IMDYLLTRA Powder for solution for infusion Ref.[116661] Active ingredients: Tarlatamab

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)

Administration of tarlatamab has been associated with CRS, including life-threatening or fatal events, see section 4.8. CRS may be associated with symptoms including pyrexia, hypotension, hypoxia, fatigue, tachycardia, headache, chills, nausea, and vomiting.

Patients and caregivers should be advised of the potential for CRS onset after discharge and instructed to seek immediate medical attention if any signs or symptoms occur.

Tarlatamab should be administered in a healthcare facility equipped to monitor and manage CRS. It should be ensured that patients are euvolemic prior to initiating the infusions. Patients should be closely monitored for signs and symptoms of CRS during the initiation of tarlatamab treatment. To mitigate the risk of CRS, it is important to initiate tarlatamab at the recommended starting dose in table 1.

CRS should be managed according to the recommendations in table 4.

Immune effector cell-associated neurotoxicity syndrome (ICANS)

Administration of tarlatamab has been associated with ICANS, including life-threatening or fatal events, see section 4.8. ICANS can occur up to several weeks following administration of tarlatamab. Adverse reactions that may be associated with ICANS include headache, encephalopathy, confusion, delirium, seizure, ataxia, neurotoxicity, and tremor. Patients should be closely monitored for signs and symptoms of ICANS during tarlatamab treatment.

Patients and caregivers should be advised of the potential for ICANS onset after discharge and instructed to seek immediate medical attention if any signs or symptoms occur.

ICANS should be managed according to the recommendations in table 5.

Neutropenia

Administration of tarlatamab has been associated with neutropenia, see section 4.8. Patients should be closely monitored for signs and symptoms of neutropenia during tarlatamab treatment.

Neutropenia should be managed according to the recommendations in table 6.

Infections

Serious infections, including life-threatening and fatal infections, have been reported in patients treated with tarlatamab. The most frequent infections include pneumonia, urinary tract infection, COVID-19, upper respiratory tract infection, respiratory tract infection, candida infection, oral candidiasis and nasopharyngitis.

Patients should be monitored for signs and symptoms of infections prior to and during treatment with tarlatamab.

Hypersensitivity

Hypersensitivity reactions have been reported in patients treated with tarlatamab including rare severe events. Clinical signs and symptoms of hypersensitivity may include but are not limited to rash and bronchospasm. Patients should be monitored for signs and symptoms of hypersensitivity during treatment with tarlatamab and managed as clinically indicated. It should be considered to withhold or to permanently discontinue tarlatamab based on severity, see table 6 for management of other adverse reactions.

Hepatotoxicity

Administration of tarlatamab has been associated with elevated liver enzymes. Liver enzyme elevation can occur with or without concurrent CRS.

Liver enzymes and bilirubin should be monitored prior to treatment with tarlatamab, and as clinically indicated. Potential toxicities should be managed according to the recommendations in table 6.

Women of child bearing potential/contraception

Pregnancy status of females of child bearing potential should be verified prior to initiating treatment with tarlatamab. Females of reproductive potential have to use effective contraception during treatment and for 2 months after the last dose of tarlatamab (see section 4.6).

Excipients with known effect

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

This medicinal product contains 0.04 mg of polysorbate 80 in each 1 mg vial and 0.2 mg in each 10 mg vial. Polysorbates may cause allergic reactions.

No interaction studies have been performed. Initiation of tarlatamab treatment causes transient release of cytokines that may suppress CYP450 enzymes and may result in increased exposures of concomitant CYP substrates. Patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index, should be monitored for known adverse events. The dose of the concomitant medicinal product should be adjusted as needed.

Women of child bearing potential/contraception

Women of child bearing potential have to use effective contraception during and for 2 months after treatment with tarlatamab.

Pregnancy

There are no available data from the use of tarlatamab in pregnant women.

A reproductive toxicity study conducted in mice using the murine surrogate molecule muS757 showed transplacental transport of muS757 (see section 5.3). Based on its mechanism of action and potential development of adverse reactions (like CRS) following tarlatamab exposure, tarlatamab may cause foetal harm when administered to a pregnant woman (see section 5.1).

Tarlatamab is not recommended during pregnancy and in women of child bearing potential not using contraception.

Pregnancy status for females of child-bearing potential should be verified prior to starting treatment with tarlatamab.

Breast-feeding

It is unknown whether tarlatamab is secreted in human milk. Because many medicinal products, including antibodies, can be secreted in human milk, a risk to the newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with tarlatamab and for at least 2 months after the last dose.

Fertility

There are no clinical trials to evaluate the effect of tarlatamab on fertility.

Due to the potential for ICANS associated neurological events following tarlatamab infusion, tarlatamab may have major influence on the ability to drive and use machines. In the event of any neurologic symptoms, patients should be advised to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, until they resolve.

Summary of the safety profile

The safety of IMDYLLTRA was evaluated in 473 patients with small cell lung cancer (SCLC) who received the tarlatamab target dose of 10 mg as monotherapy in clinical trials.

The most common adverse reactions are: CRS (56.7%), decreased appetite (36.4%), pyrexia (31.9%), dysgeusia (31.3%), constipation (30.4%), anaemia (30.0%), fatigue (29.8%), nausea (24.9%), asthenia (19.0%), neutropenia (16.9%), hyponatraemia (16.7%), headache (16.3%), lymphopenia (15.6%).

The most common serious adverse reactions are CRS (19.7%) and pyrexia (4.7%).

Tabulated list of adverse reactions

Adverse reactions reported in clinical trials are listed by system organ class and by frequency. The frequencies of adverse reactions is based on pooled data from one phase 1, one phase 2, and one phase 3 clinical trials with 473 patients. The median duration of exposure was 18.0 weeks (range: 0.1 to 175.1 weeks).

Adverse reactions are listed according to the MedDRA system organ classification and by frequency. Frequency categories are defined as 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 8. Adverse reactions:

^a Includes neutrophil count decreased.
^b Includes lymphocyte count decreased.
^c Additional information is provided in "Descriptions of selected adverse reactions".

Description of selected adverse reactions

Cytokine release syndrome (CRS)

In clinical trials with pooled safety data from 473 patients with SCLC receiving the IMDYLLTRA 1 mg as first dose and 10 mg second and later dose, CRS occurred in 56.7% of patients, with grade 1 in 39.3%, grade 2 in 15.4% of patients, grade 3 in 1.7% of patients and grade 4 events in 0.2% of patients. Serious events of CRS were reported in 19.7% of patients. After the first dose of IMDYLLTRA, 41.4% of patients experienced any grade CRS, with 34.0% of patients experiencing any grade CRS after the second dose. The majority of CRS events occurred after the first two doses, with 8.5% of patients experiencing CRS following third dose or later. Following the day 1 infusion, 13.7% of patients experienced ≥ grade 2 CRS. Following the day 8 infusion, 4.4% of patients experienced ≥ grade 2 CRS. The median time from the most recent dose of IMDYLLTRA to the first onset of CRS was 15.9 hours (range: 9.0 to 26.5 hours). For those grade 1 events that progressed to grade 2 or greater, the median time from grade 1 event to grade 2 or greater events was 22.1 hours (interquartile range: 8.5 - 31.6 hours). Cytokine release syndrome led to treatment interruption and/or dose modification in 2.1% of patients and to discontinuation of tarlatamab in 0.6% of patients.

Fatal CRS cases have been reported in the post-marketing setting.

For clinical management of CRS, see section 4.4.

Immune effector cell-associated neurotoxicity syndrome (ICANS)

Tarlatamab can cause ICANS, including life-threatening or fatal events.

In clinical trials with pooled safety data from 473 patients with SCLC receiving IMDYLLTRA at 10 mg, ICANS was reported in 4.7% of patients. The median time from the first dose of IMDYLLTRA to the first onset of ICANS was 9.0 days (interquartile range: 2 to 13 days). The median time to resolution of ICANS was 4 days (interquartile range: 2 to 8 days).

For clinical management of ICANS, see section 4.4.

Neutropenia

In clinical trials with pooled safety data from 473 patients with SCLC receiving IMDYLLTRA at 10 mg, neutropenia occurred in 16.9% of patients including 8.2% of patients experiencing grade 3 or grade 4 events. The median time from the first dose of IMDYLLTRA to the first onset of neutropenia was 43 days (range: 29 to 109 days). Neutropenia leading to dose interruption occurred in 3.2% patients with none leading to treatment discontinuation. Treatment with G-CSF was required in 6% of patients.

For clinical management of neutropenia, see section 4.4.

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.

No known incompatibilities.