COLUMVI Concentrate for solution for infusion Ref.[51062] Active ingredients: Glofitamab

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.

CD20-negative disease

There are limited data available on patients with CD20-negative DLBCL treated with Columvi and it is possible that patients with CD20-negative DLBCL may have less benefit compared to patients with CD20-positive DLBCL. The potential risks and benefits associated with treatment of patients with CD20-negative DLBCL with Columvi should be considered.

Cytokine release syndrome

CRS, including life-threatening reactions, has been reported in patients receiving Columvi (see section 4.8).

The most common manifestations of CRS were pyrexia, tachycardia, hypotension, chills and hypoxia. Infusion-related reactions may be clinically indistinguishable from manifestations of CRS.

Most CRS events occurred following the first dose of Columvi. Elevated liver function tests (AST and alanine transaminase [ALT] >3 × ULN and/or total bilirubin >2 × ULN) concurrent with CRS have been reported after Columvi use (see section 4.8).

Patients in study NP30179 were pre-treated with obinutuzumab, 7 days prior to initiation of Columvi therapy, and patients should be premedicated with an anti-pyretic, antihistamine and a glucocorticoid (see section 4.2).

At least 1 dose of tocilizumab for use in the event of CRS must be available prior to Columvi infusion at Cycles 1 and 2. Access to an additional dose of tocilizumab within 8 hours of use of the previous tocilizumab dose must be ensured. Patients must be monitored during all Columvi infusions and for at least 10 hours after completion of the first infusion. For complete information on monitoring, see section 4.2. Patients must be counselled to seek immediate medical attention should signs or symptoms of CRS occur at any time (see Patient card below).

Patients should be evaluated for other causes of fever, hypoxia and hypotension, such as infections or sepsis. CRS should be managed based on the patient’s clinical presentation and according to the CRS management guidance provided in Table 3 (section 4.2).

Patient card

The prescriber must inform the patient of the risk of CRS and signs and symptoms of CRS. Patients must be instructed to seek immediate medical attention if they experience signs and symptoms of CRS. Patients should be provided with the patient card and instructed to carry the card at all times. This card describes symptoms of CRS which, if experienced, should prompt the patient to seek immediate medical attention.

Interaction with CYP450 substrates

The initial release of cytokines associated with the start of Columvi treatment could suppress CYP450 enzymes and lead to fluctuations in concentrations of concomitantly administered drugs. On initiation of Columvi therapy, patients being treated with CYP450 substrates with a narrow therapeutic index should be monitored as fluctuations in the concentration of concomitant drugs may lead to toxicity, loss of effect or adverse events (see section 4.5).

Serious infections

Serious infections (such as sepsis and pneumonia) have occurred in patients treated with Columvi (see section 4.8).

Columvi must not be administered to patients with an active infection. Caution should be exercised when considering the use of Columvi in patients with a history of chronic or recurrent infection, those with underlying conditions that may predispose them to infections, or those who have had significant prior immunosuppressive treatment. Patients should be monitored before and during Columvi treatment for the emergence of possible bacterial, fungal, and new or reactivated viral infections and treated appropriately.

Columvi should be temporarily withheld in the presence of an active infection until the infection has resolved. Patients should be instructed to seek medical advice if signs or symptoms suggestive of an infection occur.

Febrile neutropenia has been reported during treatment with Columvi. Patients with febrile neutropenia should be evaluated for infection and treated promptly.

Tumour flare

Tumour flare has been reported in patients receiving Columvi (see section 4.8). Manifestations included localised pain and swelling.

Consistent with the mechanism of action of Columvi, tumour flare is likely due to the influx of T cells into tumour sites following Columvi administration and may mimic progression of disease. Tumour flare does not imply treatment failure or represent tumour progression.

Specific risk factors for tumour flare have not 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. Monitoring and evaluation for tumour flare at critical anatomical sites is recommended in patients treated with Columvi and managed as clinically indicated. Corticosteroids and analgesics should be considered to treat tumour flare.

Tumour lysis syndrome

Tumour lysis syndrome (TLS) has been reported in patients receiving Columvi (see section 4.8). Patients with high tumour burden, rapidly proliferative tumours, renal dysfunction or dehydration are at greater risk of tumour lysis syndrome.

Patients at risk should be monitored closely by appropriate laboratory and clinical tests for electrolyte status, hydration and renal function. Appropriate prophylactic measures with anti-hyperuricaemics (e.g., allopurinol or rasburicase) and adequate hydration should be considered prior to obinutuzumab pre-treatment and prior to Columvi infusion.

Management of TLS may include aggressive hydration, correction of electrolyte abnormalities, anti-hyperuricaemic therapy and supportive care.

Immunisation

The safety of immunisation with live vaccines during or following Columvi therapy has not been studied. Immunisation with live vaccines is not recommended during Columvi therapy.

No interaction studies have been performed. No interactions with Columvi are expected via the cytochrome P450 enzymes, other metabolizing enzymes or transporters.

The initial release of cytokines associated with the start of Columvi treatment could suppress CYP450 enzymes. The highest drug-drug interaction risk is during the period of one week following each of the first 2 doses of Columvi (i.e., Cycle 1 Day 8 and 15) in patients who are receiving concomitant CYP450 substrates with a narrow therapeutic index (e.g., warfarin, cyclosporine). On initiation of Columvi therapy, patients being treated with CYP450 substrates with a narrow therapeutic index should be monitored.

Women of childbearing potential / Contraception

Female patients of childbearing potential must use highly effective contraceptive methods during treatment with Columvi and for at least 2 months following the last dose of Columvi.

Pregnancy

There are no data on the use of Columvi in pregnant women. No reproductive toxicity studies have been performed in animals (see section 5.3).

Glofitamab is an immunoglobulin G (IgG). IgG is known to cross the placenta. Based on its mechanism of action, glofitamab is likely to cause foetal B cell depletion when administered to a pregnant woman.

Columvi is not recommended during pregnancy and in women of childbearing potential not using contraception. Female patients receiving Columvi should be advised of the potential harm to the foetus. Female patients should be advised to contact the treating physician, should pregnancy occur.

Breast-feeding

It is not known whether glofitamab is excreted in human milk. No studies have been conducted to assess the impact of glofitamab on milk production or its presence in breast milk. Human IgG is known to be present in human milk. The potential for absorption of glofitamab and the potential for adverse reactions in the breast-feeding child is unknown. Women should be advised to discontinue breast-feeding during treatment with Columvi and for 2 months after the final dose of Columvi.

Fertility

No human data on fertility are available. No fertility assessments in animals have been performed to evaluate the effect of glofitamab on fertility (see section 5.3).

Columvi has minor influence on the ability to drive and use machines. Patients experiencing symptoms of neurological adverse events and/or CRS (pyrexia, tachycardia, hypotension, chills, hypoxia) should be advised not to drive or use machines until symptoms resolve (see sections 4.4 and 4.8).

Summary of the safety profile

The most common adverse reactions (≥20%) were cytokine release syndrome, neutropenia, anaemia, thrombocytopenia, and rash.

The most common serious adverse reactions reported in ≥2% of patients were cytokine release syndrome (22.1%), sepsis (4.1%), COVID-19 (3.4%), tumour flare (3.4%), COVID-19 pneumonia (2.8%), febrile neutropenia (2.1%), neutropenia (2.1%), and pleural effusion (2.1%).

Permanent discontinuation of Columvi due to an adverse reaction occurred in 5.5% of patients. The most common adverse reactions leading to permanent discontinuation of Columvi were COVID-19 (1.4%) and neutropenia (1.4%).

Tabulated list of adverse reactions

Adverse reactions occurring in relapsed or refractory DLBCL patients treated with Columvi monotherapy (n=145) in study NP30179 are listed in Table 4. Patients received a median of 5 cycles of Columvi treatment (range: 1 to 13 cycles).

The adverse reactions are listed by MedDRA system organ class and categories of frequency. The following categories of frequency have been used: 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). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Table 4. Adverse reactions reported in patients with relapsed or refractory DLBCL treated with Columvi monotherapy:

^* Grade 5 reactions reported. See serious infections in Description of selected adverse reactions.
^** No Grade 3-4 events were reported.
¹ Includes COVID-19, COVID-19 pneumonia, herpes zoster, influenza, and ophthalmic herpes zoster.
² Includes vascular device infection, bacterial infection, Campylobacter infection, biliary tract infection bacterial, urinary tract infection bacterial, Clostridium difficile infection, Escherichia infection, and peritonitis.
³ Includes upper respiratory tract infection, sinusitis, nasopharyngitis, chronic sinusitis, and rhinitis.
⁴ Includes sepsis and septic shock.
⁵ Includes lower respiratory tract infection and bronchitis.
⁶ Includes urinary tract infection and Escherichia urinary tract infection.
⁷ Includes oesophageal candidiasis and oral candidiasis.
⁸ Includes febrile neutropenia and neutropenic infection.
⁹ Based on ASTCT consensus grading (Lee 2019).
¹⁰ Myelitis occurred concurrently with CRS.
¹¹ Includes gastrointestinal haemorrhage, large intestinal haemorrhage, and gastric haemorrhage.
¹² Includes rash, rash pruritic, rash maculo-papular, dermatitis, dermatitis acneiform, dermatitis exfoliative,
erythema, palmar erythema, pruritis, and rash erythematous.

Description of selected adverse reactions

Cytokine release syndrome

In study NP30179, any grade CRS (by ASTCT criteria) occurred in 67.6% of patients, with Grade 1 CRS being reported in 50.3% of patients, Grade 2 CRS in 13.1% patients, Grade 3 CRS in 2.8% of patients and Grade 4 CRS in 1.4% of patients. CRS occurred more than once in 32.4% (47/145) of patients; 36/47 patients experienced multiple Grade 1 CRS events only. There were no fatal cases of CRS. CRS resolved in all patients except one. One patient discontinued treatment due to CRS.

In patients with CRS, the most common manifestations of CRS included pyrexia (99.0%), tachycardia (25.5%), hypotension (23.5%), chills (14.3%) and hypoxia (12.2%). Grade 3 or higher events associated with CRS included hypotension (3.1%), hypoxia (3.1%), pyrexia (2.0%) and tachycardia (2.0%).

CRS of any grade occurred in 54.5% of patients following the first 2.5 mg dose of Columvi at Cycle 1 Day 8 with median time to onset (from start of infusion) of 12.6 hours (range: 5.2 to 50.8 hours) and median duration of 31.8 hours (range: 0.5 to 316.7 hours); in 33.3% of patients following the 10 mg dose at Cycle 1 Day 15 with median time to onset of 26.8 hours (range: 6.7 to 125.0 hours) and median duration of 16.5 hours (range: 0.3 to 109.2 hours); and in 26.8% of patients following the 30 mg dose at Cycle 2 with median time to onset of 28.2 hours (range: 15.0 to 44.2 hours) and median duration of 18.9 hours (range: 1.0 to 180.5 hours). CRS was reported in 0.9% of patients at Cycle 3 and in 2% of patients beyond Cycle 3.

Grade ≥ 2 CRS occurred in 12.4% of patients following the first Columvi dose (2.5 mg) with median time to onset of 9.7 hours (range: 5.2 to 19.1 hours) and median duration of 50.4 hours (range: 6.5 to 316.7 hours). Following Columvi 10 mg dose at Cycle 1 Day 15, the incidence of Grade ≥ 2 CRS decreased to 5.2% of patients with median time to onset of 26.2 hours (range: 6.7 to 144.2 hours) and median duration of 30.9 hours (range: 3.7 to 227.2 hours). Grade ≥ 2 CRS following Columvi 30 mg dose at Cycle 2 Day 1 occurred in one patient (0.8%) with time to onset of 15.0 hours and duration of 44.8 hours. No Grade ≥ 2 CRS was reported beyond Cycle 2.

In 145 patients, 7 (4.8%) patients experienced elevated liver function tests (AST and ALT > 3 × ULN and/or total bilirubin > 2 × ULN) reported concurrently with CRS (n=6) or with disease progression (n=1).

Among the 25 patients who experienced Grade ≥ 2 CRS after Columvi, 22 (88.0%) received tocilizumab, 15 (60.0%) received corticosteroids and 14 (56.0%) received both tocilizumab and corticosteroids. Ten patients (40.0%) received oxygen. All 6 patients (24.0%) with Grade 3 or 4 CRS received a single vasopressor.

Hospitalisations due to patients experiencing CRS following Columvi administration occurred in 22.1% of patients and the reported median duration of hospitalisation was 4 days (range: 2 to 15 days).

Serious infections

In study NP30179, serious infections were reported in 15.9% of patients. The most frequent serious infections reported in ≥2% of patients were sepsis (4.1%), COVID-19 (3.4%), and COVID-19 pneumonia (2.8%). Infection-related deaths were reported in 4.8% of patients (due to sepsis, COVID-19 pneumonia and COVID-19). Four patients (2.8%) experienced serious infections concurrently with Grade 3 or 4 neutropenia.

Neutropenia

Neutropenia (including neutrophil count decreased) was reported in 40.0% of patients and severe neutropenia (Grade 3 or 4) was reported in 29.0% of patients. The median time to onset of the first neutropenia event was 29 days (range: 1 to 203 days). Prolonged neutropenia (lasting longer than 30 days) occurred in 11.7% of patients. The majority of patients with neutropenia (79.3%) were treated with G-CSF. Febrile neutropenia was reported in 3.4% of patients.

Tumour flare

Tumour flare was reported in 11.7% of patients, including Grade 2 tumour flare in 4.8% of patients and Grade 3 tumour flare in 2.8% of patients. Tumour flare was reported involving lymph nodes in the head and neck presenting with pain and involving lymph nodes in the thorax with symptoms of breathlessness due to development of pleural effusion. Most tumour flare events (16/17) occurred during Cycle 1, and no tumour flare events were reported beyond Cycle 2. The median time to onset of tumour flare of any grade was 2 days (range: 1 to 16 days), and the median duration was 3.5 days (range: 1 to 35 days).

Among the 11 patients who experienced Grade ≥ 2 tumour flare, 2 (18.2%) patients received analgesics, 6 (54.5%) patients received corticosteroids and analgesics including morphine derivatives, 1 (0.9%) patient received corticosteroids and anti-emetics, and 2 (18.2%) patients did not require treatment. All tumour flare events resolved except in one patient with a Grade ≥ 2 event. No patients discontinued treatment due to tumour flare.

Tumour lysis syndrome

TLS was reported in 2 patients (1.4%) and was Grade 3 in severity in both cases. The median time to onset of TLS onset was 2 days, and the median duration was 4 days (range: 3 to 5 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.