DOSAGE & ADMINISTRATION

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ADMINISTRATION

Instructions for Reconstitution, Dilution, and Administration

LUMOXITI must be reconstituted and diluted by a health care provider using aseptic technique. Refer to the Healthcare Provider Instructions for Use for LUMOXITI for full reconstitution, dilution, and administration information.1

Step 1: Calculate Dose1

  • Calculate the dose (mg) and the number of LUMOXITI vials (1 mg/vial) to be reconstituted. The final concentration of the reconstituted LUMOXITI solution is 1 mg/mL
    • DO NOT round down for partial vials
  • Lumoxiti reconstitution calculation

  • Individualize dosing based on the patient’s actual body weight prior to the first dose of the first treatment cycle
    • A change in dose should only be made between cycles when a change in weight of greater than 10% is observed from the weight used to calculate the first dose of the first treatment cycle. No change in dose should be made during a particular cycle

Step 2: Reconstitution1

Reconstitute LUMOXITI vials with Sterile Water for Injection, USP only.

  • Reconstitute each LUMOXITI (1 mg/vial) with 1.1 mL Sterile Water for Injection, USP. The resulting 1 mg/mL solution allows a withdrawal volume of 1 mL
    • Direct the Sterile Water for Injection, USP along the walls of the vial and not directly at the lyophilized cake or powder
    • DO NOT reconstitute LUMOXITI vials with the IV Solution Stabilizer
  • Gently swirl the vial until completely dissolved. Invert the vial to ensure all cake or powder in the vial is dissolved. Do not shake
  • Visually inspect that the reconstituted solution is clear to slightly opalescent, colorless to slightly yellow, and free from visible particles. Do not use if solution is cloudy, discolored, or contains any particles
  • Use reconstituted solution immediately. Do not store reconstituted LUMOXITI vials. See the table below for storage times and conditions for the reconstituted solution

Step 3: Dilution1

Add the IV Solution Stabilizer to the infusion bag prior to adding LUMOXITI solution to the infusion bag. Vial of IV Solution Stabilizer is packaged separately.

  • Obtain a 50 mL 0.9% Sodium Chloride Injection, USP infusion bag.
  • Add 1 mL IV Solution Stabilizer to the infusion bag containing 50 mL 0.9% Sodium Chloride Injection, USP
    • Only one vial of IV Solution Stabilizer should be used per administration of LUMOXITI
    • Gently invert the bag to mix the solution. Do not shake
  • Withdraw the required volume (calculated from Step 1) of LUMOXITI solution from the reconstituted vial(s)
    • Inject LUMOXITI into the infusion bag containing 50 mL 0.9% Sodium Chloride Injection, USP and 1 mL IV Solution Stabilizer
    • Gently invert the bag to mix the solution. Do not shake
  • Discard any partially used or empty vials of LUMOXITI and IV Solution Stabilizer
  • See the table below for storage times and conditions for the diluted solution

Step 4: Administration Instructions1

For intravenous infusion only.

  • Administer the diluted solution intravenously over 30 minutes
  • Do not mix LUMOXITI, or administer as an infusion with other medicinal products
  • After the infusion, flush the IV administration line with 0.9% Sodium Chloride Injection, USP at the same rate as the infusion. This ensures that the full LUMOXITI dose is delivered

Storage Times and Conditions for Reconstituted and Diluted LUMOXITI Solution

LUMOXITI Storage Times

RECOMMENDED CONCOMITANT TREATMENT

Hydration

Intravenously administer 1 L of isotonic solution (eg, 5% Dextrose Injection, USP and 0.45% or 0.9% Sodium Chloride Injection, USP) over 2-4 hours before and after each LUMOXITI infusion. Administer 0.5 L to patients under 50 kg.1

Advise all patients to adequately hydrate with up to 3 L (twelve 8-oz glasses) of oral fluids (eg, water, milk, or juice) per 24 hours on Days 1 through 8 of each 28-day cycle. In patients under 50 kg, up to 2 L (eight 8-oz glasses) per 24 hours is recommended.1

Monitor fluid balance and serum electrolytes to avoid fluid overload and/or electrolyte abnormalities. [see Warnings and Precautions].

Thromboprophylaxis

Consider low-dose aspirin on Days 1 through 8 of each 28-day cycle.1

Monitor for signs and symptoms of thrombosis.1 [see Warnings and Precautions].

Premedication

Premedicate 30-90 minutes prior to each LUMOXITI infusion with1:

  • An antihistamine (eg, hydroxyzine or diphenhydramine)
  • Acetaminophen antipyretic
  • A histamine-2 receptor antagonist (eg, ranitidine, famotidine, or cimetidine)

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 and before each LUMOXITI infusion thereafter.1 [see Warnings and Precautions].

Post-infusion Medication

  • Consider oral antihistamines and antipyretics for up to 24 hours following LUMOXITI infusions1
  • An oral corticosteroid (eg, 4 mg dexamethasone) is recommended to decrease nausea and vomiting1
  • Maintain adequate oral fluid intake1

MONITORING TO ASSESS SAFETY

Manage adverse reactions by withholding and/or discontinuing LUMOXITI as described below.1

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

Monitoring for CLS and HUS1

Monitoring and Dosage Adjustment for HUS and CLS

Adverse reactions graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.

Capillary Leak Syndrome (CLS)

Patients who experience Grade 2 or higher CLS should receive appropriate supportive measures, including treatment with oral or intravenous corticosteroids, with monitoring of weight, albumin levels, and blood pressure until resolution.1

CLS Grading and Management Guidance1

CLS Grading and Management Guidance

Per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.

Hemolytic Uremic Syndrome (HUS)

Discontinue LUMOXITI in patients with HUS. Treat with appropriate supportive measures and fluid replacement, with monitoring of blood chemistry, complete blood counts, and renal function until resolution.1

Increased Creatinine

For patients with baseline serum creatinine within normal limits, delay dosing for Grade 2 or higher creatinine increases (greater than 1.5-times baseline or the upper limit of normal). Resume LUMOXITI upon recovery to Grade 1 (1- to 1.5-times baseline, or between the upper limit of normal and 1.5-times the upper limit of normal).1

For patients with baseline serum creatinine of Grades 1 or 2, delay dosing for creatinine increases to Grade 3 or higher (greater than 3-times baseline or the upper limit of normal). Resume LUMOXITI upon recovery to baseline grade or lower.1

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IMPORTANT SAFETY INFORMATION

WARNING: CAPILLARY LEAK SYNDROME and HEMOLYTIC UREMIC SYNDROME

  • Capillary Leak Syndrome (CLS), including life-threatening cases, occurred in patients receiving LUMOXITI. Monitor weight and blood pressure; check labs, including albumin, if CLS is suspected. Delay dosing or discontinue LUMOXITI as recommended.
  • Hemolytic Uremic Syndrome (HUS), including life-threatening cases, occurred in patients receiving LUMOXITI. Monitor hemoglobin, platelet count, serum creatinine, and ensure adequate hydration. Discontinue LUMOXITI in patients with HUS.

WARNINGS AND PRECAUTIONS

  • 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.

    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.

  • 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. 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.

    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.

  • 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.

    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.

    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.

  • 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, including Grade 3 events in 11% (9/80) of 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. Premedicate with antihistamines and antipyretics prior to each LUMOXITI dose. 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.

  • 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.

ADVERSE REACTIONS

  • Most common non-laboratory adverse reactions (≥ 20%) of any grade were infusion related reactions (50%), edema peripheral (39%), nausea (35%), fatigue (34%), headache (33%), pyrexia (31%), constipation (23%), anemia (21%), and diarrhea (21%). The most common Grade 3 or 4 adverse reactions (reported in at least ≥ 5% of patients) were hypertension, febrile neutropenia, and HUS.
  • 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%).

SPECIFIC POPULATIONS

  • Pregnancy: There are no available data on LUMOXITI use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. Advise pregnant women of the potential risk to a fetus.
  • Lactation: Advise women not to breastfeed.
  • Geriatric Use: Exploratory analyses 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.

Please see full Prescribing Information, including Boxed WARNING, and Medication Guide and Instructions for Use.

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IMPORTANT SAFETY INFORMATION+

WARNING: CAPILLARY LEAK SYNDROME and HEMOLYTIC UREMIC SYNDROME

  • Capillary Leak Syndrome (CLS), including life-threatening cases, occurred in patients receiving LUMOXITI. Monitor...Read More weight and blood pressure; check labs, including albumin, if CLS is suspected. Delay dosing or discontinue LUMOXITI as recommended.
  • Hemolytic Uremic Syndrome (HUS), including life-threatening cases, occurred in patients receiving LUMOXITI. Monitor hemoglobin, platelet count, serum creatinine...Read More