pain, stomatitis, swollen tongue, tongue discomfort, tongue erythema, tongue oedema and tongue ulceration.
⁹ Xerosis includes: dry eye, dry skin and xerosis.
¹⁰ Oedema includes: fluid retention, gingival swelling, hypervolaemia, joint swelling, lip swelling, oedema, oedema peripheral, periorbital oedema, peripheral swelling and swelling.
¹¹ Injection site reaction includes: injection site discomfort, injection site erythema, injection site haemorrhage, injection site inflammation, injection site irritation, injection site plaque, injection site pruritus, injection site rash and injection site reaction.
¹² Transaminase elevation includes: alanine aminotransferase increased, aspartate aminotransferase increased, and transaminases increased.

Description of selected adverse reactions

Cytokine release syndrome

In MonumenTAL-1 (N=339), CRS occurred in 77% of patients. Most events were Grade 1 or 2, with Grade 3 events occurring in 1.5% of patients. Thirty one percent (31%) of patients experienced more than one CRS event. Most events occurred during the step-up phase following the 0.01 mg/kg dose (29%), the 0.06 mg/kg dose (44%), the 0.3 mg/kg dose (for patients who received biweekly [every 2 weeks] dosing; 33%), or the initial treatment dose (0.4 mg/kg [30%] or 0.8 mg/kg [12%]). Less than 4% of CRS events occurred from week 5 onward; all events were Grade 1. The median time to onset of CRS was 27 hours from the last dose, 91% of events occurred within 48 hours from the last dose, and the median duration was 17 hours. Tocilizumab, corticosteroids and tocilizumab in combination with corticosteroids were used to treat CRS in 39%, 5% and 3.5% of CRS events, respectively. Clinical signs and symptoms of CRS may include but are not limited to pyrexia (76%), hypotension (15%), chills (12%), hypoxia (7%), headache (4.7%), tachycardia (5%) and elevated transaminases (aspartate aminotransferase [1.5%] and alanine aminotransferase [0.9%]).

Neurologic toxicities

In MonumenTAL-1 (N=339), neurologic toxicity events were reported in 29% of patients receiving TALVEY. Neurologic toxicity events were Grade 1 (17%), Grade 2 (11%), Grade 3 (2.3%) or Grade 4 (0.3%). The most frequently reported neurologic toxicity event was headache (9%).

ICANS were only collected for Phase 2 in MonumenTAL-1. Of the 265 patients in Phase 2, ICANS occurred in 9.8% (n=26) of patients. Most events were Grade 1 or 2, with Grade 3 and 4 events occurring in 2.3% of patients. The most frequent clinical manifestation of ICANS reported were confusional state (3.8%), disorientation (1.9%), somnolence (1.9%) and depressed level of consciousness (1.9%). Sixty-eight percent (68%) were concurrent with CRS (during or within 7 days of CRS resolution). Three percent (3%) of patients experienced more than one ICANS event. In addition, one fatal ICANS event was reported in MonumenTAL-1. Most patients experienced ICANS during the step-up phase following the 0.01 mg/kg dose, the 0.06 mg/kg dose, or the initial treatment dose (0.4 mg/kg and 0.8 mg/kg) (3% each). The median time to onset of ICANS was 28 hours from the last dose, 68% of events started within 48 hours from the last dose, 32% of events occurred after 48 hours, and the median duration of ICANS was 9 hours.

Oral toxicity

In MonumenTAL-1 (N=339), seventy-eight percent (78%) of patients had Grade 1 or 2 events, with Grade 3 events occurring in 2% of patients. Oral toxicity events included dysgeusia, dry mouth, dysphagia, and stomatitis were reported.

Serious infections

In MonumenTAL-1 (N=339), Grade 3 or Grade 4 infections occurred in 19% of patients; fatal infections occurred in 1.5% of patients – COVID-19 pneumonia, fungal sepsis, infection and septic shock. The most frequently reported (≥2%) Grade 3 or 4 infection was pneumonia. Febrile neutropenia was observed in 1% of patients with 1.2% experiencing serious febrile neutropenia. See section 4.4 for monitoring and management guidance.

Hypogammaglobulinaemia

Post baseline IgG values of less than 500 mg/dl consistent with hypogammaglobulinaemia have been reported in 64% of patients treated with talquetamab at the 0.4 mg/kg weekly dose schedule, 66% of patients at the 0.8 mg/kg biweekly dose schedule and in 71% of patients with prior T cell redirection therapy (see section 4.4).

Skin reactions

In MonumenTAL-1 (N=339), the majority of rash cases were Grade 1 or 2, with Grade 3 events occurring in 3.5% of patients. The median time to onset from the first treatment dose for rash was 22 days. The majority of non-rash skin toxicities were Grade 1 or 2, with Grade 3 pruritus occurring in 0.3% of patients. Nail disorders occurred in 56% of patients and were Grade 1 or 2. See section 4.4 for management guidance.

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.

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