4.1. Therapeutic indications

Columvi in combination with gemcitabine and oxaliplatin is indicated for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma not otherwise specified (DLBCL NOS) who are ineligible for autologous stem cell transplant (ASCT).

Columvi as monotherapy is indicated for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), after two or more lines of systemic therapy.

4.2. Posology and method of administration

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).

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 (see section 4.4).

Pre-treatment with obinutuzumab

All patients in study NP30179 and in study GO41944 (STARGLO) received a single 1 000 mg dose of obinutuzumab as pre-treatment on Cycle 1 Day 1 (7 days prior to initiation of Columvi treatment) to lower the circulating and lymphoid B cells to reduce the risk of CRS (see Table 2, Delayed or Missed Doses, and section 5.1).

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. Recommended premedication for CRS (see section 4.4) 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.

Infection prophylaxis

Prophylaxis is recommended to reduce the risk of infection (see section 4.4).

Consider prophylaxis for cytomegalovirus (CMV), herpes, pneumocystis jiroveci pneumonia, and other opportunistic infections in patients at increased risk (see Section 4.8).

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. Each cycle is 21 days.

Table 2. Columvi monotherapy dose step-up schedule for patients with relapsed or refractory DLBCL

Treatment cycle, Day

Dose of Columvi

Duration of infusion

Cycle 1

(Pre-treatment and step-up dose)

Day 1

Pre-treatment with obinutuzumab 1 000mg1

Day 8

2.5 mg

4 hours2

Day 15

10 mg

Cycle 2

Day 1

30 mg

Cycle 3 to 12

Day 1

30 mg

2 hours3

1 Refer to “Pre-treatment with obinutuzumab“ described above.

2 For patients who experience CRS with their previous dose of Columvi, the duration of infusion may be extended up to 8 hours (see section 4.4).

3 At the discretion of the treating physician, if the previous infusion was well tolerated. If the patient experienced CRS with a previous dose, the duration of infusion should be maintained at 4 hours.

Columvi dose step-up schedule in combination with gemcitabine and oxaliplatin

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 3), after completion of pre-treatment with obinutuzumab on Cycle 1 Day 1. Columvi is given in combination with gemcitabine and oxaliplatin at Cycles 1-8 and as monotherapy at Cycles 9-12. Each cycle is 21 days.

Table 3. Columvi dose step-up schedule in combination with gemcitabine and oxaliplatin for patients with relapsed or refractory DLBCL

Treatment cycle, Day

Dose of Columvi (duration of infusion)

Dose of gemcitabine

Dose of oxaliplatin

Cycle 1

(Pre-treatment and step-up dose)

Day 1

Pre-treatment with obinutuzumab

1000mga

Day 2

--

1000 mg/m2b

100 mg/m2b

Day 8

2.5 mg (4 hours)c

--

--

Day 15

10 mg (4 hours)c

Cycle 2

Day 1

30 mg (4 hours)c, d

1000 mg/m2b,d

100 mg/m2b,d

Cycle 3 to 8

Day 1

30 mg (2 hours)d,e

1000 mg/m2b,d

100 mg/m2b,d

Cycle 9 to 12

Day 1

30 mg (2 hours)e

--

--

a Refer to “Pre-treatment with obinutuzumab” described above.

b Cycles 1-8: Administer gemcitabine before oxaliplatin

c For patients who experience CRS with their previous dose of Columvi, the time of infusion may be extended up to 8 hours (see section 4.4).

d Cycles 2-8: Administer Columvi before gemcitabine and oxaliplatin. Gemcitabine and oxaliplatin may be given on Day 1 or 2.

e Infusion time may be shortened to 2 hours at the discretion of the treating physician, if the previous infusion was well tolerated. If the patient experienced CRS with a previous dose, the duration of infusion should be maintained at 4 hours.

Patient monitoring

● When Columvi is given as monotherapy, patients must be monitored for signs and symptoms of potential CRS during all Columvi infusions and for at least 24 hours after completion of the infusion of the first Columvi dose (2.5 mg on Cycle 1 Day 8). The prescriber should use the information on CRS times to onset and grade after each dose, provided in Section 4.8, when determining the appropriate monitoring strategy, according to local guidelines and policies

• When Columvi is given in combination with gemcitabine and oxaliplatin, patients must be monitored for signs and symptoms of potential CRS during all Columvi infusions and for 12 hours after completion of the first Columvi dose (2.5 mg on Cycle 1 Day 8) (see section 4.8).

Patients who experienced Grade ≥ 2 CRS with their previous infusion should be monitored after completion of the infusion (see Table 4).

All patients must be monitored for signs and symptoms of CRS and immune effector cell-associated neurotoxicity syndrome (ICANS) following Columvi administration.

All patients must be counselled on the risk, signs and symptoms of CRS and ICANS and advised to contact the healthcare provider immediately should they experience signs and symptoms of CRS and/or ICANS at any time (see section 4.4).

Duration of treatment

Treatment with Columvi monotherapy is recommended for a maximum of 12 cycles or until disease progression or unmanageable toxicity, whichever occurs first. Each cycle is 21 days.

Treatment with Columvi in combination with gemcitabine and oxaliplatin is recommended for 8 cycles, followed by 4 cycles of Columvi monotherapy for a maximum of 12 cycles of Columvi in total or until disease progression or unmanageable toxicity, whichever occurs first. Each cycle is 21 days.

Delayed or missed doses

During step-up dosing (weekly dosing):

● Following pre-treatment with obinutuzumab, if the Columvi 2.5 mg dose is delayed by more than 1 week, then repeat pre-treatment with obinutuzumab.

● Following Columvi 2.5 mg dose or 10 mg dose, if there is a Columvi treatment-free interval of 2 weeks to 6 weeks, then repeat the last tolerated Columvi dose and resume the planned step-up dosing.

● Following Columvi 2.5 mg dose or 10 mg dose, if there is a Columvi treatment-free interval of more than 6 weeks, then repeat pre-treatment with obinutuzumab and Columvi step-up dosing (see Cycle 1 in Table 2 and Table 3).

After Cycle 2 (30 mg dose):

● If there is a Columvi treatment-free interval of more than 6 weeks between cycles, then repeat pre-treatment with obinutuzumab and Columvi step-up dosing (see Cycle 1 in Table 2 and Table 3), and then resume the planned treatment cycle (30 mg dose).

Dose modifications

No dose reductions of Columvi are recommended. Adverse events should be managed with dose interruption, treatment discontinuation and reduction of the infusion rate (see 'Delayed or missed doses' and 'Management of cytokine release syndrome').

Management of Cytokine Release Syndrome (CRS)

CRS should be identified based on the clinical presentation (see sections 4.4 and 4.8). Patients should be evaluated for other causes of fever, hypoxia, and hypotension, such as infections or sepsis. If CRS is suspected, it should be managed according to the CRS management recommendations based on American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading in Table 4.

Table 4. ASTCT CRS grading and CRS management guidance

Grade1

CRS management

For next scheduled Columvi infusion

Grade 1

Fever ≥ 38 °C

If CRS occurs during infusion:

• Interrupt infusion and treat symptoms

• Restart infusion at slower rate when symptoms resolve

• If symptoms recur, discontinue current infusion

If CRS occurs post-infusion:

• Treat symptoms

If CRS lasts more than 48 h after symptomatic management:

• Consider corticosteroids3

• Consider tocilizumab4

For CRS with concurrent ICANS, refer to Table 5.

• Ensure symptoms are resolved for at least 72 hours prior to next infusion

• Consider slower infusion rate2

Grade 2

Fever ≥ 38 °C and/or hypotension not requiring vasopressors and/or hypoxia requiring low-flow oxygen by nasal cannula or blow-by

If CRS occurs during infusion:

• Discontinue current infusion and treat symptoms

• Administer corticosteroids3

• Consider tocilizumab4

If CRS occurs post-infusion:

• Treat symptoms

• Administer corticosteroids3

• Consider tocilizumab4

For CRS with concurrent ICANS, refer to Table 5.

• Ensure symptoms are resolved for at least 72 hours prior to next infusion

• Consider slower infusion rate2

• Monitor patients post-infusion5

For Grade 2: Tocilizumab use

Do not exceed 3 doses of tocilizumab in a period of 6 weeks.

If no prior use of tocilizumab or if 1 dose of tocilizumab was used within the last 6 weeks:

• Administer first dose of tocilizumab4

• If no improvement within 8 hours, administer second dose of tocilizumab4

• After 2 doses of tocilizumab, consider alternative anti-cytokine therapy and/or alternative immunosuppressant therapy

If 2 doses of tocilizumab were used within the last 6 weeks:

• Administer only one dose of tocilizumab4

• If no improvement within 8 hours, consider alternative anti-cytokine therapy and/or alternative immunosuppressant therapy

Grade 3

Fever ≥ 38 °C and/or hypotension requiring a vasopressor (with or without vasopressin) and/or hypoxia requiring high-flow oxygen by nasal cannula, face mask, non-rebreather mask, or Venturi mask

If CRS occurs during infusion:

• Discontinue current infusion and treat symptoms

• Administer corticosteroids3

• Administer tocilizumab4

If CRS occurs post-infusion:

• Treat symptoms

• Administer corticosteroids3

• Administer tocilizumab4

For CRS with concurrent ICANS, refer to Table 5.

• Ensure symptoms are resolved for at least 72 hours prior to next infusion

• Consider slower infusion rate2

• Monitor patients post-infusion5

• If Grade ≥ 3 CRS recurs at subsequent infusion, stop infusion immediately and permanently discontinue Columvi

Grade 4

Fever ≥ 38 °C and/or hypotension requiring multiple vasopressors (excluding vasopressin) and/or hypoxia requiring oxygen by positive pressure (e.g., CPAP, BiPAP, intubation, and mechanical ventilation)

If CRS occurs during infusion or post-infusion:

• Permanently discontinue Columvi and treat symptoms

• Administer corticosteroids3

• Administer tocilizumab4

For CRS with concurrent ICANS, refer to Table 5.

For Grade 3 and Grade 4: Tocilizumab use

Do not exceed 3 doses of tocilizumab in a period of 6 weeks.

If no prior use of tocilizumab or if 1 dose of tocilizumab was used within the last 6 weeks:

• Administer first dose of tocilizumab4

• If no improvement within 8 hours or rapid progression of CRS, administer second dose of tocilizumab4

• After 2 doses of tocilizumab, consider alternative anti-cytokine therapy and/or alternative immunosuppressant therapy

If 2 doses of tocilizumab were used within the last 6 weeks:

• Administer only one dose of tocilizumab4

• If no improvement within 8 hours or rapid progression of CRS, consider alternative anti-cytokine therapy and/or alternative immunosuppressant therapy

1 American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading criteria (Lee DW et al ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. Biol Blood Marrow Transplant. 2019;25:625-38.

2 Duration of infusion may be extended up to 8 hours, as appropriate for that cycle (see Table 2).

3 Corticosteroids (e.g., 10 mg intravenous dexamethasone, 100 mg intravenous prednisolone, 1-2 mg/kg intravenous methylprednisolone per day, or equivalent).

4 Tocilizumab 8 mg/kg intravenously (not to exceed 800 mg), as administered in Study NP30179.

5 See section 4.8 for frequency and time to onset of Grade ≥2 CRS following Columvi 10mg and 30mg doses

Management of immune effector cell-associated neurotoxicity syndrome (ICANS)

At the first sign of ICANS, based on the type and severity, consider supportive therapy, neurology evaluation, and withholding Columvi (see Table 5). Rule out other causes of neurologic symptoms. If ICANS is suspected, it should be managed according to the recommendations in Table 5.

Table 5. ICANS grading and management guidance

Grade1

Presenting symptoms2

ICANS management

Concurrent CRS

No concurrent CRS

Grade 1

ICE3 score 7-9

Or depressed level of consciousness4: awakens spontaneously

• Manage CRS per Table 4.

• Monitor neurologic symptoms and consider neurology consultation and evaluation, per physician discretion.

• Monitor neurologic symptoms and consider neurology consultation and evaluation, per physician discretion.

Withhold Columvi until ICANS resolves.

Consider non-sedating, anti-seizure medicinal products (e.g., levetiracetam) for seizure prophylaxis.

Grade 2

ICE3 score 3-6

Or depressed level of consciousness4: awakens to voice

• Administer tocilizumab per Table 4 for management of CRS.

• If no improvement after starting tocilizumab, administer dexamethasone5 10 mg intravenously every 6 hours if not already taking other corticosteroids. Continue dexamethasone use until resolution to Grade 1 or less, then taper.

• Administer dexamethasone5 10 mg intravenously every 6 hours.

• Continue dexamethasone use until resolution to Grade 1 or less, then taper.

Withhold Columvi until ICANS resolves.

Consider non-sedating, anti-seizure medicinal products (e.g., levetiracetam) for seizure prophylaxis. Consider neurology consultation and other specialists for further evaluation, as needed

Grade 3

ICE3 score 0-2

Or depressed level of consciousness4: awakens only to tactile stimulus;

Or seizures4, either:

• any clinical seizure, focal or generalised that resolves rapidly, or

• non-convulsive seizures on electroencephalogram (EEG) that resolve with intervention;

Or raised intracranial pressure: focal/local oedema on neuroimaging4

• Administer tocilizumab per Table 4 for management of CRS.

• In addition, administer dexamethasone5 10 mg intravenously with the first dose of tocilizumab, and repeat dose every 6 hours, if not already taking other corticosteroids. Continue dexamethasone use until resolution to Grade 1 or less, then taper.

• Administer dexamethasone5 10 mg intravenously every 6 hours.

• Continue dexamethasone use until resolution to Grade 1 or less, then taper.

Withhold Columvi until ICANS resolves.

For Grade 3 ICANS events which do not improve within 7 days, consider permanently discontinuing Columvi.

Consider non-sedating, anti-seizure medicinal products (e.g., levetiracetam) for seizure prophylaxis. Consider neurology consultation and other specialists for further evaluation, as needed

Grade 4

ICE3 score 0

Or depressed level of consciousness4, either:

• patient is unarousable or requires vigorous or repetitive tactile stimuli to arouse, or

• stupor or coma;

Or seizures4, either:

• life-threatening prolonged seizure (> 5 minutes), or

• repetitive clinical or electrical seizures without return to baseline in between;

Or motor findings4:

• deep focal motor weakness such as hemiparesis or paraparesis;

Or raised intracranial pressure/cerebral oedema4, with signs/symptoms, such as:

• diffuse cerebral oedema on neuroimaging, or

• decerebrate or decorticate posturing, or

• cranial nerve VI palsy, or

• papilloedema, or

• Cushing's triad

• Administer tocilizumab per Table 4 for management of CRS.

• As above, or consider administration of methylprednisolone 1 000 mg per day intravenously with first dose of tocilizumab, and continue methylprednisolone 1 000 mg per day intravenously for 2 or more days.

• Administer dexamethasone5 10 mg intravenously every 6 hours.

• Continue dexamethasone use until resolution to Grade 1 or less, then taper.

• Alternatively, consider administration of methylprednisolone 1 000 mg per day intravenously for 3 days; if symptoms improve, then manage as above.

Permanently discontinue Columvi.

Consider non-sedating, anti-seizure medicinal products (e.g., levetiracetam) for seizure prophylaxis. Consider neurology consultation and other specialists for further evaluation, as needed. In case of raised intracranial pressure/cerebral oedema, refer to institutional guidelines for management.

1 ASTCT consensus grading criteria for ICANS (Lee 2019).

2 Management is determined by the most severe event, not attributable to any other cause.

3 If patient is arousable and able to perform Immune Effector Cell-Associated Encephalopathy (ICE) Assessment, assess:

Orientation (oriented to year, month, city, hospital = 4 points);

Naming (name 3 objects, e.g., point to clock, pen, button = 3 points);

Following Commands (e.g., “show me 2 fingers” or “close your eyes and stick out your tongue” = 1 point);

Writing (ability to write a standard sentence = 1 point);

Attention (count backwards from 100 by ten = 1 point).

If patient is unarousable and unable to perform ICE Assessment (Grade 4 ICANS) = 0 points.

4 Attributable to no other cause.

5 All references to dexamethasone administration are dexamethasone or equivalent.

Special populations

Elderly

No dose adjustment is required in patients 65 years of age and older (see section 5.2).

Hepatic impairment

No dose adjustment is required in patients with mild hepatic impairment (total bilirubin > upper limit of normal [ULN] to ≤ 1.5 x ULN or aspartate transaminase [AST] > ULN). Columvi has not been studied in patients with moderate or severe hepatic impairment (see section 5.2).

Renal impairment

No dose adjustment is required in patients with mild or moderate renal impairment (CrCL 30 to < 90 mL/min). Columvi has not been studied in patients with severe renal impairment (see section 5.2).

Paediatric population

The safety and efficacy of Columvi in children below 18 years of age have not been established. No data are available.

Method of administration

Columvi is for intravenous use only.

Columvi must be diluted by a healthcare professional using aseptic technique, prior to intravenous administration. It must be administered as an intravenous infusion through a dedicated infusion line.

Columvi must not be administered as an intravenous push or bolus.

For instructions on dilution of Columvi before administration, see section 6.6.

4.3. Contraindications

Hypersensitivity to the active substance, to obinutuzumab, or to any of the excipients listed in section 6.1.

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

4.4. Special warnings and precautions for use

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.

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 x ULN and/or total bilirubin > 2 x ULN) concurrent with CRS have been reported after Columvi use (see section 4.8).

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 24 hours after completion of the first infusion.

The prescriber should use the information on CRS times to onset and grade after each dose, provided in Section 4.8, when determining the appropriate monitoring strategy, according to local guidelines and policies.

When Columvi is given in combination with gemcitabine and oxaliplatin, patients must be monitored during all Columvi infusions and for 12 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 4 (section 4.2).

Immune effector cell-associated neurotoxicity syndrome

Serious cases of immune effector cell-associated neurotoxicity syndrome (ICANS) which could be life-threatening or fatal have occurred following treatment with Columvi (see section 4.8).

The onset of ICANS can be concurrent with CRS, following resolution of CRS, or in the absence of CRS. Clinical signs and symptoms of ICANS may include but are not limited to confusion, depressed level of consciousness, disorientation, seizure, aphasia, and dysgraphia.

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

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

Patient card

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

Serious infections

Serious infections, including opportunistic infections,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. Administer prophylactic antimicrobials, as appropriate. 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.

4.5. Interaction with other medicinal products and other forms of interaction

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

The pharmacokinetics (PK) of glofitamab are not affected by co-administration with gemcitabine or oxaliplatin.

4.6. Fertility, pregnancy and lactation

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).

4.7. Effects on ability to drive and use machines

Columvi has major influence on the ability to drive and use machines.

Due to the potential for ICANS, patients receiving Columvi are at risk of depressed level of consciousness (see section 4.4). Patients should be instructed to avoid driving or operating machines for 48 hours after each of the first two doses during the step-up dosing and in the event of new onset of any symptoms of ICANS (confusion, disorientation, depressed level of consciousness) and/or CRS (pyrexia, tachycardia, hypotension, chills, hypoxia) until symptoms resolve (see sections 4.4 and 4.8).

4.8. Undesirable effects

Summary of the safety profile

Columvi monotherapy

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%).

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.

The most common serious adverse reactions reported in ≥ 2% of patients were cytokine release syndrome (20.3%), pyrexia (6.4%), pneumonia (5.8%), COVID-19 (5.8%), thrombocytopenia (4.7%), respiratory tract infection (3.5%), sepsis (2.3%), febrile neutropenia (2.3%), and diarrhoea (2.3%).

Permanent discontinuation of Columvi due to an adverse reaction occurred in 20.9% of patients. The most common adverse reactions leading to permanent discontinuation of Columvi were COVID 19 (11.6%), sepsis (1.2%), and pneumonitis (1.2%).

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.

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**

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. 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 ICANS based on Lee 2019 and includes somnolence, cognitive disorder, confusional state, delirium, and disorientation.

11 Myelitis occurred concurrently with CRS.

12 Includes gastrointestinal haemorrhage, large intestinal haemorrhage, and gastric haemorrhage.

13 Includes rash, rash pruritic, rash maculo-papular, dermatitis, dermatitis acneiform, dermatitis exfoliative, erythema, palmar erythema, pruritis, and rash erythematous.

Table 7. Adverse reactions reported in patients with relapsed or refractory DLBCL treated with Columvi in combination with gemcitabine and oxaliplatin

System organ class

Adverse reaction

All grades

Grade 3−4

Infections and infestations

COVID-191

Very common

Common*

Respiratory tract infections2

Very Common

Common*

Pneumonia3

Very Common

Common*

Cytomegalovirus infections4

Common

Uncommon

Herpes viral infections5

Common

Uncommon

Urinary tract infection6

Common

Common

Sepsis7

Common

Common*

Candida infections8

Common

Very rare**

Pneumocystis jiroveci pneumonia

Uncommon

Uncommon

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Tumour flare9

Common

Very rare**

Blood and lymphatic system disorders

Thrombocytopenia

Very common

Very Common

Neutropenia

Very common

Very Common

Anaemia

Very common

Very Common

Lymphopenia

Very common

Very Common

Febrile neutropenia

Common

Common

Immune system disorders

Cytokine release syndrome10

Very common

Common

Metabolism and nutrition disorders

Hypokalaemia

Very common

Common

Hyponatraemia

Very common

Uncommon

Hypomagnesaemia

Common

Very rare**

Hypocalcaemia

Common

Uncommon

Hypophosphataemia

Common

Common

Tumour lysis syndrome

Common

Common

Nervous system disorders

Peripheral Neuropathy11

Very common

Common

Immune effector cell-associated neurotoxicity syndrome12

Common

Uncommon

Headache

Common

Very rare**

Tremor

Uncommon

Very rare**

Respiratory, thoracic and mediastinal disorders

Pneumonitis

Common

Very rare*,**

Gastrointestinal disorders

Nausea

Very common

Uncommon

Diarrhoea

Very common

Common

Vomiting

Very common

Uncommon

Abdominal pain13

Very common

Common

Constipation

Very common

Very rare**

Colitis14

Common

Common

Pancreatitis15

Common

Common

Skin and subcutaneous tissue disorders

Rash16

Very common

Uncommon

Musculoskeletal and connective tissue disorders

Musculoskeletal pain17

Very common

Uncommon

General disorders and administration site conditions

Pyrexia

Very common

Uncommon

Investigations

Aspartate aminotransferase increased

Very common

Common

Alanine aminotransferase increased

Very common

Common

Blood alkaline phosphatase increased

Very common

Uncommon

Gamma-glutamyltransferase increased

Very common

Common

Blood lactate dehydrogenase increased

Very common

Very rare**

Blood bilirubin increased18

Common

Very rare**

Hepatic enzyme increased

Uncommon

Very rare**

* Grade 5 reactions reported. See Description of selected adverse reactions.

** No Grade 3-4 events were reported.

1 Includes COVID-19, COVID-19 pneumonia, and SARS-CoV-2 test positive.

2 Includes upper respiratory tract infection, lower respiratory tract infection, respiratory tract infection, and respiratory tract infection bacterial.

3 Includes pneumonia, pneumonia bacterial, and pneumonia pneumococcal.

4 New onset or reactivation. Includes cytomegalovirus infection, cytomegalovirus test positive, cytomegalovirus infection reactivation and cytomegalovirus viraemia.

5 New onset or reactivation. Includes herpes zoster and herpes virus infection

6 Includes urinary tract infection and urosepsis.

7 Includes sepsis, streptococcal sepsis, septic shock, and enterococcal sepsis.

8 Includes oral candidiasis and candida infection.

9 Includes tumour flare and tumour pain.

10 Based on ASTCT consensus grading (Lee 2019).

11 Includes neuropathy peripheral, peripheral sensory neuropathy, dysaesthesia, paraesthesia, hypoaesthesia, peripheral motor neuropathy, and polyneuropathy.

12 Includes confusional state, delirium, and ICANS.

13 Includes abdominal pain, abdominal discomfort, abdominal pain upper, abdominal pain lower, and gastrointestinal pain.

14 Includes colitis, colitis ischaemic, and enterocolitis.

15 Includes pancreatitis and pancreatitis acute.

16 Includes rash, rash pruritic, rash maculo-papular, erythema, pruritus, rash erythematous, urticaria, and erythema multiforme.

17 Includes arthralgia, musculoskeletal pain, back pain, bone pain, myalgia, neck pain, pain in extremity, musculoskeletal chest pain, and non-cardiac chest pain.

18 Includes blood bilirubin increased and hyperbilirubinaemia.

Description of selected adverse reactions

The descriptions below reflect information for significant adverse reactions for Columvi monotherapy and/or combination therapy. Details for the significant adverse reactions for Columvi when given in combination are presented separately if clinically relevant differences were noted in comparison to Columvi monotherapy.

Cytokine release syndrome

Columvi monotherapy

Any grade CRS (by ASTCT criteria) occurred in 67.6% of patients who received Columvi monotherapy, with Grade 1 CRS reported in 50.3% of patients, Grade 2 CRS in 13.1% of 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 patients (4.8%) experienced elevated liver function tests (AST and ALT > 3 x ULN and/or total bilirubin > 2 xULN) 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).

Columvi in combination with gemcitabine and oxaliplatin

Any grade CRS (by ASTCT criteria) occurred in 44.2% of patients who received Columvi with gemcitabine and oxaliplatin, with Grade 1 CRS reported in 31.4% of patients, Grade 2 CRS in 10.5% of patients, and Grade 3 CRS in 2.3% of patients. CRS occurred more than once in 21.5% (37/172) of patients; 30/37 patients experienced multiple Grade 1 CRS events only.

There were no Grade 4 or 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 (98.7%), hypotension (22.4%), chills (17.1%) and hypoxia (14.5%). Grade 3 or higher events associated with CRS included hypotension (6.6%), hypoxia (5.3%), pyrexia (3.9%), chills (1.3%) and diarrhoea (1.3%). CRS of any grade occurred in 34.9% 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: 4.4 to 54.7 hours) and median duration of 19.8 hours (range: 2.0 to 168.0 hours); in 14.4% of patients following the 10 mg dose at Cycle 1 Day 15 with median time to onset of 22.8 hours (range: 7.4 to 81.2 hours) and median duration of 10.6 hours (range: 1.0 to 248.5 hours); and in 9.3% of patients following the 30 mg dose at Cycle 2 with median time to onset of 23.5 hours (range: 14.7 to 33.4 hours) and median duration of 18.4 hours (range: 8.3 to 137.0 hours). CRS was reported in 6.7% of patients at Cycle 3 and in 11.0% of patients beyond Cycle 3. Grade ≥2 CRS occurred in 10.5% of patients following the first Columvi dose (2.5 mg) with median time to onset of 12.0 hours (range: 4.4 to 30.5 hours) and median duration of 42.3 hours (range: 3.5 to 143.7 hours). The majority (14/18) of patients who experienced Grade ≥2 CRS had onset of CRS within 8 hours of the start of the first Columvi dose (2.5 mg) or presented with a fever ≥ 1.5 hours before the onset of other symptoms of a grade ≥2 CRS. Following Columvi 10 mg dose at Cycle 1 Day 15, the incidence of Grade ≥2 CRS decreased to 1.8% of patients with median time to onset of 22.3 hours (range: 7.4 to 22.8 hours) and median duration of 37.0 hours (range: 34.8 to 248.5 hours). There were no Grade ≥2CRS events following Columvi 30 mg dose at Cycle 2 Day 1. Three patients (2.0%) had Grade ≥2 CRS beyond Cycle 2 (all Grade 2 events).

Of the 172 patients, 2 patients (1.2%) experienced elevated liver function tests (AST and ALT > 3 x ULN) reported concurrently with CRS.

Out of the 76 patients with any grade CRS, 28 patients (36.8%) were treated with tocilizumab, 39 patients (51.3%) were treated with corticosteroids, and 18 patients (23.7%) received both tocilizumab and corticosteroids.

Among the 22 patients who experienced Grade ≥2 CRS after Columvi, 16 (72.7%) received tocilizumab, 15 (68.2%) received corticosteroids, and 12 (54.5%) received both tocilizumab and corticosteroids. Eleven patients (50.0%) received oxygen. All 4 patients (18.2%) with Grade 3 CRS received a single vasopressor.

Hospitalisations due to patients experiencing CRS following Columvi administration occurred in 19.8% of patients and the reported median duration of hospitalisation was 5 days (range: 2 to 85 days).

Immune effector cell-associated neurotoxicity syndrome

ICANS, including Grade 3 and higher, was reported in clinical trials and with post-marketing experience. The most frequent clinical manifestations of ICANS were confusion, depressed level of consciousness, disorientation, seizure, aphasia, and dysgraphia. Based on the available data, the onset of neurologic toxicity was concurrent with CRS in the majority of cases.

The observed time to onset of the majority of ICANS was 1-7 days with median of 2 days after the most recent dose. Only few events were reported to have occurred more than one month after the initiation of Columvi.

Serious infections

Serious infections were reported in 15.9% of patients who received Columvi monotherapy. 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.

Serious infections were reported in 22.7% of patients who received Columvi with gemcitabine and oxaliplatin. The most frequent serious infections reported in ≥2% of patients were pneumonia (5.8%), COVID-19 (4.7%), and lower respiratory tract infection (2.9%). Infection-related deaths were reported in 3.5% of patients (due to COVID-19, pneumonia, respiratory tract infection, and septic shock). One patient (0.6%) experienced a serious infection (pneumonia) concurrently with Grade 3 neutropenia.

Pneumonitis

Pneumonitis events (excluding pneumonia of infectious aetiology) were reported in 2 patients (1.2%) who received Columvi with gemcitabine and oxaliplatin, both of which were fatal events. The median time to onset of pneumonitis from the first Columvi dose was 168 days (range: 102 to 255 days).

Colitis

Colitis (Grade 4) was reported in 1 patient (0.7%) who received Columvi monotherapy, with time to onset from the first Columvi dose of 104 days.

Colitis events (excluding infectious aetiology) were reported in 4/172 patients (2.3%) who received Columvi with gemcitabine and oxaliplatin. Two patients (1.2%) had Grade 3 events. The median time to onset of colitis from the first Columvi dose was 154 days (range: 115 to 187 days).

Opportunistic infections

CMV events were reported in 6/467 patients (1.3%) who received Columvi monotherapy, with 1 patient (0.2%) experiencing Grade 3 CMV chorioretinitis. Pneumocystis jiroveci pneumonia was reported in 4/467 patients (0.9%), 3 f whom (0.6%) had Grade 3 events.

CMV events were reported in 11 patients (6.4%) who received Columvi with gemcitabine and oxaliplatin, with 1 patient (0.6%) experiencing Grade 3 CMV viraemia. Oral candidiasis was reported in 3 patients (1.7%) all of which were Grade 1-2 events. Pneumocystis jirovecii pneumonia (Grade 3) was reported in 1 patient (0.6%), the same patient with Grade 3 CMV viraemia. Borellia meningitis (Grade 2) was reported in 1 patient (0.6%).

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 who received Columvi monotherapy. 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 who received Columvi monotherapy, 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 patients (18.2%) received analgesics, 6 patients (54.5%) received corticosteroids and analgesics including morphine derivatives, 1 patient (9.1%) received corticosteroids and anti-emetics, and 2 patients (18.2%) 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%) who received Columvi monotherapy 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 (see details below).

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4.9. Overdose

In case of overdose, patients should be closely monitored for signs or symptoms of adverse reactions, and appropriate symptomatic treatment instituted.