Posology : מינונים

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).
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 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 (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

Patients requiring
Treatment cycle (Day)                               Premedication            Administration premedication

Intravenous          Completed at least 1 hour glucocorticoid1      prior to Columvi infusion
Cycle 1 (Day 8, Day 15);
Cycle 2 (Day 1);            All patients            Oral analgesic /
Cycle 3 (Day 1)                                     anti-pyretic2        At least 30 minutes before Columvi infusion
Anti-histamine3
Oral analgesic / anti-pyretic2        At least 30 minutes before
All patients
Columvi infusion
Anti-histamine3
All subsequent infusions
Patients who experienced CRS         Intravenous          Completed at least 1 hour with the previous       glucocorticoid1, 4   prior to Columvi infusion dose
1 20 mg dexamethasone or 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.

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 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 Day 1                        Pre-treatment with obinutuzumab1
Cycle 1
(Pre-treatment and                   Day 8                        2.5 mg step-up dose)
Day 15                         10 mg                       4 hours2
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.

Patient monitoring
•     All patients must be monitored for signs and symptoms of potential CRS during infusion and for at least 10 hours after completion of the infusion 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 3 in section 4.2).

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

Duration of treatment
Treatment with Columvi is recommended for a maximum of 12 cycles or until disease progression or unmanageable toxicity. 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).


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 then resume the planned treatment cycle (30 mg dose).

Dose modifications
No dose reductions of Columvi are recommended.

Management of cytokine release syndrome
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 3.

Table 3. ASTCT CRS grading and CRS management guidance

Grade1                    CRS management                                     For next scheduled Columvi infusion
Grade 1                   If CRS occurs during infusion:                     • Ensure symptoms are Fever ≥ 38 °C               • Interrupt infusion and treat symptoms            resolved for at least • Restart infusion at slower rate when             72 hours prior to next symptoms resolve                                 infusion
• If symptoms recur, discontinue current         • Consider slower infusion                                         infusion rate2
If CRS occurs post-infusion:
• Treat symptoms

If CRS lasts more than 48 h after symptomatic management:
• Consider corticosteroids3
• Consider tocilizumab4
Grade 2                   If CRS occurs during infusion:                     • Ensure symptoms are Fever ≥ 38 °C and/or        • Discontinue current infusion and treat           resolved for at least hypotension not               symptoms                                         72 hours prior to next requiring vasopressors      • Administer corticosteroids3                      infusion and/or hypoxia              • Consider tocilizumab4                          • Consider slower requiring low-flow                                                             infusion rate2 If CRS occurs post-infusion: oxygen by nasal            • Treat symptoms                                  • Monitor patients cannula or blow-by
• Administer corticosteroids3                       post-infusion5, 6 • Consider tocilizumab4
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


Grade1                      CRS management                                         For next scheduled Columvi infusion
Grade 3                     If CRS occurs during infusion:                         • Ensure symptoms are Fever ≥ 38 °C and/or          • Discontinue current infusion and treat               resolved for at least hypotension requiring           symptoms                                             72 hours prior to next a vasopressor (with or        • Administer corticosteroids3                          infusion without vasopressin)          • Administer tocilizumab4                            • Consider slower and/or hypoxia                                                                       infusion rate2 If CRS occurs post-infusion: requiring high-flow                                                                • Monitor patients • Treat symptoms oxygen by nasal               • Administer corticosteroids3 post-infusion5, 6 cannula, face mask,                                                                • If Grade ≥ 3 CRS • Administer tocilizumab4 non-rebreather mask,                                                                 recurs at subsequent or Venturi mask                                                                      infusion, stop infusion immediately and permanently discontinue Columvi
Grade 4                  If CRS occurs during infusion or post-infusion: Fever ≥ 38 °C and/or       • Permanently discontinue Columvi and treat symptoms hypotension requiring      • Administer corticosteroids3 multiple vasopressors      • Administer tocilizumab4
(excluding vasopressin) and/or hypoxia requiring oxygen by positive pressure (e.g., CPAP,
BiPAP, intubation, and mechanical ventilation)
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 ASTCT consensus grading criteria (Lee 2019).
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
In Study NP30179, Grade ≥ 2 CRS following Columvi 10 mg dose at Cycle 1 Day 15 occurred in 5.2% of patients, with a median time to onset of 26.2 hours from the start of infusion (range: 6.7 to 144.2 hours).
6
In Study NP30179, Grade ≥ 2 CRS following Columvi 30 mg dose at Cycle 2 Day 1 occurred in one patient (0.8%), with a time to onset of 15.0 hours from the start of infusion.


Neurologic Toxicity, Including ICANS (Immune Effector Cell-Associated Neurotoxicity Syndrome) Management recommendations for neurologic toxicity, including ICANS, is summarized in Table 4.
At the first sign of neurologic toxicity, including ICANS, consider neurology evaluation and withholding Columvi based on the type and severity of neurotoxicity.
Rule out other causes of neurologic symptoms.
Provide supportive therapy, which may include intensive care.

Table 4:        Recommended Dosage Modification for Neurologic Toxicity (Including ICANS) 
Adverse Reaction               Severity1,2                 Actions
Continue Columvi and monitor neurologic toxicity
Grade 1                     symptoms.
If ICANS, manage per current practice guidelines.

Withhold Columvi until neurologic toxicity symptoms improve to Grade 1 or baseline.3, 4
Grade 2                     Provide supportive therapy, and consider neurologic evaluation.
If ICANS, manage per current practice guidelines.
Neurologic Toxicity1                                       Withhold Columvi until neurologic toxicity symptoms (including ICANS2)                                          improve to Grade 1 or baseline for at least 7 days.4, 5 For Grade 3 neurologic events lasting more than 7 days,
Grade 3                      consider permanently discontinuing Columvi.
Provide supportive therapy, and consider neurology evaluation.
If ICANS, manage per current practice guidelines.
Permanently discontinue Columvi.
Provide supportive therapy, which may include
Grade 4                     intensive care, and consider neurology evaluation.
If ICANS, manage per current practice guidelines.
1
Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03.
2
Based on ASTCT 2019 grading for ICANS.
3
Consider the type of neurologic toxicity before deciding to withhold Columvi.
4
See Dosage and Administration (2.2) on restarting Columvi after dose delays.
5
Evaluate benefit-risk before restarting Columvi.

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  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.