LUNSUMIO Solution for injection Ref.[116162] 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 subcutaneous injection (see section 4.8). Signs and symptoms included pyrexia, hypotension, and hypoxia, CRS events occurred predominantly in cycle 1 and were mainly associated with Day 1 and Day 8 dose administrations. The most frequently reported CRS signs and symptoms in ≥10% of patients treated with Lunsumio subcutaneous injection in the who experienced CRS events of any grade by ASTCT 2019 (36 patients) were pyrexia, hypotension, hypoxia, chills, tachycardia and headache.

Patients should be premedicated with corticosteroids, antipyretics and antihistamines at least through cycle 1. Patients must receive adequate hydration prior to the administration of Lunsumio subcutaneous injection. 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, COVID-19, and sepsis have occurred in patients receiving Lunsumio subcutaneous injection, some of which were life-threatening or fatal events (see section 4.8). Febrile neutropenia was observed in patients after receiving Lunsumio subcutaneous injection.

Lunsumio subcutaneous injection should not be administered in the presence of active infections. Caution should be exercised when considering the use of Lunsumio subcutaneous injection 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 subcutaneous injection 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.

Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS)

ICANS have occurred in patients receiving Lunsumio subcutaneous injection, including serious and life threatening reactions. The onset of ICANS can be concurrent with CRS, following resolution of CRS, or in the absence of CRS. Manifestations of ICANS reported in clinical trials included confusional state, lethargy, encephalopathy, depressed level of consciousness, and memory impairment. The majority of cases occurred during Cycle 1.

Patients should be monitored for signs and symptoms of ICANS following Lunsumio subcutaneous injection administration. Patients must be counselled to seek immediate medical attention should signs or symptoms occur at any time (see Patient card below).

Patients should be advised to exercise caution while (or avoid if symptomatic) driving, cycling or using heavy or potentially dangerous machines (see section 4.7).

At the first signs or symptoms of ICANS, manage according to the ICANS guidance provided in Table 5. Treatment with Lunsumio subcutaneous injection should be withheld or discontinued permanently as recommended.

Haemophagocytic lymphohistiocytosis

Haemophagocytic lymphohistiocytosis (HLH), including fatal cases, have been reported in patients receiving Lunsumio. HLH is a life-threatening syndrome characterized by fever, hepatomegaly and cytopenias. HLH should be considered when the presentation of CRS is atypical or prolonged. Patients should be monitored for clinical signs and symptoms of HLH (see Section 4.2). For suspected HLH, Lunsumio must be interrupted and treatment for HLH initiated.

Tumour flare

Tumour flare has been reported in patients treated with Lunsumio subcutaneous injection (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 subcutaneous injection, tumour flare is likely due to the influx of T-cells into tumour sites following Lunsumio subcutaneous injection 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 subcutaneous injection should be monitored and evaluated for tumour flare at critical anatomical sites.

Tumour lysis syndrome (TLS)

TLS can occur in patients receiving Lunsumio subcutaneous injection (see section 4.8). Patients must have adequate hydration prior to the administration of Lunsumio subcutaneous injection. Patients should be administered prophylactic anti-hyperuricemic 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 subcutaneous injection. 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 ICANS, including instructions on when a patient should seek medical attention.

Excipients with known effect

This medicinal product contains polysorbate 20. Each vial of Lunsumio 5 mg solution for injection contains 0.3 mg of polysorbate 20, and each vial of Lunsumio 45 mg solution for injection contains 0.6 mg of polysorbate 20, which is equivalent to 0.6 mg/mL. Polysorbates may cause allergic reactions.

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 subcutaneous injection treatment causes a transient increase in cytokine levels which may cause inhibition of CYP450 enzymes. On initiation of Lunsumio subcutaneous injection 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 subcutaneous injection and for at least 3 months after the last injection of Lunsumio subcutaneous injection.

Pregnancy

There are no data from the use of Lunsumio subcutaneous injection in pregnant women. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). Lunsumio subcutaneous injection 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 subcutaneous injection.

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 subcutaneous injection has major influence on the ability to drive and use machines. Due to the potential for ICANS, patients receiving Lunsumio subcutaneous injection are at risk of depressed level of consciousness (see section 4.4). Due to the potential for ICANS, patients should be advised to exercise caution while (or avoid if symptomatic) driving, cycling or using heavy or potentially dangerous machines.

Summary of safety profile

The adverse reactions described in this section were identified from the pivotal clinical trial GO29781 in patients treated at the recommended intravenous dose (n=218) and the recommended subcutaneous dose (n=139). Patients had follicular lymphoma (51.8%), diffuse large B-cell lymphoma (26.9%), transformed follicular lymphoma (9.8%) mantle cell lymphoma (7.3%), Richter's transformation (3.9%), and other histologies (0.3%). The median number of cycles of Lunsumio subcutaneous received was 8 (range 1-17), 47.5% of patients received 8 cycles, and 16.6% received more than 8 cycles up to 17 cycles.

Patients who received the recommended intravenous dose (n=218) and subcutaneous (n=139) dose are pooled (n=357) for this safety population. In this pooled safety population, the most common adverse reactions (≥20%) observed were cytokine release syndrome, neutropenia, rash and upper respiratory tract infection and injection site reactions in those treated with subcutaneous mosunetuzumab. The most common serious adverse reactions (≥2%) observed included cytokine release syndrome (CRS) (17% by ASTCT grading system), pyrexia (3%), sepsis (3%), upper respiratory tract infection (3%) and pneumonia (5%). Permanent discontinuation of Lunsumio due to an adverse reaction occurred in 5.8% (21/357) of patients. In patients who received the recommended subcutaneous dose (n=139), the adverse reactions that led to discontinuation in more than one patient were COVID-19 1.4% (2/139) and COVID-19 pneumonia 3.6% (5/139).

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 6. Adverse reactions occurring in patients treated with Lunsumio:

¹ Upper respiratory tract infection includes upper respiratory tract infection, viral upper respiratory tract infection, nasopharyngitis, sinusitis, rhinovirus infection, sinusitis bacterial, viral sinusitis, respiratory tract infection, COVID-19 and respiratory tract infection viral
² Urinary tract infection (UTI) includes UTI, Escherichia UTI, pyelonephritis acute
³ Pneumonia includes pneumonia and COVID-19 pneumonia
⁴ Lower respiratory tract infection includes lower respiratory tract infection and bronchitis
⁵ Sepsis includes sepsis, septic shock, bacteraemia, Candida sepsis
⁶ Tumour flare includes tumour flare, pleural effusion, tumour inflammation and flank pain
⁷ Neutropenia includes neutropenia and neutrophil count decreased
⁸ Thrombocytopenia includes thrombocytopenia and platelet count decreased
⁹ By American Society for Transplantation and Cellular Therapy
¹⁰ Haemophagocytic lymphohistocytosis (HLH) includes HLH
¹¹ Hypophosphatemia includes hypophosphatemia and blood phosphorus decreased
¹² Hypokalemia includes hypokalemia and blood potassium decreased
¹³ Hypomagnesemia includes hypomagnesemia and blood magnesium decrease
¹⁴ Headache includes headache, migraine and head discomfort
¹⁵ Dizziness includes dizziness and vertigo
¹⁶ Consistent with the medical concept of ICANS according to American Society for Transplantation and Cellular Therapy and includes confusional state, ICANS, lethargy, encephalopathy, depressed level of consciousness, and memory impairment
¹⁷ The frequency calculation is based on additional clinical studies
¹⁸ Rash includes rash, rash erythematous, exfoliative rash, rash macular, rash maculo-papular, rash pruritic, rash pustular, erythema, palmar erythema, dermatitis, dermatitis acneiform, dermatitis contact, palmar-planta erythrodysaesthesia and rash morbiliform
¹⁹ Grade 5 AEs only occurred for ADR terms HLH, pneumonia, sepsis and URTI (i.e., COVID-19) in mosuntezumab subcutaneous injection (1 each) and for ADR terms pneumonia and sepsis in mosunetuzumab intravenous infusion (1 each)

Description of selected adverse reactions

Cytokine release syndrome (CRS)

CRS (ASTCT grading system) of any grade occurred in 26% (36/139) of patients, with grade 2 occurring in 7.2%, grade 3 occurring in 1.4% treated with Lunsumio subcutaneous injection.

CRS of any grade occurred in 15.8% of patients after the Cycle 1, Day 1 dose; 11.7% after the Cycle 1, Day 8 dose; 2.2% after the Cycle 1, Day 15 dose, 0.8% occurred in patients after the Cycle 2 and 0% in Cycles 3 and beyond. The median time to CRS onset from the start of administration in Cycle 1 Day 1 was 17.62 hours (range: 7.2-33.4 hours), Cycle 1 Day 8 was 51.5 hours (range: 30.3- 112.5 hours), Cycle 1 Day 15 was 46.7 hours (range: 23.2-61.5 hours), and Cycle 2 Day 1 was 34.85 hours (range: 34.8-34.8 hours). CRS resolved in all patients, and the median duration of CRS events was 2 days (range 1-15 days).

Of the 36 patients that experienced CRS, the most common signs and symptoms of CRS included pyrexia (97.2%), hypotension (22%), hypoxia (19.4%), chills (13.9%), headache (11.1%) and tachycardia (11.1%).

Tocilizumab and/or corticosteroids were used to manage a CRS event in 12% of patients: 5.7% received tocilizumab alone, 4.3% received corticosteroids alone, and 1.4% received both tocilizumab and corticosteroids. Patients with grade 3 CRS received tocilizumab, corticosteroids, vasopressors and/or oxygen supplementation.

Hospitalisations due to CRS occurred in 11.5% of patients and the median duration of hospitalisation for serious CRS events was 4.0 days (range 1-34 days).

Neutropenia

In patients treated with Lunsumio intravenous infusion or subcutaneous injection, neutropenia of any grade occurred in 26.1% (93/357) of patients, including 22.7% Grade 3-4 events. The median time to onset of first neutropenia/neutrophil count decreased events was 50 days (range: 1-280 days), with median duration of 8 days (range: 1-487 days). Of the 93 patients who had neutropenia/neutrophil count decreased events 68% (63/93) received treatment G-CSF to treat the events.

Serious infections

In patients treated with Lunsumio intravenous infusion or subcutaneous injection, serious infections of any grade occurred in 17% (60/357) of patients. Five (1.4%) of patients experienced serious infections concurrently with grade 3-4 neutropenia. The median time to onset of first serious infection was 92 days (range: 1-408 days), with median duration of 15.5 days (range: 2-174 days). Grade 5 events occurred in 2.5% (9/357) of patients, which included COVID-19 pneumonia, COVID-19, pneumonia, septic shock and sepsis.

Immune Effector Cell-Associated Neurotoxicity Syndrome

Across a broader clinical trial population, Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) occurred in 2.1% (20/949) of patients, 19 patients had Grade 1-2 events and 1 patient had Grade 3 event. The majority of events occurred during the first cycle of treatment. The majority of cases resolved. The median time to onset from initial dose was 17 days (range: 1 to 48 days). The median duration was 3 days (range: 1-20 days). Immune Effector Cell-Associated Encephalopathy (ICE) scoring was not systematically performed across the referenced trial population.

Tumour flare

In patients treated with Lunsumio intravenous infusion or subcutaneous injection, tumour flare (including pleural effusion and tumour inflammation) occurred in 3.1% (11/357) of patients, which included 1.4% grade 2 and 1.4% grade 3 events. The median time to onset was 13 days (range 2-84 days), and median duration was 36 days (range 15-105 days).

Tumour Lysis Syndrome (TLS)

In patients treated with Lunsumio intravenous infusion or subcutaneous injection, TLS occurred in 0.6% (2/357) 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 3 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.

No incompatibilities between Lunsumio Subcutaneous formulation and polypropylene or polycarbonate syringe material or stainless- steel transfer and injection needles and polyethylene Luer cone stoppers have been observed.