Columvi

Columvi must only be administered under the supervision of a healthcare professional experienced in the diagnosis and treatment of cancer patients and who has access to appropriate medical support to manage severe reactions associated with cytokine release syndrome (CRS) and immune effector cell- associated neurotoxicity syndrome (ICANS).

3 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. 4). 1). Obinutuzumab was administered as an intravenous infusion at 50 mg/h. The rate of infusion was escalated in 50 mg/h increments every 30 minutes to a maximum of 400 mg/h.

Refer to the obinutuzumab prescribing information for complete information on premedication, preparation, administration and management of adverse reactions of obinutuzumab. Premedication and prophylaxis Cytokine release syndrome prophylaxis Columvi should be administered to well-hydrated patients.

4) is outlined in Table 1. Table 1. Premedication before Columvi infusion Treatment cycle (Day) Patients requiring premedication Premedication Administration Cycle 1 (Day 8, Day 15); Cycle 2 (Day 1); Cycle 3 (Day 1) All patients 20 mg intravenous dexamethasone1 Completed at least 1 hour prior to Columvi infusion Oral analgesic / anti-pyretic2 At least 30 minutes before Columvi infusion Anti-histamine3 All subsequent infusions All patients Oral analgesic / anti-pyretic2 At least 30 minutes before Columvi infusion Anti-histamine3 Patients who experienced CRS with the previous dose 20 mg intravenous dexamethasone1, 4 Completed at least 1 hour prior to Columvi infusion 1 If patient has an intolerance to dexamethasone or dexamethasone is unavailable, administer 100 mg prednisone/prednisolone or 80 mg methylprednisolone.

2 For example, 1 000 mg paracetamol. 3 For example, 50 mg diphenhydramine. 4 To be administered in addition to the premedication required for all patients. 4). 8). 4 Posology Columvi dosing begins with a step-up dosing schedule (which is designed to decrease the risk of CRS), leading to the recommended dose of 30 mg.

Columvi monotherapy dose step-up schedule Columvi must be administered as an intravenous infusion according to the dose step-up schedule leading to the recommended dose of 30 mg (as shown in Table 2), after completion of pre-treatment with obinutuzumab on Cycle 1 Day 1.

Summary of the safety profile Columvi monotherapy The most common adverse reactions (≥ 20%) were cytokine release syndrome, neutropenia, anaemia, thrombocytopenia, and rash. 1%). 5% of patients. 4%). Columvi in combination with gemcitabine and oxaliplatin The most common adverse reactions (≥ 20%) were thrombocytopenia, cytokine release syndrome, neutropenia, anaemia, nausea, peripheral neuropathy, diarrhoea, aspartate aminotransferase increased, alanine aminotransferase increased, rash, lymphopenia, pyrexia, and vomiting.

3%). 9% of patients. 2%). 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 6. Patients received a median of 5 cycles of Columvi treatment (range: 1 to 13 cycles).

Adverse reactions occurring in relapsed or refractory DLBCL patients treated with Columvi in combination with gemcitabine and oxaliplatin (n=172) in study GO41944 (STARGLO) are listed in Table 7. Patients received a median of 11 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. 16 Table 6. Adverse reactions reported in patients with relapsed or refractory DLBCL treated with Columvi monotherapy System organ class Adverse reaction All grades Grade 34 Infections and infestations Viral infections1 Very common Common* Bacterial infections2 Common Common Upper respiratory tract infections3 Common Very rare** Sepsis4 Common Common* Lower respiratory tract infections5 Common Very rare** Pneumonia Common Uncommon Urinary tract infection6 Common Uncommon Fungal infections7 Common Very rare** Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumour flare Very common Common Blood and lymphatic system disorders Neutropenia Very common Very Common Anaemia Very common Common Thrombocytopenia Very common Common Lymphopenia Common Common Febrile neutropenia8 Common Common Immune system disorders Cytokine release syndrome9 Very common Common Metabolism and nutrition disorders Hypophosphataemia Very common Common Hypomagnesaemia Very common Very rare** Hypocalcaemia Very common Very rare** Hypokalaemia Very common Uncommon Hyponatraemia Common Common Tumour lysis syndrome Common Common Psychiatric disorders Confusional state Common Very rare** Nervous system disorders Headache Very common Very rare** Immune effector cell-associated neurotoxicity syndrome10 Common Uncommon* Somnolence Common Uncommon Tremor Common Very rare** Myelitis11 Uncommon Uncommon Gastrointestinal disorders Constipation Very common Very rare** Diarrhoea Very common Very rare** Nausea Very common Very rare** Gastrointestinal haemorrhage12 Common Common Vomiting Common Very rare** Colitis Uncommon Uncommon Skin and subcutaneous tissue disorders Rash13 Very common Common General disorders and administration site conditions Pyrexia Very common Very rare** 17 System organ class Adverse reaction All grades Grade 34 Investigations Alanine aminotransferase increased Common Common Aspartate aminotransferase increased Common Common Blood alkaline phosphatase increased Common Common Gamma-glutamyltransferase increased Common Common Blood bilirubin increased Common Uncommon Hepatic enzyme increased Common Common * Grade 5 reactions reported.

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. 8). 12 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. 8). Patients in studies NP30179 and GO41944 (STARGLO) were pre-treated with obinutuzumab to lower the circulating and lymphoid B cells, 7 days prior to initiation of Columvi therapy.

All patients should be premedicated with an anti-pyretic, antihistamine, and a glucocorticoid (see Table 1). 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.

When Columvi is given as monotherapy, patients must be monitored during all Columvi infusions and for at least 10 hours after completion of the first infusion. When Columvi is given in combination with gemcitabine and oxaliplatin, patients must be monitored during all Columvi infusions and for 4 hours after completion of the first infusion.

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.

1. For specific contraindications on obinutuzumab, please refer to the obinutuzumab prescribing information.