LUMOXITI Powder for solution for injection Ref.[10359] Active ingredients:

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/mm ³ 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 11% (9/80) 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.

The following adverse reactions are discussed in greater detail in other sections of the labeling.

• Capillary Leak Syndrome [see Warnings and Precautions (5.1)]
• Hemolytic Uremic Syndrome [see Warnings and Precautions (5.2)]
• Renal Toxicity [see Warnings and Precautions (5.3)]
• Infusion Related Reactions [see Warnings and Precautions (5.4)]
• Electrolyte Abnormalities [see Warnings and Precautions (5.5)]

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.

Table 4. Adverse Reactions^* in ≥20% (All Grades) of Patients with HCL in Study 1053:

^* Per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.
^† Infusion related reactions: includes patients who were reported to have one or more infusion event that may be infusion-related on the day of study drug infusion.

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%).

Table 5. Laboratory Abnormalities^* in ≥20% (All Grades) Reported in Patients with HCL in Study 1053:

ALT=alanine aminotransferase; AST=aspartate aminotransferase; GGT=gamma glutamyl transferase
^* Per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03 and based on laboratory measurements worsening from baseline

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)].

Risk Summary

Based on its mechanism of action and findings in non-pregnant female animals, LUMOXITI is expected to cause maternal and embryo-fetal toxicity when administered to a pregnant woman [see Clinical Pharmacology (12.1) and Nonclinical Toxicology (13.2)]. There are no available data on LUMOXITI use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. Animal reproduction or developmental toxicity studies have not been conducted with LUMOXITI. Advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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.

Risk Summary

No data are available regarding the presence of moxetumomab pasudotox-tdfk in human milk, the effects on the breastfed child, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for LUMOXITI and any potential adverse effects on the breastfed child from LUMOXITI or from the underlying maternal condition.

Contraception

Females

To avoid potential exposure to the fetus, women of reproductive potential should use effective contraception during treatment with LUMOXITI and for at least 30 days after the last dose is received. Verify the pregnancy status of females of reproductive potential prior to initiating LUMOXITI.

Safety and effectiveness have not been established in pediatric patients.

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.