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Preparation and administration of COLUMVI™1

Preparation

  1. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. COLUMVI is a colorless clear solution. Discard the vial if the solution is cloudy, discolored, or contains visible particles.
  2. Use aseptic technique when preparing the COLUMVI diluted solution for intravenous infusion.
  3. Determine the dose, total volume of COLUMVI solution, and the number of COLUMVI vials needed (see chart below).

Dilution

  1. Withdraw the volume of 0.9% Sodium Chloride Injection or 0.45% Sodium Chloride Injection from the infusion bag according to the chart below and discard.
  2. Withdraw the required volume of COLUMVI from vial(s) using a sterile needle and syringe and dilute into the infusion bag of 0.9% Sodium Chloride Injection or 0.45% Sodium Chloride Injection according to chart below to a final concentration of 0.1 mg/mL to 0.6 mg/mL. Discard any unused portion left in the vial.
  3. Gently invert infusion bag to mix the solution, in order to avoid excessive foaming. Do not shake.
  4. Immediately use diluted COLUMVI solution. If not used immediately, the diluted solution can be stored:
    • Refrigerated at 2 °C to 8 °C (36 °F to 46 °F) for up to 64 hours, or
    • At room temperature up to 25 °C (77 °F) for up to 4 hours
    • Do not freeze the diluted infusion solution
    • Discard diluted infusion solution if storage time exceeds these limits
Dilution of COLUMVI for infusion
Dose of COLUMVI Size of infusion bag Volume of 0.9% Sodium Chloride Injection or 0.45% Sodium Chloride Injection to be withdrawn and discarded Volume of COLUMVI to be added in the infusion bag
2.5 mg 50 mL 27.5 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

COLUMVI diluted with 0.9% Sodium Chloride Injection is compatible with intravenous infusion bags composed of polyvinyl chloride (PVC), polyethylene (PE), polypropylene (PP) or non-PVC polyolefin. When diluted with 0.45% Sodium Chloride 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.

Administration of COLUMVI1

COLUMVI should only be administered by a healthcare professional with immediate access to appropriate medical support, including supportive medications to manage severe CRS

  • Administer COLUMVI to well-hydrated patients
  • Administer only as an intravenous (IV) infusion through a dedicated infusion line that includes a sterile 0.2-micron in-line filter
  • Premedicate before each dose
  • Do not mix COLUMVI with other drugs
  • Due to the risk of CRS, patients should be hospitalized during and for 24 hours after completion of infusion of step-up dose 1 (2.5 mg on Cycle 1 Day 8)
  • Patients who experienced any grade CRS during step-up dose 1 should be hospitalized during and for 24 hours after completion of step-up dose 2 (10 mg on Cycle 1 Day 15). CRS with step-up dose 2 can occur in patients who did not experience CRS with step-up dose 1
  • For subsequent doses, patients who experienced Grade ≥ 2 CRS with their previous infusion should be hospitalized during and for 24 hours after the completion of the next COLUMVI infusion

Pretreatment with obinutuzumab

Pretreat all patients with a single 1,000 mg dose of obinutuzumab administered as an intravenous infusion on Cycle 1 Day 1, 7 days prior to initiation of COLUMVI treatment (see Dosing Schedule) to deplete the circulating and lymphoid tissue B cells.

Obinutuzumab should be administered as an intravenous infusion at 50 mg/h. The rate of infusion can be escalated in 50 mg/h increments every 30 minutes to a maximum of 400 mg/h. Refer to the obinutuzumab prescribing information for complete dosing information.

Step-up dosing of COLUMVI

COLUMVI dosing begins with a step-up dose schedule designed to decrease the risk of CRS. After completion of pretreatment with obinutuzumab on Cycle 1 Day 1, step-up dosing of COLUMVI is administered as 2.5 mg on Cycle 1 Day 8 followed by 10 mg on Cycle 1 Day 15, leading to the recommended dosage of 30 mg once every 3 weeks for Cycles 2-12.

Recommended premedications

The following prophylactic medications are recommended to reduce the risk of CRS and infusion-related reactions
Day of Treatment Cycle Patients Requiring Premedication Premedication Administration
Cycle 1 (Day 8, Day 15);
Cycle 2;
Cycle 3		 All patients Dexamethasone 20 mg intravenously* Completed at least 1 hour prior to COLUMVI infusion.
Acetaminophen 500 mg to 1,000 mg orally At least 30 minutes before COLUMVI infusion.
Antihistamine (diphenhydramine 50 mg orally or intravenously or equivalent) Completed 30 minutes before COLUMVI infusion.
All subsequent infusions All patients Acetaminophen 500 mg to 1,000 mg orally At least 30 minutes before COLUMVI infusion.
Antihistamine (diphenhydramine 50 mg orally or intravenously or equivalent) Completed at least 30 minutes before COLUMVI infusion.
Patients who experienced CRS with previous dose Dexamethasone 20 mg intravenously* Completed at least 1 hour prior to COLUMVI infusion.

*If dexamethasone is not available, administer prednisone 100 mg, prednisolone 100 mg, or methylprednisolone 80 mg intravenously.

Tumor Lysis Syndrome Prophylaxis

Before starting COLUMVI, administer anti-hyperuricemics to patients at risk of tumor lysis syndrome and ensure adequate hydration status, and monitor as appropriate.

Antiviral Prophylaxis

Before starting COLUMVI, consider initiation of antiviral prophylaxis to prevent herpes virus reactivation. Consider prophylaxis for cytomegalovirus infection in patients at increased risk.

Pneumocystis jirovecii Pneumonia (PJP)

Consider PJP prophylaxis prior to starting COLUMVI in patients at increased risk.

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CRS=cytokine release syndrome.

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Important Safety Information & Indication

Indication

COLUMVI (glofitamab-gxbm) is indicated for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma not otherwise specified (DLBCL), or large B-cell lymphoma (LBCL) arising from follicular lymphoma, after two or more lines of systemic therapy.

This indication is approved under accelerated approval based on response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

BOXED WARNING

Cytokine Release Syndrome (CRS), including serious or fatal reactions, can occur in patients receiving COLUMVI. Premedicate before each dose, and initiate treatment with the COLUMVI step-up dosing schedule to reduce the risk of CRS. Withhold COLUMVI until CRS resolves or permanently discontinue based on severity.

Warnings and Precautions

Cytokine Release Syndrome (CRS)

COLUMVI can cause serious and fatal CRS.

Among the 145 patients who received COLUMVI, CRS occurred in 70%, with Grade 1 CRS developing in 52% of patients, Grade 2 in 14%, Grade 3 in 2.8% of patients, and Grade 4 in 1.4%. The most common manifestations of CRS included fever, tachycardia, hypotension, chills, and hypoxia.

CRS occurred in 56% of patients after the 2.5 mg dose of COLUMVI, 35% after the 10 mg dose, 29% after the initial 30 mg target dose, and 2.8% after subsequent doses. With the first step-up dose of COLUMVI, the median time to onset of CRS (from the start of infusion) was 14 hours (range: 5 to 74 hours). CRS after any dose resolved in 98% of cases, with a median duration of CRS of 2 days (range: 1 to 14 days). Recurrent CRS occurred in 34% of all patients. CRS can first occur with the 10 mg dose; of 135 patients treated with the 10 mg dose of COLUMVI, 15 patients (11%) experienced their first CRS event with the 10 mg dose, of which 13 events were Grade 1, 1 event was Grade 2, and 1 event was Grade 3.

Administer COLUMVI in a facility equipped to monitor and manage CRS. Initiate therapy according to the COLUMVI step-up dosing schedule to reduce the risk of CRS, administer pretreatment medications, and ensure adequate hydration. Patients should be hospitalized during and for 24 hours after completing infusion of the 2.5 mg step-up dose. Patients who experienced any grade CRS during the 2.5 mg step-up dose should be hospitalized during and for 24 hours after completion of the 10 mg step-up dose. For subsequent doses, patients who experienced Grade ≥2 CRS with their previous infusion should be hospitalized during and for 24 hours after the next COLUMVI infusion.

At the first sign of CRS, immediately evaluate patients for hospitalization, manage per current practice guidelines, and administer supportive care; withhold or permanently discontinue COLUMVI based on severity.

Neurologic Toxicity

COLUMVI can cause serious neurologic toxicity, including Immune Effector Cell-Associated Neurotoxicity (ICANS).

Among 145 patients who received COLUMVI, the most frequent neurologic toxicities of any grade were headache (10%), peripheral neuropathy (8%), dizziness or vertigo (7%), and mental status changes (4.8%, including confusional state, cognitive disorder, disorientation, somnolence, and delirium). Grade 3 or higher neurologic adverse reactions occurred in 2.1% of patients and included somnolence, delirium, and myelitis. Cases of ICANS of any grade occurred in 4.8% of patients.

Coadministration of COLUMVI with other products that cause dizziness or mental status changes may increase the risk of neurologic toxicity. Optimize concomitant medications and hydration to avoid dizziness or mental status changes. Institute fall precautions as appropriate.

Monitor patients for signs and symptoms of neurologic toxicity, evaluate, and provide supportive therapy; withhold or permanently discontinue COLUMVI based on severity.

Evaluate patients who experience neurologic toxicity such as tremors, dizziness, or adverse reactions that may impair cognition or consciousness promptly, including potential neurology evaluation. Advise affected patients to refrain from driving and/or engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, until the neurologic toxicity fully resolves.

Serious Infections

COLUMVI can cause serious or fatal infections.

Serious infections were reported in 16% of patients, including Grade 3 or 4 infections in 10%, and fatal infections in 4.8% of patients. Grade 3 or higher infections reported in ≥ 2% patients were COVID-19 infection (6%), including COVID-19 pneumonia, and sepsis (4.1%). Febrile neutropenia occurred in 3.4% of patients.

COLUMVI should not be administered to patients with an active infection. Administer antimicrobial prophylaxis according to guidelines. Monitor patients before and during COLUMVI treatment for infection and treat appropriately. Withhold or consider permanent discontinuation of COLUMVI based on severity.

Tumor Flare

COLUMVI can cause serious tumor flare. Manifestations included localized pain and swelling at the sites of the lymphoma lesions and/or dyspnea from new pleural effusions.

Tumor flare was reported in 12% of patients who received COLUMVI, including Grade 2 tumor flare in 4.8% of patients and Grade 3 tumor flare in 2.8%. Recurrent tumor flare occurred in two (12%) of the affected patients. Most tumor flare events occurred during Cycle 1, with a median time to first onset of 2 days (range: 1 to 16 days) after the first dose of COLUMVI. The median duration was 3.5 days (range: 1 to 35 days).

Patients with bulky tumors or disease located in close proximity to airways or a vital organ should be monitored closely during initial therapy. Monitor for signs and symptoms of compression or obstruction due to mass effect secondary to tumor flare, and institute appropriate treatment. Withhold COLUMVI until tumor flare resolves.

Embryo-Fetal Toxicity

Based on its mechanism of action, COLUMVI may cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with COLUMVI and for 1 month after the last dose.

Most Common Adverse Reactions

The most common (≥ 20%) adverse reactions, excluding laboratory abnormalities, are CRS (70%), musculoskeletal pain (21%), rash (20%), and fatigue (20%). The most common Grade 3 to 4 laboratory abnormalities (≥ 20%) are lymphocyte count decreased (83%), phosphate decreased (28%), neutrophil count decreased (26%), uric acid increased (23%), and fibrinogen decreased (21%).

Drug Interactions

For certain CYP substrates where minimal concentration changes may lead to serious adverse reactions, monitor for toxicities or drug concentrations of such CYP substrates when coadministered with COLUMVI.

Glofitamab-gxbm causes the release of cytokines that may suppress the activity of CYP enzymes, resulting in increased exposure of CYP substrates. Increased exposure of CYP substrates is more likely to occur after the first dose of COLUMVI on Cycle 1 Day 8 and up to 14 days after the first 30 mg dose on Cycle 2 Day 1 and during and after CRS.

Use in Specific Populations

Lactation
There are no data on the presence of glofitamab-gxbm in human milk or the effects on the breastfed child or milk production. Because human IgG is present in human milk, and there is potential for glofitamab-gxbm absorption leading to B-cell depletion, advise women not to breastfeed during treatment with COLUMVI and for 1 month after the last dose of COLUMVI.

Geriatric Use
Of the 145 patients with relapsed or refractory LBCL who received COLUMVI in study NP30179, 55% were 65 years of age or older, and 23% were 75 years of age or older. There was a higher rate of fatal adverse reactions, primarily from COVID-19, in patients 65 years of age or older compared to younger patients. No overall differences in efficacy were observed between patients 65 years of age or older and younger patients.

You may report side effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at 1-888-835-2555.

Please see the COLUMVI full Prescribing Information for additional Important Safety Information, including BOXED WARNING.

    • COLUMVI. Prescribing Information. Genentech, Inc.

      COLUMVI. Prescribing Information. Genentech, Inc.

    • Dickinson MJ, Carlo-Stella C, Morschhauser F, et al. Glofitamab for relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2022;387(24):2220-2231. doi:10.1056/NEJMoa2206913.

      Dickinson MJ, Carlo-Stella C, Morschhauser F, et al. Glofitamab for relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2022;387(24):2220-2231. doi:10.1056/NEJMoa2206913.

    • Bacac M, Colombetti S, Herter S, et al. CD20-TCB with obinutuzumab pretreatment as next-generation treatment of hematologic malignancies. Clin Cancer Res. 2018;24(19):4785-4797. doi: 10.1158/1078-0432.CCR-18-0455.

      Bacac M, Colombetti S, Herter S, et al. CD20-TCB with obinutuzumab pretreatment as next-generation treatment of hematologic malignancies. Clin Cancer Res. 2018;24(19):4785-4797. doi: 10.1158/1078-0432.CCR-18-0455.

    • Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for B-Cell Lymphomas V.5.2023. © National Comprehensive Cancer Network, Inc. 2023. All rights reserved. Accessed July 7, 2023. To view the most recent and complete version of the guideline, go online to NCCN.org.

      Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for B-Cell Lymphomas V.5.2023. © National Comprehensive Cancer Network, Inc. 2023. All rights reserved. Accessed July 7, 2023. To view the most recent and complete version of the guideline, go online to NCCN.org.

    • Data on file. Genentech, Inc.

      Data on file. Genentech, Inc.