Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: Roche Registration GmbH, Emil-Barell-Strasse 1, 79639 Grenzach-Wyhlen, Germany
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.
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).
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.
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 | Intravenous glucocorticoid1 | 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 | Intravenous glucocorticoid1,4 | Completed at least 1 hour prior to Columvi infusion |
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.
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 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 obinutuzumab1 | |
| 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.
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).
Treatment with Columvi is recommended for a maximum of 12 cycles or until disease progression or unmanageable toxicity. Each cycle is 21 days.
During step-up dosing (weekly dosing):
After Cycle 2 (30 mg dose):
No dose reductions of Columvi are recommended.
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 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 | • 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 | • Ensure symptoms are resolved for at least 72 hours prior to next infusion • Consider slower infusion rate2 • Monitor patients post-infusion5,6 |
| 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 | • Ensure symptoms are resolved for at least 72 hours prior to next infusion • Consider slower infusion rate2 • Monitor patients post-infusion5,6 • 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 tocilizumab^4 | |
| 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.
No dose adjustment is required in patients 65 years of age and older (see section 5.2).
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).
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).
The safety and efficacy of Columvi in children below 18 years of age have not been established. No data are available.
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.
There is no experience with overdose in clinical trials. In case of overdose, patients should be closely monitored for signs or symptoms of adverse reactions, and appropriate symptomatic treatment instituted.
Unopened vial:
2 years.
Diluted solution for intravenous infusion:
Chemical and physical in-use stability have been demonstrated for a maximum of 72 hours at 2°C to 8°C and 24 hours at 30°C followed by a maximum infusion time of 8 hours.
From a microbiological point of view, the diluted solution should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C to 8°C, unless dilution has taken place in controlled and validated aseptic conditions.
Store in a refrigerator (2°C-8°C).
Do not freeze.
Keep the vial in the outer carton in order to protect from light.
For storage conditions after dilution of the medicinal product, see section 6.3.
Columvi 2.5 mg concentrate for solution for infusion:
2.5 mL concentrate for solution for infusion in a 6 mL vial (colourless Type I glass) with stopper (butyl rubber).
Pack size of 1 vial.
Columvi 10 mg concentrate for solution for infusion:
10 mL concentrate for solution for infusion in a 15 mL vial (colourless Type I glass) with stopper (butyl rubber).
Pack size of 1 vial.
Table 6. Dilution of Columvi for infusion:
| Dose of Columvi to be administered | Size of infusion bag | Volume of sodium chloride 9 mg/mL (0.9%) or 4.5 mg/mL (0.45%) solution for injection to be withdrawn and discarded | Volume of Columvi concentrate to be added |
|---|---|---|---|
| 2.5 mg | 50 mL | 27.5 mL | 2.5 mL |
| 100 mL | 77.5 mL | 2.5 mL | |
| 10 mg | 50 mL | 10 mL | 10 mL |
| 100 mL | 10 mL | 10 mL | |
| 30 mg | 50 mL | 30 mL | 30 mL |
| 100 mL | 30 mL | 30 mL |
Only sodium chloride 9 mg/mL (0.9%) or 4.5 mg/mL (0.45%) solution for injection should be used to dilute Columvi, since other solvents have not been tested.
When diluted with sodium chloride 9 mg/mL (0.9%) solution for injection, Columvi is compatible with intravenous infusion bags composed of polyvinyl chloride (PVC), polyethylene (PE), polypropylene (PP) or non-PVC polyolefin. When diluted with sodium chloride 4.5 mg/mL (0.45%) solution for injection, Columvi is compatible with intravenous infusion bags composed of PVC.
No incompatibilities have been observed with infusion sets with product-contacting surfaces of polyurethane (PUR), PVC or PE, and in-line filter membranes composed of polyethersulfone (PES) or polysulfone. The use of in-line filter membranes is optional.
Columvi vial is for single use only.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
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