0.5 Ml Mosunetuzumab-axgb 10 Mg/ml Injection [lunsumio]

1.1 Follicular Lymphoma

LUNSUMIO VELO is indicated for the treatment of adult patients with relapsed or refractory follicular lymphoma after two or more lines of systemic therapy.

This indication is approved under accelerated approval based on response rate [see Clinical Studies (14)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

2.1 Important Dosing Information

LUNSUMIO VELO and LUNSUMIO have different dosage and administration instructions [see Dosage and Administration (2.2) and Warnings and Precautions (5.7)]. LUNSUMIO VELO is for subcutaneous use only. Check the product label to ensure that the correct formulation (LUNSUMIO VELO or LUNSUMIO) is being prescribed and administered. Do not substitute LUNSUMIO VELO for or with LUNSUMIO. Administer LUNSUMIO VELO to well-hydrated patients. Premedicate before each dose in Cycle 1 [see Dosage and Administration (2.3)]. LUNSUMIO VELO should only be administered by a qualified healthcare professional with appropriate medical support to manage severe reactions such as CRS and neurologic toxicity, including ICANS [see Warnings and Precautions (5.1 and 5.2)].

2.2 Recommended Dosage

The recommended dosage for LUNSUMIO VELO subcutaneous injection is presented in Table 1.

Administer for 8 cycles unless patients experience unacceptable toxicity or disease progression.

For patients who achieve a complete response, no further treatment beyond 8 cycles is required. For patients who achieve a partial response or have stable disease in response to treatment with LUNSUMIO VELO after 8 cycles, an additional 9 cycles of treatment (17 cycles total) should be administered, unless a patient experiences unacceptable toxicity or disease progression.

Day of Treatment		Subcutaneous Dose of LUNSUMIO VELO
Cycle 1	Day 1	5 mg
	Day 8	45 mg
	Day 15	45 mg
Cycles 2+	Day 1	45 mg

Last Subcutaneous Dose Administered	Time Since Last Dose Administered	Action for Next Subcutaneous Dose(s)
5 mg Cycle 1 Day 1	1 week to 2 weeks	Administer 45 mg (Cycle 1 Day 8)Administer premedication as per Cycle 1., then resume the planned treatment schedule.
	Greater than 2 weeks	Repeat 5 mg (Cycle 1 Day 1), then administer 45 mg (Cycle 1 Day 8) and resume the planned treatment schedule.
45 mg Cycle 1 Day 8	1 week to less than 6 weeks	Administer 45 mg (Cycle 1 Day 15), then resume the planned treatment schedule.
	Greater than or equal to 6 weeks	Repeat 5 mg, then administer 45 mg (Cycle 1 Day 15) 7 days later and resume the planned treatment schedule.
45 mg Cycle 1 Day 15	1 week to less than 6 weeks	Administer 45 mg (Cycle 2 Day 1), then resume the planned treatment schedule.
	Greater than or equal to 6 weeks	Repeat 5 mg (Cycle 2 Day 1), then administer 45 mg (Cycle 2 Day 8) followed by 45 mg on Day 1 of subsequent cycles.
45 mg Cycle 2 onwards	3 weeks to less than 6 weeks	Administer 45 mg, then resume the planned treatment schedule.
	Greater than or equal to 6 weeks	Repeat 5 mg on Day 1 during the next cycle, then administer 45 mg on Day 8, followed by 45 mg on Day 1 of subsequent cycles.

2.3 Recommended Premedication

Premedications to reduce the risk of CRS are outlined in Table 3 [see Warnings and Precautions (5.1)].

Treatment Cycle	Patients Requiring Premedication	Premedication	Dosage
Cycle 1	All patients	Corticosteroid	Dexamethasone 20 mg (preferred) oral or intravenous or methylprednisolone 80 mg oral or intravenous
		AntihistamineAntihistamine and antipyretic premedications are optional in all cycles.	Diphenhydramine hydrochloride 50 mg to 100 mg or equivalent oral or intravenous antihistamine
		Antipyretic	Oral acetaminophen (500 mg to 1,000 mg)
Cycles 2+	Patients who experienced any grade CRS with the previous dose	Corticosteroid	Dexamethasone 20 mg (preferred) oral or intravenous or methylprednisolone 80 mg oral or intravenous
		Antihistamine	Diphenhydramine hydrochloride 50 mg to 100 mg or equivalent oral or intravenous antihistamine
		Antipyretic	Oral acetaminophen (500 mg to 1,000 mg)

2.4 Dosage Modifications for Adverse Reactions

See Tables 4 and 5 for the recommended dosage modifications for adverse reactions of CRS and neurologic toxicity, including immune effector cell-associated neurotoxicity (ICANS). See Table 6 for the recommended dosage modifications for other adverse reactions following administration of LUNSUMIO VELO.

Dosage Modifications for Cytokine Release Syndrome

Identify CRS based on clinical presentation [see Warnings and Precautions (5.1)]. Evaluate for and treat other causes of fever, hypoxia, and hypotension.

If CRS is suspected, withhold LUNSUMIO VELO until CRS resolves, manage according to the recommendations in Table 4 and per current practice guidelines. Administer supportive therapy for CRS, which may include intensive care for severe or life-threatening CRS.

GradeBased on American Society for Transplantation and Cellular Therapy (ASTCT) 2019 grading for CRS.	Presenting Symptoms	ActionsIf CRS is refractory to management, consider other causes including hemophagocytic lymphohistiocytosis.
Grade 1	Fever ≥ 100.4°F (38°C)Premedication may mask fever, therefore if clinical presentation is consistent with CRS, follow these management guidelines.	Ensure CRS symptoms are resolved prior to the next dose of LUNSUMIO VELO.Refer to Table 2 for information on restarting LUNSUMIO VELO after dose delays [see Dosage and Administration (2.2)]. Administer premedicationRefer to Table 3 for additional information on premedication. prior to next dose of LUNSUMIO VELO and monitor patient more frequently.
Grade 2	Fever ≥ 100.4°F (38°C) with:	Ensure CRS symptoms are resolved for at least 72 hours prior to the next dose of LUNSUMIO VELO.
	Hypotension not requiring vasopressors	Administer premedication prior to next dose of LUNSUMIO VELO.
	and/or	For the next dose of LUNSUMIO VELO, monitor more frequently and consider hospitalization.
	hypoxia requiring low-flow oxygenLow-flow oxygen defined as oxygen delivered at < 6 L/minute; high-flow oxygen defined as oxygen delivered at ≥ 6 L/minute. by nasal cannula or blow-by.	Recurrent Grade 2 CRS Manage per Grade 3 CRS.
Grade 3	Fever ≥ 100.4°F (38°C) with:	Ensure CRS symptoms are resolved for at least 72 hours prior to the next dose of LUNSUMIO VELO.
	Hypotension requiring a vasopressor (with or without vasopressin)	Administer premedication prior to next dose of LUNSUMIO VELO.
	and/or	For the next dose of LUNSUMIO VELO, monitor more frequently and hospitalize for the next dose.
	hypoxia requiring high flow oxygen by nasal cannula, face mask, non-rebreather mask, or Venturi mask.	If CRS occurred after the 5 mg or 45 mg dose, administer 5 mg as the next dose. Resume treatment schedule after recovery. If the 5 mg dose is tolerated without grade 3 CRS, resume subsequent doses at 45 mg.
		Recurrent Grade 3 CRS Permanently discontinue LUNSUMIO VELO. Manage CRS per current practice guidelines and provide supportive therapy, which may include intensive care.
Grade 4	Fever ≥ 100.4°F (38°C) with:	Permanently discontinue LUNSUMIO VELO. Manage CRS per current practice guidelines and provide supportive therapy, which may include intensive care.
	Hypotension requiring multiple vasopressors (excluding vasopressin)
	and/or
	hypoxia requiring oxygen by positive pressure (e.g., CPAP, BiPAP, intubation and mechanical ventilation).

Dosage Modifications for Neurologic Toxicity, including ICANS

Management recommendations for neurologic toxicity, including ICANS, are summarized in Table 5. At the first sign of neurologic toxicity, including ICANS, consider neurology evaluation and withholding of LUNSUMIO VELO based on the type and severity of neurotoxicity. Rule out other causes of neurologic symptoms. Provide supportive therapy, which may include intensive care.

Adverse Reaction	SeverityBased on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.0. , Based on American Society for Transplantation and Cellular Therapy (ASTCT) 2019 grading for ICANS.	Actions
Neurologic Toxicity (including ICANS)	Grade 1	Continue LUNSUMIO VELO and monitor neurologic toxicity symptoms. If ICANS, manage per current practice guidelines.
	Grade 2	Withhold LUNSUMIO VELO until neurologic toxicity symptoms improve to Grade 1 or baseline for at least 72 hours.See Table 2 for recommendations on restarting LUNSUMIO VELO after dose delays [see Dosage and Administration (2.2)]. Provide supportive therapy, and consider neurologic evaluation. If ICANS, manage per current practice guidelines.
	Grade 3	Withhold LUNSUMIO VELO until neurologic toxicity symptoms improve to Grade 1 or baseline for at least 72 hours. Provide supportive therapy, which may include intensive care, and consider neurology evaluation. If ICANS, manage per current practice guidelines. If recurrence of ICANS, permanently discontinue LUNSUMIO VELO.
	Grade 4	Permanently discontinue LUNSUMIO VELO. Provide supportive therapy, which may include intensive care, and consider neurology evaluation. If ICANS, manage per current practice guidelines.

Other Adverse Reactions

Adverse ReactionsBased on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.0.	Severity	Actions
Infections [see Warnings and Precautions (5.3)]	Grades 1 – 4	Withhold LUNSUMIO VELO in patients with active infection until the infection resolves.See Table 2 for recommendations on restarting LUNSUMIO VELO after dose delays [see Dosage and Administration (2.2)]. For Grade 4, consider permanent discontinuation of LUNSUMIO VELO.
Neutropenia [see Warnings and Precautions (5.4)]	Absolute neutrophil count less than 0.5 × 109/L	Withhold LUNSUMIO VELO until absolute neutrophil count is 0.5 × 109/L or higher.
Other Adverse Reactions [see Warnings and Precautions (5.5) and Adverse Reactions (6.1)]	Grade 3 or higher	Withhold LUNSUMIO VELO until the toxicity resolves to Grade 1 or baseline. Permanently discontinue LUNSUMIO VELO if a Grade 4 injection site reaction occurs.

2.5 Preparation and Administration

If the LUNSUMIO VELO dose is not administered immediately, refer to "Storage of Prepared Syringe" section below.

To prevent medication errors, check the vial labels to ensure that the drug being prepared and administered is LUNSUMIO VELO for subcutaneous administration. A peel-off label is provided on the LUNSUMIO VELO Prescribing Information that should be attached to the final prepared syringe. Remove the peel-off label from the Prescribing Information in the LUNSUMIO VELO carton before discarding the carton. Affix the peel-off label to the prepared LUNSUMIO VELO syringe. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if the solution is discolored, or cloudy, or if foreign particles are present. Each LUNSUMIO VELO 5 mg/0.5 mL and 45 mg/mL vial are supplied as ready-to-use solution that do not need dilution prior to subcutaneous administration. LUNSUMIO VELO vials are for one-time use in one patient only. No incompatibilities between LUNSUMIO VELO and polypropylene or polycarbonate syringe material, stainless-steel transfer and injection needles, and polyethylene or polypropylene syringe closing caps have been observed.

Preparation of the Syringe

Use aseptic technique to prepare LUNSUMIO VELO. Select the appropriate strength vial based on the prescribed dose. Withdraw the required volume of LUNSUMIO VELO solution from the vial with a syringe and an appropriately sized transfer needle (18G to 21G recommended). The smallest syringe that can accurately deliver the injection volume should be used. Discard any unused portion left in the vial. Remove the transfer needle and attach an appropriately sized injection needle (25G to 30G recommended). Apply peel-off label from the Prescribing Information to the prepared drug product. Once transferred from the vial to the syringe, LUNSUMIO VELO solution for injection should be injected immediately because LUNSUMIO VELO solution for injection does not contain any antimicrobial-preservative.

Administration

Inject the required volume of LUNSUMIO VELO into the subcutaneous tissue of the abdomen or thigh, changing the site of injection with each dose. Do not inject into tattoos, moles, scars or areas where the skin is red, bruised, tender, hard, or not intact. The dose should be administered subcutaneously over approximately 30 seconds to 1 minute.

Storage of Prepared Syringe

The prepared syringe should be used immediately. If not used immediately, replace the transfer needle with a syringe closing cap. Do not attach an injection needle. The capped syringe can be stored refrigerated at 2°C to 8°C (36°F to 46°F) for up to 32 hours protected from light and/or at 9°C to 25°C (37°F to 77°F) for up to 8 hours at ambient light. Once removed from refrigerated storage, the solution can be equilibrated to ambient temperature up to 25°C (77°F) prior to administration. Do not warm LUNSUMIO VELO in any other way.

5.1 Cytokine Release Syndrome

LUNSUMIO VELO can cause CRS, including serious or life-threatening reactions [see Adverse Reactions (6.1)].

CRS occurred in 30% of patients who received LUNSUMIO VELO at the recommended dosage in the clinical trial (N = 94), with Grade 1 CRS occurring in 20%, Grade 2 in 7%, and Grade 3 in 2.1% of patients. Among 28 patients who experienced CRS, CRS recurred in 14%. CRS occurred most commonly after the first two doses: 19% of patients experienced CRS after the Cycle 1 Day 1 dose, 13% after the Cycle 1 Day 8 dose, and 2.1% after the Cycle 1 Day 15 dose.

The median time to CRS onset from the start of LUNSUMIO VELO administration was 17 hours (range: 7 to 33 hours) with the Cycle 1 Day 1 dose, and 62 hours (range: 30 to 113 hours) with the Cycle 1 Day 8 dose. CRS resolved in all patients, after a median duration of 2 days (range: 1 to 15 days).

Clinical signs and symptoms of CRS included fever, hypotension, hypoxia, chills, tachycardia, and headache. Concurrent neurologic adverse reactions occurred in 5% of patients and included but were not limited to headache, dizziness, lethargy, memory impairment, and peripheral neuropathy.

Initiate therapy according to LUNSUMIO VELO step-up dosing schedule to reduce the risk of CRS [see Dosage and Administration (2.3)]. Administer pretreatment medications to reduce the risk of CRS, ensure adequate hydration, and monitor patients following administration of LUNSUMIO VELO accordingly.

At the first sign of CRS, immediately evaluate patients for hospitalization, manage per current practice guidelines, and administer supportive care; withhold or permanently discontinue LUNSUMIO VELO based on severity [see Dosage and Administration (2.4)].

Patients who experience CRS (or other adverse reactions that impair consciousness) should be evaluated and advised not to drive and to refrain from operating heavy or potentially dangerous machinery until resolution.

5.2 Neurologic Toxicity, including Immune Effector Cell-Associated Neurotoxicity Syndrome

LUNSUMIO VELO can cause serious and life-threatening neurologic toxicity, including immune effector cell-associated neurotoxicity syndrome (ICANS) [see Adverse Reactions (6.1)].

Neurologic toxicity occurred in 53% of patients who received LUNSUMIO VELO at the recommended dosage in the clinical trial (N = 94), with Grade 3 neurologic toxicity occurring in 1.1% of patients. The most frequent neurologic toxicities were headache (17%), insomnia (15%), dizziness (10%), and mental status changes (7%, including confusion and lethargy). ICANS or suspected ICANS was reported in 3.1% of patients (all Grade 1).

Across a broader clinical trial population, ICANS or suspected ICANS occurred in 2.2% (21/949) of patients who received LUNSUMIO or LUNSUMIO VELO. The most frequent manifestations included confusional state and lethargy. Twenty patients had Grade 1-2 reactions and 1 patient had a Grade 3 event. The majority of cases (75%) occurred during the first cycle of treatment. The median time to onset was 17 days (range: 1 to 48 days). In total, 88% of cases resolved after a median duration of 3 days (range: 1 to 20 days).

Coadministration of LUNSUMIO VELO with other products that cause dizziness or mental status changes may increase the risk of neurologic toxicity.

Monitor patients for signs and symptoms of neurologic toxicity during treatment. At the first sign of neurologic toxicity, including ICANS, immediately evaluate the patient, consider neurology evaluation as appropriate, and provide supportive therapy based on severity; withhold or permanently discontinue LUNSUMIO VELO based on severity and follow management recommendations [see Dosage and Administration (2.4)].

Patients who experience neurologic toxicity such as tremors, dizziness, insomnia, severe neurotoxicity, or any other adverse reactions that impair consciousness should be evaluated, including potential neurology evaluation, and patients at increased risk should be advised not to drive and to refrain from operating heavy or potentially dangerous machinery until resolution.

5.3 Infections

LUNSUMIO VELO can cause serious or fatal infections [see Adverse Reactions (6.1)].

Among patients who received LUNSUMIO VELO at the recommended dosage in the clinical trial, serious infections, including opportunistic infections, occurred in 17%, with Grade 3 or 4 infections in 16% and fatal infections in 3.2% of patients. The most common Grade 3 or greater infections were pneumonia, sepsis, and COVID-19.

Monitor patients for signs and symptoms of infection prior to and during treatment with LUNSUMIO VELO and treat appropriately. LUNSUMIO VELO should not be administered in the presence of active infection. Caution should be exercised when considering use in patients with a history of recurring or chronic infections (e.g., chronic, active Epstein-Barr Virus), with underlying conditions that may predispose to infections or who have had significant prior immunosuppressive treatment. Administer prophylactic antimicrobials according to guidelines.

Withhold LUNSUMIO VELO or consider permanent discontinuation based on severity [see Dosage and Administration (2.4)].

5.4 Hemophagocytic Lymphohistiocytosis

LUNSUMIO VELO can cause fatal or serious hemophagocytic lymphohistiocytosis (HLH). HLH is a potentially life-threatening, hyperinflammatory syndrome that is independent of CRS. Common manifestations include fever, elevated ferritin, hemophagocytosis, cytopenias, coagulopathy, hepatitis, and splenomegaly.

Across a broader clinical trial population, HLH occurred in 0.5% (7/1536) of patients who received LUNSUMIO or LUNSUMIO VELO. Most cases (5/7) were identified within the first 28 days following initiation of treatment, with 3 cases preceded by diagnosed or suspected CRS. Of the 7 cases of HLH, 6 had fatal outcomes, with 2 deaths from HLH alone and 4 deaths with concurrent unresolved HLH. Of the 7 cases of HLH, 4 occurred in the context of concurrent EBV and/or CMV infection.

Monitor for clinical signs and symptoms of HLH. Consider HLH when the presentation of CRS is atypical or prolonged, or when there are features of macrophage activation. For suspected HLH, interrupt LUNSUMIO VELO and evaluate and treat promptly for HLH per current practice guidelines.

5.5 Cytopenias

LUNSUMIO VELO can cause serious or severe cytopenias, including lymphopenia, neutropenia, anemia, and thrombocytopenia [see Adverse Reactions (6.1)].

Among patients who received LUNSUMIO VELO at the recommended dosage in the clinical trial (N = 94), Grade 3 or 4 decreased lymphocytes occurred in 69%, decreased neutrophils occurred in 26%, decreased hemoglobin in 10%, and decreased platelets in 6% of patients. Grade 4 decreased lymphocytes occurred in 22%, decreased neutrophils in 9% and decreased platelets in 3.2% of patients. Febrile neutropenia occurred in 2.1% of patients.

Monitor complete blood counts throughout treatment. Based on the severity of cytopenias, temporarily withhold, or permanently discontinue LUNSUMIO VELO. Consider prophylactic granulocyte colony-stimulating factor administration as applicable [see Dosage and Administration (2.4)].

5.6 Tumor Flare

LUNSUMIO VELO can cause serious or severe tumor flare [see Adverse Reactions (6.1)].

Among patients who received LUNSUMIO VELO at the recommended dosage in the clinical trial (N = 94), tumor flare occurred in 1.1% of patients. Manifestations may include new or worsening pleural effusions, localized pain and swelling at the sites of lymphoma lesions, and tumor inflammation.

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. If compression or obstruction develops, institute standard treatment of these complications.

5.7 Risk of Medication Errors with Incorrect Product Use

Mosunetuzumab-axgb is available in two formulations: as an injection for subcutaneous use (LUNSUMIO VELO) and an injection for intravenous use (LUNSUMIO). Check the product labels to ensure that the correct formulation is being prescribed, dispensed, and administered to the patient [see Dosage and Administration (2.2 and 2.5)]. Do not substitute LUNSUMIO VELO for or with LUNSUMIO.

5.8 Embryo-Fetal Toxicity

Based on its mechanism of action, LUNSUMIO VELO 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 LUNSUMIO VELO and for 3 months after the last dose [see Use in Specific Populations (8.1, 8.3)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Relapsed or Refractory Follicular Lymphoma

The safety of LUNSUMIO VELO was evaluated in an open-label, multicenter study which included a cohort of 94 patients with relapsed or refractory follicular lymphoma (FL) after at least two lines of systemic therapy [see Clinical Studies (14)]. Patients received step-up doses of 5 mg via subcutaneous injection on Cycle 1 Day 1 and 45 mg on Cycle 1 Day 8, followed by 45 mg on Cycle 1 Day 15, then 45 mg every 3 weeks in subsequent cycles. A treatment cycle was 21 days. The median number of cycles was 8 (range: 1 to 17), with 78% of patients exposed for at least 8 cycles and 6% exposed for 17 cycles.

The median age was 65 years (range: 35 to 84 years), 56% were male, 85% were White, 2.1% were Black or African American, 11% were Asian, and 2% were Hispanic or Latino.

Serious adverse reactions occurred in 39% of patients. Serious adverse reactions in ≥ 10% of patients included infection (17%, including pneumonia, other respiratory tract infections, and sepsis) and CRS (15%). Fatal adverse reactions occurred in 4.3% of patients from COVID-19 (3.2%) and HLH (1.1%).

Permanent discontinuation LUNSUMIO VELO due to an adverse reaction occurred in 7% of patients, including from COVID-19.

Dosage interruptions of LUNSUMIO VELO due to an adverse reaction occurred in 40% of patients. Adverse reactions which required dosage interruption in ≥ 5% of patients included COVID-19 and neutropenia.

The most common adverse reactions (≥ 20%), excluding laboratory abnormalities, were injection site reactions, fatigue, rash, CRS, COVID-19 infection, musculoskeletal pain, and diarrhea. The most common Grade 3-4 laboratory abnormalities (≥ 15%) were decreased lymphocyte count, decreased neutrophil count, and increased uric acid. Grade 4 laboratory abnormalities in > 5% included lymphocyte count decreased (22%) and neutrophil count decreased (9%).

Table 7 summarizes the adverse reactions.

Adverse Reaction	LUNSUMIO VELO (N = 94)
	All Grades (%)	Grade 3 or 4 (%)
Immune system disorders
The table includes a combination of grouped and ungrouped terms. Adverse reactions were graded based on CTCAE Version 4.0, with the exception of CRS, which was graded per ASTCT 2019 criteria.
Cytokine release syndrome	30	2.1
General disorders and administration site conditions
Injection site reactionsInjection site reactions includes injection site reaction, injection site discharge, injection site erythema, injection site edema, injection site pain, injection site pruritus and injection site rash.	69	0
FatigueFatigue includes fatigue, asthenia, and lethargy.	39	0
EdemaEdema includes edema, edema peripheral, face edema, pulmonary edema, fluid overload, and related terms.	13	0
Pyrexia	11	1.1
Chills	11	0
Skin and subcutaneous tissue disorders
RashRash includes rash, injection site rash, erythema, dermatitis, palmar-plantar erythrodysesthesia, erythema multiforme, urticaria, and related terms.	35	3.2
Dry skin	11	0
Nervous system
Headache	17	0
Peripheral neuropathyPeripheral neuropathy includes peripheral neuropathy, peripheral sensory neuropathy, peripheral motor neuropathy, paresthesia, dysesthesia, hypoesthesia, burning sensation, and neuralgia.	11	0
DizzinessDizziness includes dizziness and vertigo.	10	0
Musculoskeletal and connective tissue disorders
Musculoskeletal painMusculoskeletal pain includes musculoskeletal pain, back pain, myalgia, musculoskeletal chest pain, and neck pain.	20	0
Arthralgia	13	0
Respiratory, thoracic, and mediastinal disorders
Cough	13	0
Dyspnea	11	0
Gastrointestinal disorders
Diarrhea	20	0
Nausea	14	0
Constipation	14	0
Abdominal pain	13	0
Infections
COVID-19Adverse reaction with fatal outcome. , Grade 5 COVID-19 occurred in 3.2% of patients.	27	4.3
Upper respiratory tract infectionUpper respiratory tract infection includes upper respiratory tract infection, nasopharyngitis, sinusitis, rhinovirus infection, and related terms.	15	2.1
PneumoniaPneumonia includes lung consolidation and specific types of pneumonia including COVID-19 pneumonia.	13	4.3
Psychiatric disorder
Insomnia	15	0

Clinically relevant adverse reactions in < 10% of patients who received LUNSUMIO VELO included pruritus, skin exfoliation, herpes zoster infection, tremor, sepsis, cytomegalovirus (CMV) infection, ICANS, febrile neutropenia, capillary leak syndrome, tumor flare, and HLH .

Table 8 summarizes select laboratory abnormalities.

Laboratory Abnormality	LUNSUMIO VELOThe denominator used to calculate the rate varied from 85 to 94 based on the number of patients with a baseline value and at least one post-treatment value.
	All Grades (%)	Grade 3 or 4 (%)
Hematology
Lymphocyte count decreased	84	69
Hemoglobin decreased	60	10
Neutrophils decreased	50	26
Platelets decreased	33	6.4
Chemistry
Phosphate decreased	48	11
Alanine aminotransferase increased	34	1.1
Gamma-glutamyl transferase increased	31	1.1
Uric acid increased	28	28
Aspartate aminotransferase increased	28	2.1
Potassium decreased	27	0
Magnesium decreased	25	2.1

Clinically relevant laboratory abnormalities in < 20% of patients included glucose increased.

8.1 Pregnancy

Risk Summary

Based on the mechanism of action, LUNSUMIO VELO may cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on the use of LUNSUMIO VELO in pregnant women to evaluate for a drug-associated risk. No animal reproductive or developmental toxicity studies have been conducted with mosunetuzumab-axgb.

Mosunetuzumab-axgb causes T-cell activation and cytokine release; immune activation may compromise pregnancy maintenance. In addition, based on expression of CD20 on B-cells and the finding of B-cell depletion in non-pregnant animals, mosunetuzumab-axgb can cause B-cell lymphocytopenia in infants exposed to mosunetuzumab-axgb in-utero. Human immunoglobulin G (IgG) is known to cross the placenta; therefore, LUNSUMIO VELO has the potential to be transmitted from the mother to the developing fetus. Advise women of the potential risk to the fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% – 4% and 15% – 20%, respectively.

8.2 Lactation

Risk Summary

There is no information regarding the presence of mosunetuzumab-axgb in human milk, the effect on the breastfed child, or milk production. Because human IgG is present in human milk, and there is potential for mosunetuzumab-axgb absorption leading to B-cell depletion, advise women not to breastfeed during treatment with LUNSUMIO VELO and for 3 months after the last dose.

8.3 Females and Males of Reproductive Potential

LUNSUMIO VELO may cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to initiating LUNSUMIO VELO.

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with LUNSUMIO VELO and for 3 months after the last dose.

8.4 Pediatric Use

The safety and efficacy of LUNSUMIO VELO have not been established in pediatric patients.

8.5 Geriatric Use

Among the 94 patients treated with LUNSUMIO VELO, 51% were 65 years of age or older. There is an insufficient number of patients 65 years of age or older to assess whether there are differences in safety or effectiveness by age group.

12.1 Mechanism of Action

Mosunetuzumab-axgb is a T-cell engaging bispecific antibody that binds to the CD3 receptor expressed on the surface of T-cells and CD20 expressed on the surface of lymphoma cells and some healthy B-lineage cells.

In vitro, mosunetuzumab-axgb activated T-cells, caused the release of proinflammatory cytokines, and induced lysis of B-cells.

12.2 Pharmacodynamics

After subcutaneous administration of the recommended dosage of LUNSUMIO VELO, peripheral B-cell counts decreased to undetectable levels (< 5 cells/microliter) in most patients (94%) by Cycle 2 Day 1 and the depletion was sustained at later cycles including at Cycle 4 and Cycle 8.

LUNSUMIO VELO caused hypogammaglobulinemia (defined as IgG levels < 500 mg/dL). Among 49 patients with baseline IgG levels ≥ 500 mg/dL, 39% experienced a decrease in their IgG levels to < 500 mg/dL after receiving LUNSUMIO VELO.

Plasma concentrations of cytokines (IL-2, IL-6, IL-10, TNF-α and IFN-γ) were measured with subcutaneous administration of LUNSUMIO VELO, and transient elevation of cytokines were observed at doses of 1.6 mg and above. After administration of the recommended dosage of LUNSUMIO VELO, the highest elevation of cytokines was generally observed within 48 hours after the first dose on Cycle 1 Day 8 and generally returned to baseline prior to the third 45 mg full dose on Cycle 2 Day 1. The observed pattern of cytokine release appeared slower and reduced relative to intravenous administration.

12.3 Pharmacokinetics

Mosunetuzumab-axgb subcutaneously administered PK exposure increased proportionally over a dose range from 1.6 mg to 45 mg (0.04 to 1 times the recommended treatment dosage).

When comparing mosunetuzumab exposures following the recommended LUNSUMIO VELO subcutaneous dosing regimen to the recommended LUNSUMIO intravenous dosing regimen in patients with relapsed or refractory follicular lymphoma in Study GO29781 [see Clinical Studies (14)], the geometric mean ratios (GMRs) (90% CI) for observed Cycle 3 C_trough was 1.39 (1.20 to 1.61) and AUC over 0-84 days was 1.06 (0.92 to 1.21). PK exposures for the recommended dosage of LUNSUMIO VELO via subcutaneous injection are summarized in Table 9 and Figure 1.

	AUC (day∙µg/mL)Values are geometric mean with geometric CV%.	Cmax (µg/mL)	Ctrough (µg/mL)
All values reported are model-predicted exposure metrics.
Cycle 1 (0 – 21 days)	36.7 (57.0)	3.8 (53.9)	3.5 (54.1)
Cycle 2 (21 – 42 days)	82.3 (50.9)	5.2 (50.3)	2.5 (55.7)
Cycle 3 (42 – 63 days)	72.9 (42.8)	4.5 (44.0)	2.4 (52.3)
Steady stateSteady state values are approximated at Cycle 4 (63 – 84 days).	72.8 (34.5)	4.4 (36.7)	2.4 (34.2)

Figure 1. Model-Predicted Mosunetuzumab-axgb Subcutaneous Injection Concentration Time Profile

Pharmacokinetic parameters (Table 10) were evaluated at the recommended dosage and are presented as geometric mean (CV%) unless otherwise specified.

Parameter	LUNSUMIO VELO via Subcutaneous Infusion
Tmax = time to peak concentration
Bioavailability	89.8%
Tmax median (range), daysSteady-state	4.2 (2.5 – 7.1)
Volume of distributiona (L)	5.5 (31%)
Half-lifea (days)	17.0 (15%)
Systemic clearance (L/day)	1.1 (63%) at baseline 0.58 (18%) at steady state

Specific Populations

There were no clinically significant differences in the pharmacokinetics of mosunetuzumab-axgb based on age (18 to 96 years), sex, race (Asian and Non-Asian), ethnicity (Hispanic/Latino and not Hispanic/Latino), mild or moderate renal impairment (estimated creatinine clearance [CrCL] by Cockcroft-Gault formula: 30 to 89 mL/min), or mild hepatic impairment (total bilirubin less than or equal to upper limit of normal [ULN] with AST greater than ULN or total bilirubin greater than 1 to 1.5 times ULN with any AST).

The effects of severe renal impairment (CrCL 15 to 29 mL/min) or moderate to severe hepatic impairment (total bilirubin greater than 1.5 times ULN with any AST) on the pharmacokinetics of mosunetuzumab-axgb are unknown.

Drug Interaction Studies

No clinical studies evaluating the drug interaction potential of mosunetuzumab-axgb have been conducted.

12.6 Immunogenicity

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the study described below with the incidence of anti-drug antibodies in other studies, including those of mosunetuzumab-axgb.

During treatment in Study GO29781 (up to 12 months) [see Clinical Studies (14)], using an enzyme-linked immunosorbent assay (ELISA), no patients (N = 216) treated with LUNSUMIO VELO monotherapy developed anti-mosunetuzumab-axgb antibodies. Based on these data, the clinical relevance of anti-mosunetuzumab-axgb antibodies could not be assessed.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity or genotoxicity studies have been conducted with mosunetuzumab-axgb.

No dedicated studies have been conducted to evaluate the effects of mosunetuzumab-axgb on fertility. No adverse effects on either male or female reproductive organs were identified in a 26-week repeat dose chronic toxicity study in sexually mature cynomolgus monkeys.

Store refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light.

Do not freeze. Do not shake.