ORDSPONO Concentrate for solution for infusion Ref.[113373] Active ingredients: Odronextamab

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. If an Albumin (Human) solution is used in cases as suggested under section 6.6, the name and batch number should be clearly recorded to ensure full traceability.

Cytokine release syndrome (CRS) and infusion-related reactions (IRR)

Ordspono can cause cytokine release syndrome (CRS), which may be serious or life-threatening (see section 4.8).

Clinical signs and symptoms of CRS included, but were not limited to, fever, hypotension, hypoxia, tachycardia, chills, dyspnoea, and headache. CRS events occurred predominantly in Cycle 1. Transient elevation of liver enzymes has been observed in patients experiencing CRS. See sections 4.2 and 4.8 for CRS monitoring and management guidance.

Therapy according to the step-up dosing schedule should be initiated, premedications should be administered to reduce the risk of CRS, and patients should be monitored accordingly for potential CRS following Ordspono. The step-up dosing schedule and premedications were established to mitigate the risk of CRS and should be followed (see section 4.2).

Monitoring and management of CRS

Patients should be monitored for signs and symptoms of CRS during and following Ordspono administration for immediate management and should remain within proximity of a qualified healthcare facility for at least 24 hours after administration of each dose within the Ordspono step-up dosing regimen and after the first full dose. At the first sign of CRS, patients should be immediately evaluated for hospitalisation, managed per the guidance provided in Table 4, and supportive care should be administered; withhold or permanently discontinue Ordspono based on severity. Patients should be counselled to seek immediate medical attention should signs or symptoms of CRS occur at any time.

Patients who experience CRS (or other adverse reactions that impair consciousness) should be evaluated and advised not to drive and to refrain from operating heavy or potentially dangerous machinery until resolution (see section 4.7).

Some manifestations of infusion-related reactions (IRR) may be clinically indistinguishable from manifestations of CRS. For IRR, withhold, slow the rate of infusion, or permanently discontinue Ordspono based on severity of reaction (see section 4.2).

Serious infections

Ordspono can cause serious or fatal infections (see section 4.8).

Monitoring and management of serious infections

Patients should be monitored before and during treatment with Ordspono treatment for the emergence of possible bacterial, fungal, and new or reactivated viral infections and treated appropriately. Ordspono should not be administered in the presence of active infection. Caution should be exercised when considering the use of Ordspono in patients with a history of recurring or chronic infections. Administer prophylactic antimicrobials as appropriate.

Prophylactic treatment for Pneumocystis jirovecii pneumonia (PJP) is recommended for all patients. Prophylactic treatment is recommended for patients with a history of herpes virus infections and cytomegalovirus (CMV) infections. Antiviral treatment is recommended for patients with positive hepatitis B surface antigen, hepatitis B core antibody, and/or measurable viral load. Intravenous immunoglobulin (IVIG) should be considered per guidelines.

Febrile neutropenia has been reported during treatment with Ordspono. In the event of febrile neutropenia, patients should be evaluated for infection and managed with antibiotics, fluids, and other supportive care, according to local guidelines.

Withhold Ordspono or consider permanent discontinuation of Ordspono based on severity (see section 4.2).

Neurologic toxicity

Neurologic toxicities, such as immune effector cell-associated neurotoxicity syndrome (ICANS), aphasia, and encephalopathy, which may be severe, occurred following treatment with Ordspono.

Monitoring and management of neurologic toxicities

Patients should be monitored for signs and symptoms of neurologic toxicity, evaluated, and provided supportive care; withhold or permanently discontinue Ordspono based on severity (see section 4.2).

Patients should be counselled to seek medical attention should signs or symptoms of neurologic toxicity occur.

Tumour lysis syndrome (TLS)

TLS has been reported in patients receiving odronextamab (see section 4.8). Patients with high tumour burden, rapidly proliferative tumours, or renal dysfunction are at greater risk of tumour lysis syndrome. Patients at an increased risk for TLS should have adequate hydration and prophylactic anti-hyperuricemics (e.g., allopurinol or rasburicase) prior to the administration of odronextamab.

Monitoring and management of TLS

Patients should be monitored for signs and symptoms of TLS, including blood chemistries, and any abnormalities should be managed promptly.

Pneumonitis/Interstial lung disease (ILD)

Pneumonitis/ILD, which may be life-threatening or fatal, has been reported in patients receiving odronextamab and should be considered in case of respiratory symptoms without any causative pathogen.

Patient card

The Patient Card describes the common signs and symptoms of CRS and neurologic toxicity, including ICANS, and provides instructions on when a patient should seek immediate medical attention. The prescriber must discuss the risks of Ordspono therapy with the patient. Patients should be provided with the Patient Card, instructed to carry it at all times, and show it to all of their healthcare providers.

Immunisation

Live and/or live-attenuated vaccines should not be given concurrently with Ordspono. Studies have not been conducted in patients who recently received live vaccines.

No interaction studies have been performed. Initiation of treatment with Ordspono causes a transient elevation of cytokines, which may suppress CYP450 enzyme activities. The highest risk is during Cycle 1 in patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index (e.g., warfarin, cyclosporine, or theophylline). On initiation of therapy with Ordspono in patients being treated with CYP450 substrates with a narrow therapeutic index, therapeutic monitoring should be considered.

Women of childbearing potential/Contraception

Females of reproductive potential should use effective contraception during treatment with Ordspono and for at least 6 months after the last dose.

Pregnancy

There are no available data on the use of Ordspono in pregnant women. No animal reproductive or developmental toxicity studies have been conducted with odronextamab. Human immunoglobulin G (IgG) is known to cross the placenta; therefore, odronextamab has the potential to be transferred from the mother to the developing foetus. Based on its mechanism of action, odronextamab may cause foetal harm, including B-cell lymphocytopenia, when administered to a pregnant woman (see section 5.1). Ordspono is not recommended during pregnancy and in women of childbearing potential not using contraception.

Breast-feeding

There is no information regarding the presence of odronextamab in human milk, the effects on the breastfed infant, or the effects on milk production. It is known that human IgG can be secreted in human milk. Women should be advised not to breastfeed during treatment with Ordspono and for at least 6 months after the last dose due to the potential risk for serious adverse reactions in the breastfed child.

Fertility

No human data on the effect of odronextamab on fertility are available. Animal studies do not indicate harmful effects on male or female reproductive organs or fertility parameters (see section 5.3).

Ordspono has minor influence on the ability to drive and use machines. Patients who experience CRS (or other adverse reactions that impair consciousness) should be evaluated and advised not to drive and to refrain from operating heavy or potentially dangerous machinery until resolution.

Summary of safety profile

The most common adverse reactions were cytokine release syndrome (54%), neutropenia (41%), pyrexia (39%), anaemia (38%), thrombocytopenia (27%), diarrhoea (24%), and COVID-19 (22%).

The most common severe (NCI CTCAE Grade ≥ 3) adverse reactions were neutropenia (34%), anaemia (19%), thrombocytopenia (13%), lymphopenia (12%), pneumonia (10%), leukopenia (9%), COVID-19 (8%), hypokalaemia (6%), and hyperglycaemia (5%).

The most common serious adverse reactions were cytokine release syndrome (14%), pneumonia (9%), COVID-19 (9%), and pyrexia (6%).

The frequency of infusion interruption of Ordspono due to an adverse reaction was 16%. The frequency of treatment discontinuation due to an adverse reaction was 14%. The most common adverse reactions leading to discontinuation were COVID-19 (2.4%), pneumonia (1.3%), and encephalopathy (0.8%).

Tabulated list of adverse reactions

Unless otherwise stated, the frequencies of adverse reactions are based on all-cause adverse event frequencies identified in a pooled safety population of 372 patients who received odronextamab as a single agent in two open-label, multi-centre studies (Study 1333 and Study 1625), including 153 patients with r/r FL and 219 patients with r/r DLBCL. The median exposure to odronextamab was 20.4 weeks (range: 0.4 to 195.7 weeks) (see section 5.1).

Two different step-up regimens were used during development. The step-up regimen was modified to mitigate the risk of CRS after 175 patients (74 with r/r FL and 101 with r/r DLBCL) were enrolled. Data for CRS and IRR are reported in 197 patients (79 with r/r FL and 118 with r/r DLBCL) who received the recommended step-up dosing regimen.

The adverse reactions are listed below in Table 7 by MedDRA system organ class (SOC) and categories of 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 (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in decreasing order of frequency by SOC and preferred term.

Table 7. Adverse reactions in patients treated with Ordspono:

Adverse reactions were graded based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03 in study 1333 and Version 5.0 in study 1625. CRS was graded using American Society for Transplantation and Cellular Therapy (ASTCT) consensus criteria (Lee et al., 2019).)
^a Includes COVID-19 and COVID-19 pneumonia.
^b Includes bacterial, fungal, and viral pneumonia, including CMV and PJP.
^c Includes CMV infections, reactivations, and viraemia.
^d Includes nasopharyngitis, upper respiratory tract infection, and viral upper respiratory tract infection.
^e Includes herpes virus infection and herpes zoster.
^f Includes bacterial and viral infections.
^g Includes systemic, mucosal, and skin fungal infections.
^h Includes bacterial sepsis, pseudomonal sepsis, sepsis, and septic shock.
ⁱ CRS and IRR events were reported per investigator’s discretion with guidance based on time of occurrence from the start of the infusion. Data for these events are reported in patients treated with the recommended step-up dosing regimen (N=197).
^j Includes mental status changes, cognitive disorder, encephalopathy, somnolence, confusional state, disturbance in attention, and disorientation.
^k Includes aphasia and dysarthria.
^l Immune Effector Cell-Associated Encephalopathy (ICE) scoring was not systematically performed.
^m Includes abdominal distension, abdominal discomfort, abdominal pain, abdominal pain lower, and abdominal pain upper.
ⁿ Includes dermatitis, erythema, rash maculo-papular, rash pruritic, and toxic skin eruption.
° Includes asthenia, fatigue, malaise, and lethargy.
^p Includes localised oedema, generalised oedema, and pulmonary oedema.

Description of selected adverse reactions

Cytokine release syndrome (CRS)

In patients with r/r FL treated with the recommended step-up dosing regimen, the rate of CRS was 58%, including Grade 1 CRS (47%), Grade 2 CRS (10%), and Grade 3 CRS (1.3%). Recurrent CRS occurred in 32% of patients with r/r FL. In patients with r/r DLBCL treated with the recommended step-up dosing regimen, the rate of CRS was 52%, including Grade 1 CRS (35%), Grade 2 CRS (16%), and Grade 3 CRS (0.8%). Recurrent CRS occurred in 20% of patients with r/r DLBCL.

In patients with r/r FL or r/r DLBCL (combined) treated with the recommended step-up dosing regimen, 24% experienced CRS after Cycle 1, Day 1 or 2, 29% experienced CRS after Cycle 1, Day 8 or 9, and 26% experienced CRS after Cycle 1, Day 15 or 16. From Cycle 2 on, 22% of patients experienced CRS. From Cycle 3 on, 4.6% of patients experienced CRS. With continued Ordspono dosing, the incidence and severity of CRS decreased.

Of patients who experienced CRS, 96% had an initial CRS event during the step-up dosing or with the first 80-mg dose for r/r FL or 160-mg dose for r/r DLBCL; 3.7% had their first CRS event after their second 80-mg dose for r/r FL or 160-mg dose for r/r DLBCL.

The median time to onset of CRS from the end of infusion across all doses in the combined group of patients treated with the recommended step-up dosing regimen was 19.8 hours (range: -3.4 hours to 9 days). The median time to onset of CRS from the end of infusion in Cycle 1, Day 1 or Day 2 was 6 hours (range: -2.4 hours to 4 days), Cycle 1, Day 8 or Day 9 was 22 hours (range: 3.7 hours to 5 days), and Cycle 1, Day 15 or Day 16 was 22 hours (range: -3.4 hours to 9 days). Transient elevated liver enzymes (ALT or AST > 3 x ULN) were concurrent with CRS in 6.5% of patients with CRS. One patient (0.5%) discontinued due to CRS.

99% of CRS events resolved, and the median duration of CRS was 2 days (range: 1 to 10 days).

24% of patients treated with the recommended step-up dosing regimen received tocilizumab, 26% received corticosteroids, and 13% received both tocilizumab and corticosteroids to treat CRS.

Hospitalisations due to CRS in patients treated with the recommended step-up dosing regimen occurred in 14% of patients, and the median duration was 2.0 days (range 1.0 to 9.0 days).

Serious infections

Among 153 patients with r/r FL who received Ordspono, serious infections occurred in 44%, with Grade 3 infections in 27% and Grade 4 infections in 2.6% of patients. Infections that were fatal within 90 days of the last dose occurred in 8% (13/153) of patients, and of these infections, 62% (8/13) were due to COVID-19 infection. The most common Grade 3 or greater serious infections were COVID-19 (9%), pneumonia (8%), COVID-19 pneumonia (7%), cytomegalovirus infection (3.3%), urinary tract infection (2.6%), sepsis (2.6%) and cytomegalovirus infection reactivation (2.0%).

Among 219 patients with r/r DLBCL who received Ordspono, serious infections occurred in 33%, with Grade 3 infections in 20% and Grade 4 infections in 0.9% of patients. Infections that were fatal within 90 days of the last dose occurred in 9% (19/219) of patients, and of these infections, 42% (8/19) were due to COVID-19 infection. The most common Grade 3 or greater serious infections were pneumonia (10%), COVID-19 (6%), Pneumocystis jirovecii pneumonia (3.7%), sepsis (3.2%), and COVID-19 pneumonia (2.7%).

Neurologic toxicity

Among 372 patients with r/r FL or r/r DLBCL who received ORDSPONO, the most frequent neurologic toxicities of any grade were headache (13%), dizziness (8%), anxiety (4.3%) and confusional state (3.5%), and encephalopathy (3%). Grade 3 or 4 neurologic adverse reactions occurred in 7% of patients. Event of ICANS (Grade 2) was reported in one patient (0.3%).

Tumour lysis syndrome

Among 372 patients with r/r FL or r/r DLBCL who received ORDSPONO, TLS was reported in 0.5% of patients (N=2); both events were Grade 3. For these events, TLS onset was on Day 2 and Day 7, and both resolved within 2 days.

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.

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.