Limitations of Use

LUMOXITI is not recommended in patients with severe renal impairment (CrCl ≤ 29 mL/min) [see Dosage and Administration (2.3), Warnings and Precautions (5.3), and Use in Specific Populations (8.5)].

2.1 Recommended Dosage

The recommended dose of LUMOXITI is 0.04 mg/kg administered as a 30-minute intravenous infusion on Days 1, 3, and 5 of each 28-day cycle. Continue LUMOXITI treatment for a maximum of 6 cycles, disease progression, or unacceptable toxicity.

2.2 Recommended Concomitant Treatment

2.3 Monitoring to Assess Safety

Manage adverse reactions by withholding and/or discontinuing LUMOXITI as described below.

Identify Capillary Leak Syndrome (CLS) and Hemolytic Uremic Syndrome (HUS) based on clinical presentation (see Table 1).

2.4 Instructions for Reconstitution, Dilution, and Administration

LUMOXITI must be reconstituted and diluted by a healthcare provider using aseptic technique. Refer to the Healthcare Provider Instructions for Use for LUMOXITI for full reconstitution, dilution, and administration information.

5.1 Capillary Leak Syndrome (CLS)

Capillary leak syndrome (CLS), including life-threatening cases, has been reported among patients treated with LUMOXITI and is characterized by hypoalbuminemia, hypotension, symptoms of fluid overload, and hemoconcentration. In the combined safety database of HCL patients treated with LUMOXITI, CLS occurred in 34% (44/129) of patients, including Grade 2 in 23% (30/129), Grade 3 in 1.6% (2/129), and Grade 4 in 2% (3/129).

Most cases of CLS occurred in the first 8 days (range: 1 to 19) of a treatment cycle, however, cases have also been reported on other days throughout the cycle. The median time to resolution of CLS was 12 days (range: 1 to 53).

Monitor patient weight and blood pressure prior to each LUMOXITI infusion and as clinically indicated during treatment. Assess patients for signs and symptoms of CLS, including weight gain (increase in 5.5 pounds (2.5 kg) or ≥ 5% from Day 1 of current cycle), hypotension, peripheral edema, shortness of breath or cough, and pulmonary edema and/or serosal effusions. In addition, the following changes in laboratory parameters may help identify CLS: hypoalbuminemia, elevated hematocrit, leukocytosis, and thrombocytosis [see Dosage and Administration (2.3)].

CLS may be life-threatening or fatal if treatment is delayed. Counsel patients to seek immediate medical attention should signs or symptoms of CLS occur at any time. Patients who develop CLS should receive appropriate supportive measures, including concomitant oral or intravenous corticosteroids, and hospitalization as clinically indicated. Withhold LUMOXITI for Grade 2 CLS until resolution, and permanently discontinue for Grade ≥ 3 CLS [see Dosage and Administration (2.3)].

5.2 Hemolytic Uremic Syndrome (HUS)

Hemolytic Uremic Syndrome (HUS), including life threatening cases, has been reported in patients treated with LUMOXITI and is characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and progressive renal failure. In the combined safety database of HCL patients treated with LUMOXITI, HUS occurred in 7% (9/129) of patients, including Grade 3 in 3% (4/129) and Grade 4 in 0.8% (1/129).

Most cases of HUS occurred in the first 9 days (range: 1 to 16) of a treatment cycle, however, cases have also been reported on other days throughout the cycle. The median time to resolution of HUS was 11.5 days (range: 2 to 44). All cases resolved, including those who discontinued LUMOXITI.

Avoid LUMOXITI in patients with prior history of severe thrombotic microangiopathy (TMA) or HUS. Administer prophylactic intravenous fluids before and after LUMOXITI infusions [see Dosage and Administration (2.2)]. In Study 1053, patients with a platelet count ≥ 100,000/mm3 received low-dose aspirin on Days 1 through 8 of each 28-day cycle for prophylaxis of thrombosis.

Monitor blood chemistry and complete blood counts prior to each dose and on Day 8 of each treatment cycle. Monitoring mid-cycle is also recommended. Consider the diagnosis of HUS in patients who develop hemolytic anemia, worsening or sudden onset of thrombocytopenia, increase in creatinine levels, elevation of bilirubin and/or LDH, and have evidence of hemolysis based on peripheral blood smear schistocytes [see Dosage and Administration (2.3)].

The events of HUS may be life-threatening if treatment is delayed with increased risk of progressive renal failure requiring dialysis. If HUS is suspected initiate appropriate supportive measures, including fluid repletion, hemodynamic monitoring, and consider hospitalization as clinically indicated. Discontinue LUMOXITI in patients with HUS [see Dosage and Administration (2.3)].

5.3 Renal Toxicity

Renal toxicity has been reported in patients treated with LUMOXITI therapy. In the combined safety database of HCL patients treated with LUMOXITI, 26% (34/129) reported adverse events of renal toxicity, including acute kidney injury (2.3%), renal failure (2.3%), renal impairment (1.6%), serum creatinine increased (17%), and proteinuria (8%). Grade 3 acute kidney injury occurred in 1.6% (2/129) of patients. All other events were mild to moderate in severity.

Based on laboratory findings, during treatment, serum creatinine increased by two or more grades from baseline in 22% (29/129) of patients, including increases of Grade 3 in 1.6% (2/129) of patients. At the end of treatment, serum creatinine levels remained elevated at 1.5- to 3-times the upper limit of normal in 5% of patients. Patients who experience HUS, those ≥ 65 years of age, or those with baseline renal impairment may be at increased risk for worsening of renal function following treatment with LUMOXITI [see Use in Specific Populations (8.5)].

Monitor renal function prior to each infusion of LUMOXITI, and as clinically indicated throughout treatment. Delay LUMOXITI dosing in patients with Grade ≥ 3 elevations in creatinine, or upon worsening from baseline by ≥ 2 grades [see Dosage and Administration (2.3)].

5.4 Infusion Related Reactions

Infusion related reactions occurred in patients treated with LUMOXITI, and were defined as the occurrence of any one of the following events on the day of study drug infusion: chills, cough, dizziness, dyspnea, feeling hot, flushing, headache, hypertension, hypotension, infusion related reaction, myalgia nausea, pyrexia, sinus tachycardia, tachycardia, vomiting, or wheezing. In Study 1053, infusion related reactions occurred in 50% (40/80) of patients. Grade 3 infusion related events as defined, occurred in 3.8% (3/80) of LUMOXITI-treated patients. The most frequently reported infusion related events were nausea (15%), pyrexia (14%), chills (14%), vomiting (11%), headache (9%), and infusion related reaction (9%).

Infusion related reactions may occur during any cycle of treatment with LUMOXITI. Prior to each dose of LUMOXITI, premedicate with antihistamines and antipyretics. If a severe infusion related reaction occurs, interrupt the LUMOXITI infusion and institute appropriate medical management. Administer an oral or intravenous corticosteroid approximately 30 minutes before resuming, or before the next LUMOXITI infusion [see Dosage and Administration (2.2)].

5.5 Electrolyte Abnormalities

In the combined safety database of HCL patients treated with LUMOXITI, electrolyte abnormalities occurred in 57% (73/129) of patients with the most common electrolyte abnormality being hypocalcemia occurring in 25% of patients. Grade 3 electrolyte abnormalities occurred in 14% (18/129) of patients and Grade 4 electrolyte abnormalities occurred in 0.8% (1/129) of patients. Electrolyte abnormalities co-occurred in the same treatment cycle with CLS, HUS, fluid retention, or renal toxicity in 37% (48/129) of patients.

Monitor serum electrolytes prior to each dose and on Day 8 of each treatment cycle. Monitoring mid-cycle is also recommended.

6.1 Clinical Trials Experience

As 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.

The safety data described in this section reflect exposure to LUMOXITI in 80 patients with previously treated HCL in Study 1053 [see Clinical Studies (14)]. Patients received LUMOXITI 0.04 mg/kg as an intravenous infusion over 30 minutes on Days 1, 3, and 5 of each 28-day cycle for a maximum of 6 cycles or until disease progression or unacceptable toxicity.

The median duration of treatment with LUMOXITI was 5.7 months (range: 0.9 to 6.7), with a median of 6 treatment cycles started in each patient.

The most common non-laboratory adverse reactions (≥ 20%) of any grade were infusion related reactions, edema, nausea, fatigue, headache, pyrexia, constipation, anemia, and diarrhea. The most common Grade 3 or 4 adverse reactions (reported in at least ≥ 5% of patients) were hypertension, febrile neutropenia, and HUS.

The most common laboratory abnormalities (≥ 20%) of any grade were creatinine increased, ALT increased, hypoalbuminemia, AST increased, hypocalcemia, hypophosphatemia, hemoglobin decreased, neutrophil count decreased, hyponatremia, blood bilirubin increased, hypokalemia, GGT increased, hypomagnesemia, platelet count decreased, hyperuricemia, and alkaline phosphate increased.

Adverse reactions resulting in permanent discontinuation of LUMOXITI occurred in 15% (12/80) of patients. The most common adverse reaction leading to LUMOXITI discontinuation was HUS (5%). The most common adverse reaction resulting in dose delays, omissions, or interruptions was pyrexia (3.8%).

Tables 4 and 5 present the frequency category of adverse reactions and key laboratory abnormalities observed in patients with relapsed or refractory HCL treated with LUMOXITI.

Fluid retention occurred in 63% (50/80) of patients treated with LUMOXITI in Study 1053, including Grade 3 in 1.3% (1/80) of patients. Fluid retention included all preferred terms of edema peripheral (39%), face edema (14%), abdominal distension (13%), weight increased (8%), pleural effusion (6%), edema (5%), peripheral swelling (5%), localized edema (3.8%), ascites (1.3%), fluid overload (1.3%), fluid retention (1.3%), and pericardial effusion (1.3%). Of the fifty patients with fluid retention, 29% of patients required diuretics.

Ocular adverse events occurred, including: blurred vision (9%), dry eye (8%), cataracts (5%), ocular discomfort and/or pain (4%), ocular swelling/periorbital edema (4%), conjunctivitis (1.3%), conjunctival hemorrhage (1.3%), and ocular discharge (1.3%).

6.2 Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to moxetumomab pasudotox-tdfk in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

The immunogenicity of LUMOXITI was evaluated using electrochemiluminescent (ECL)-based immunoassay to test for anti-moxetumomab pasudotox-tdfk antibodies (ADA). For patients whose serum tested positive for ADA, a cell-based assay was performed to detect neutralizing antibodies (nAb). In Study 1053, 59% (45/76) of patients tested positive for ADA prior to any treatment with moxetumomab pasudotox-tdfk. Seventy out of 80 subjects tested ADA positive at any point during the study and were subsequently tested for nAb. The results showed that 67 of 70 subjects were nAb-positive. Among these 67 patients who tested nAb-positive, 99% (66/67) had ADA specific to the PE38 binding domain, and 54% (36/67) also had ADA specific to the CD22 binding domain. In 41 out of 73 patients who had baseline and post-baseline ADA results, the median fold increase from baseline (Cycle 1, Day 1) in ADA titer was 3.75- (range: 0 to 240), 54- (range: 0 to 2560), 120- (range: 0 to 1920), and 128- (range: 0 to 2560) fold at Cycles 2, 3, 5, and end-of-treatment, respectively. Patients who tested positive for ADA had decreased systemic moxetumomab pasudotox-tdfk concentrations [see Clinical Pharmacology (12.3)].

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

Contraception

8.4 Pediatric Use

Safety and effectiveness have not been established in pediatric patients.

8.5 Geriatric Use

In the combined safety database of HCL patients treated with LUMOXITI, 31% (40/129) of patients treated with LUMOXITI were 65 years of age or older and 8% (10/129) were 75 years of age or older. Exploratory analyses across this population suggest a higher incidence of adverse reactions leading to drug discontinuation (23% versus 7%) and renal toxicity (40% versus 20%) for patients 65 years of age or older as compared to those younger than 65 years. Clinical studies of LUMOXITI did not include sufficient numbers of subjects aged 65 and over to determine whether there were differences in efficacy between younger and older patients.

12.1 Mechanism of Action

Moxetumomab pasudotox-tdfk is a CD22-directed cytotoxin. Moxetumomab pasudotox-tdfk binds CD22 on the cell surface of B-cells and is internalized. Moxetumomab pasudotox-tdfk internalization results in ADP-ribosylation of elongation factor 2, inhibition of protein synthesis, and apoptotic cell death.

12.2 Pharmacodynamics

The presence of moxetumomab pasudotox-tdfk may interfere with detection of cellular CD22, therefore, total peripheral blood B-cell counts (including normal B cells and HCL cells) were quantified using a standard assay for CD19+ B cells as a surrogate. In patients with HCL, treatment with LUMOXITI at the approved recommended dosage resulted in a reduction of circulating CD19+ B cells. The circulating CD19+ B cells on Day 8 were reduced by 89% from baseline following the first three infusions of LUMOXITI. B cell reduction was sustained for at least 1-month post-treatment.

Total counts of CD3+ T cells, CD4+ T cells, CD8+ T cells, and CD16+/CD56 Natural Killer cells and quantitative immunoglobulin (Ig) A, G, and M levels were evaluated throughout the course of treatment. On Day 8, median cell counts were reduced from baseline for the following populations: CD3+ T cells (-21%), CD4+ T cells (-20%), CD8+ T cells (-23%), and CD16+/CD56 Natural Killer cells (-47%). All monitored cell counts returned to, or were elevated above baseline levels on Day 29 and thereafter. At baseline, the median IgA, IgG, and IgM levels were 107 mg/dL (11-260), 834 mg/dL (387-3003), and 42 mg/dL (6-380), respectively, and remained generally unchanged at the end of treatment.

12.3 Pharmacokinetics

The pharmacokinetics (PK) of moxetumomab pasudotox-tdfk was studied in patients with HCL at doses ranging from 0.005 to 0.05 mg/kg (about 0.1 to 1.3 times the approved recommended dosage) administered intravenously over 30 minutes on Days 1, 3, and 5 of a 28-day cycle. Moxetumomab pasudotox-tdfk concentrations increased dose-proportionally over the studied dose range. The mean steady state moxetumomab pasudotox-tdfk exposures at the approved recommended dosages were 379 ng/mL (range: 20 to 862; SD: 262) for Cmax and 626 ng∙hour/mL (range: 5 to 1960; SD: 610) for AUC0-last. No systemic accumulation of moxetumomab pasudotox-tdfk was observed. Baseline CD19+ B cells were evaluated for association with the PK exposure and higher PK exposures were significantly associated with low baseline CD19+ counts (p < 0.001).

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No studies have been conducted to assess the carcinogenic or genotoxic potential of moxetumomab pasudotox-tdfk. Animal fertility studies have not been conducted with moxetumomab pasudotox-tdfk.

13.2 Animal Toxicology and/or Pharmacology

At a human equivalent dose > 3 times the recommended dose, degeneration of heart tissue was observed in cynomolgus monkeys. At a human equivalent dose > 10 times the recommended dose, gliosis in the brain, axonal degeneration in the spinal cord, and body tremors were observed in cynomolgus monkeys.

How Supplied

• LUMOXITI (moxetumomab pasudotox-tdfk) for injection is supplied as a sterile, preservative-free, white to off-white lyophilized cake or powder in a 1 mg single-dose vial. Each carton (NDC 73380-4700-1) contains one single-dose vial.
• IV Solution Stabilizer is supplied as a sterile, preservative-free, colorless to slightly yellow, clear solution free from visible particles in a 1 mL single-dose vial. The IV Solution Stabilizer is packaged separately from LUMOXITI. Each carton (NDC 73380-4715-9) contains one single-dose vial. Do not use the IV Solution Stabilizer to reconstitute LUMOXITI.

Only one vial of IV Solution Stabilizer should be used per administration of LUMOXITI.

Storage and Handling

Refrigerate LUMOXITI and IV Solution Stabilizer at 2°C to 8°C (36°F to 46°F), in original carton to protect from light. Do not freeze. Do not shake.

Capillary Leak Syndrome

Advise patients on the risk of developing capillary leak syndrome. Advise patients to immediately report any symptoms suggestive of capillary leak syndrome, such as difficulty breathing, rapid weight gain, hypotension, or swelling of their arms, legs, and/or face to their healthcare provider for further evaluation [see Warnings and Precautions (5.1)].

Hemolytic Uremic Syndrome

Advise patients on the risk of developing hemolytic uremic syndrome. Advise patients on the importance of maintaining high fluid intake, and the need for frequent monitoring of blood chemistry values [see Warnings and Precautions (5.2)].

Renal Toxicity

Inform patients that taking LUMOXITI may cause decreased renal function. Advise patients to report any changes to urine output to their healthcare provider for further evaluation [see Warnings and Precautions (5.3) and Adverse Reactions (6.1)].

Infusion Related Reactions

Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion related reactions [see Warnings and Precautions (5.4)].

Electrolyte Abnormalities

Advise patients to report symptoms of electrolyte abnormalities (e.g., muscle cramping, paresthesias, irregular or fast heartbeat, nausea, seizures) to their healthcare provider immediately [see Warnings and Precautions (5.5)].