LUNSUMIO Concentrate for solution for infusion Ref.[50051] Active ingredients: Mosunetuzumab

Traceability

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

Cytokine Release Syndrome (CRS)

CRS, including life-threatening reactions, have occurred in patients receiving Lunsumio (see section 4.8). Signs and symptoms included pyrexia, chills, hypotension, tachycardia, hypoxia, and headache. Infusion related reactions may be clinically indistinguishable from manifestations of CRS. CRS events occurred predominantly in cycle 1 and were mainly associated with Day 1 and Day 15 dose administrations.

Patients should be premedicated with corticosteroids, antipyretics and antihistamines at least through cycle 2. Patients must receive adequate hydration prior to the administration of Lunsumio. Patients should be monitored for signs or symptoms of CRS. Patients should be counselled to seek immediate medical attention should signs or symptoms of CRS occur at any time. Physicians should institute treatment with supportive care, tocilizumab and/or corticosteroids as indicated. (see section 4.2).

Serious infections

Serious infections such as pneumonia, bacteraemia, and sepsis or septic shock have occurred in patients receiving Lunsumio, some of which were life-threatening or fatal events (see section 4.8). Febrile neutropenia was observed in patients after receiving Lunsumio infusion.

Lunsumio should not be administered in the presence of active infections. Caution should be exercised when considering the use of Lunsumio in patients with a history of recurring or chronic infections (e.g., chronic, active Epstein-Barr Virus), with underlying conditions that may predispose to infections or who have had significant prior immunosuppressive treatment. Patients should be administered prophylactic antibacterial, antiviral and/or antifungal medicinal products, as appropriate. Patients should be monitored for signs and symptoms of infection, before and after Lunsumio administration, and treated appropriately. 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.

Tumour flare

Tumour flare has been reported in patients treated with Lunsumio (see section 4.8). Manifestations included new or worsening pleural effusions, localised pain and swelling at the sites of lymphoma lesions and tumour inflammation. Consistent with the mechanism of action of Lunsumio, tumour flare is likely due to the influx of T-cells into tumour sites following Lunsumio administration.

There are no specific risk factors for tumour flare that have been identified, however, there is a heightened risk of compromise and morbidity due to mass effect secondary to tumour flare in patients with bulky tumours located in close proximity to airways and/or a vital organ. Patients treated with Lunsumio should be monitored and evaluated for tumour flare at critical anatomical sites.

Tumour lysis syndrome (TLS)

TLS has been reported in patients receiving Lunsumio (see section 4.8). Patients must have adequate hydration prior to the administration of Lunsumio. Patients should be administered prophylactic antihyperuricemic therapy (e.g allopurinol, rasburicase), as appropriate. Patients should be monitored for signs or symptoms of TLS, especially patients with high tumour burden or rapidly proliferative tumours, and patients with reduced renal function. Patients should be monitored for blood chemistries and abnormalities should be managed promptly.

Immunisation

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

Patient card

The prescriber must discuss the risks of Lunsumio therapy with the patient. The patient should be provided with the patient card and instructed to carry it at all times. The patient card describes the common signs and symptoms of CRS, and provides instructions on when a patient should seek medical attention.

No interaction studies have been performed.

A transient clinically relevant effect on CYP450 substrates with a narrow therapeutic index (e.g. warfarin, voriconazole, cyclosporine, etc) cannot be excluded, since initiation of Lunsumio treatment causes a transient increase in cytokine levels which may cause inhibition of CYP450 enzymes. On initiation of Lunsumio therapy in patients being treated with CYP450 substrates with a narrow therapeutic index, therapeutic monitoring should be considered. The dose of the concomitant medicinal product should be adjusted as needed.

Women of childbearing potential/Contraception

Women of childbearing potential should use effective contraception while receiving Lunsumio and for at least 3 months after the last infusion of Lunsumio.

Pregnancy

There are no data from the use of Lunsumio in pregnant women. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). Lunsumio is not recommended during pregnancy and in women of childbearing potential not using contraception.

Breast-feeding

It is unknown whether mosunetuzumab/metabolites are excreted in human milk. A risk to newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with Lunsumio therapy.

Fertility

No human data on fertility are available. No impairments were observed in male or female reproductive organs in the 26-week toxicity studies with cynomolgus monkeys at exposures (AUC) similar to exposure (AUC) in patients receiving the recommended dose.

Lunsumio has minor influence on the ability to drive and use machines. Patients who experience events that impair consciousness should be evaluated and advised not to drive and to refrain from operating heavy or potentially dangerous machines until events are resolved.

Summary of safety profile

The adverse reactions (ARs) described in this section were identified from the pivotal clinical trial GO29781 in patients treated at the recommended dose (n=218). Patients had follicular lymphoma (41.3%), diffuse large B-cell lymphoma/transformed follicular lymphoma (40.4%) mantle cell lymphoma (11.5%), Richter’s transformation (6.4%), and other histologies (0.5%). The median number of cycles of Lunsumio received was 8 (range 1 -17), 37% of patients received 8 cycles, and 15% received more than 8 cycles up to 17 cycles.

The most common adverse reactions (≥20%) observed were cytokine release syndrome, neutropenia, pyrexia, hypophosphatemia and headache. The most common serious adverse reactions (≥2%) observed included cytokine release syndrome (CRS) (21% by ASTCT grading system), pyrexia (5%), and pneumonia (3%). Nine of 218 patients (4.1%) discontinued Lunsumio due to an adverse event. CRS was the only adverse reaction that led to discontinuation in more than one patient (2 patients [0.9%]).

Tabulated list of adverse reactions

The adverse reactions are listed below 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 order of decreasing seriousness.

Table 4. Adverse reactions occurring in patients treated with Lunsumio:

¹ Neutropenia includes neutropenia and neutrophil count decreased
² Thrombocytopenia includes thrombocytopenia and platelet count decreased
³ By American Society for Transplant and Cellular Therapy

Description of selected adverse reactions

Cytokine release syndrome (CRS)

CRS (ASTCT grading system) of any grade occurred in 39% (86/218) of patients, with grade 2 occurring in 14%, grade 3 occurring in 2.3%, and grade 4 occurring in 0.5% of patients treated with Lunsumio. The one patient with the grade 4 event was a patient with FL in the leukemic phase who also experienced concurrent TLS.

CRS of any grade occurred in 15% of patients after the Cycle 1, Day 1 dose; 5% after the Cycle 1, Day 8 dose; 33% after the Cycle 1, Day 15 dose, 5% occurred in patients after the Cycle 2 and 1% in Cycles 3 and beyond. The median time to CRS onset from the start of administration in Cycle 1 Day 1 was 5 hours (range: 1-73 hours), Cycle 1 Day 8 was 28 hours (range: 5-81 hours), Cycle 1 Day 15 was 25 hours (range: 0.1-391 hours), and Cycle 2 Day 1 was 46 hours (range: 12-82 hours). CRS resolved in all patients, and the median duration of CRS events was 3 days (range 1-29 days).

Of the 86 patients that experienced CRS, the most common signs and symptoms of CRS included pyrexia (98%), chills (36%), hypotension (35%), tachycardia (24%), hypoxia (22%) and headache (16%).

Tocilizumab and/or corticosteroids were used to manage a CRS event in 16% of patients: 6% received tocilizumab alone, 6% received corticosteroids alone, and 4% received both tocilizumab and corticosteroids. Among the 10% of patients who received tocilizumab (with or without a corticosteroid), 86% received only one dose of tocilizumab, with no more than two doses of tocilizumab administered for a single CRS event. In patients experiencing Grade 2 CRS, 48% of patients were treated with symptomatic management without corticosteroids or tocilizumab, 18% received tocilizumab alone, 21% received corticosteroids alone, and 12% received both corticosteroids and tocilizumab. Patients with grade 3 or grade 4 CRS received tocilizumab, corticosteroids, vasopressors and/or oxygen supplementation. Three percent of patients experienced hypotension and/or hypoxia without fever following Lunsumio administration; 2% of patients received tocilizumab and/or corticosteroids in the absence of fever.

Hospitalizations due to CRS occurred in 21% of patients and the median duration of hospitalization was 5 days (range 0-30 days).

Neutropenia

Neutropenia of any grade occurred in 28% of patients, including 24% Grade 3-4 events. The median time to onset of first neutropenia/neutrophil count decreased events was 48 days (range: 1-280 days), with median duration of 8 days (range: 1-314 days). Of the 60 patients who had neutropenia/neutrophil count decreased events 68% received treatment G-CSF to treat the events.

Serious infections

Serious infections of any grade occurred in 17% of patients. 1.8% of patients experienced serious infections concurrently with grade 3-4 neutropenia. The median time to onset of first serious infection was 50 days (range: 1-561 days), with median duration of 12 days (range: 2-174 days). Grade 5 events occurred in 0.9% of patients, which included pneumonia and sepsis.

Tumour flare

Tumour flare (including pleural effusion and tumour inflammation) occurred in 4% of patients, which included 1.8% grade 2 and 2.3% grade 3 events. The median time to onset was 13 days (range 5-84 days), and median duration was 10 days (range 1-77 days).

Tumour Lysis Syndrome (TLS)

TLS occurred in 0.9% of patients, concurrent with CRS. One patient with follicular lymphoma was in the leukemic phase who experienced Grade 4 TLS. TLS onset was on days 2 and 24, and resolved within 4 and 6 days, respectively.

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.

• Do not mix Lunsumio with, or administer through the same infusion line, as other medicinal products.
• Do not use solvents other than sodium chloride 9 mg/mL (0.9%) solution for injection or sodium chloride 4.5 mg/mL (0.45%) solution for injection to dilute Lunsumio since its use has not been tested.
• No incompatibilities have been observed between Lunsumio and intravenous infusion bags with product contacting materials of polyvinyl chloride (PVC), or polyolefins (PO) such as polyethylene (PE) and polypropylene (PP). In addition, no ncompatibilities have been observed with infusion sets or infusion aids with product contacting materials of PVC, PE, polyurethane (PUR), polybutadiene (PBD), silicone, acrylonitrile butadiene styrene (ABS), polycarbonate (PC), polyetherurethane (PEU), fluorinated ethylene propylene (FEP), or polytetrafluorethylene (PTFE), or with drip chamber filter membrane composed of polyamide (PA).
• Do not use an in-line filter.