BRIEF SUMMARY

MOXETUMOMAB PASUDOTOX-(Sept 2018)

Indn-      To  treat Hairy cell leukemia                                                                                                                                               

Comp-    Recommended dosage: 0.04 mg/kg as an intravenous infusion over 30 minutes on Days 1, 3, and 5 of each 28-day cycle.                                              LUMOXITI is a CD22-directed cytotoxin indicated for the treatment of adult patients with relapsed or refractory hairy cell leukemia (HCL) who received at least two prior systemic therapies, including treatment with a purine nucleoside analog (PNA).

Limitations of Use- Not recommended in patients with severe renal impairment (CrCl = 29 mL/min). 

CI   None.

 WARNINGS-

 Renal Toxicity: Monitor for changes in renal function prior to each infusion and as clinically indicated. Delay dosing until recovery.

Pat Inform-     

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.

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.

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U.S. FDA APPROVED  DRUGS DURING 2018

Sr.No-  36

ADVERSE REACTIONS-

Most common (= 20%) adverse reactions are infusion related reactions, edema, nausea, fatigue, headache, pyrexia, constipation, anemia, and diarrhea.

 Most common (= 50%) laboratory abnormalities are creatinine increased, ALT increased, hypoalbuminemia, AST increased, hypocalcemia, and hypophosphatemia.

 CONTRAINDICATIONS-                                                                                                      None.

 WARNINGS AND PRECAUTIONS-

# Renal Toxicity: Monitor for changes in renal function prior to each infusion and as clinically indicated. Delay dosing until recovery.

 # Infusion Related Reactions: Pre-medicate and if a severe infusion related reaction occurs, interrupt the LUMOXITI infusion and institute appropriate medical management.

 # Electrolyte Abnormalities: 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 (= 20%) adverse reactions are infusion related reactions, edema, nausea, fatigue, headache, pyrexia, constipation, anemia, and diarrhea.

 Most common (= 50%) laboratory abnormalities are creatinine increased, ALT increased, hypoalbuminemia, AST increased, hypocalcemia, and hypophosphatemia.

PATIENT COUNSELING INFORMATION-

 Advise the patient to read the FDA-approved patient labeling (Medication Guide).

 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.

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.

Decreased Renal Function-                                                                                               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.

Infusion Related Reactions Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion related reactions [see Warnings and Precautions 

 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 

 Distributed by: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850                    Manufactured by: AstraZeneca AB, Södertälje, Sweden SE-151 85 U.S. License No. 2059       LUMOXITI is a trademark of the AstraZeneca

CLINICAL PHARMACOLOGY-

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.

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.

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.

 Distribution-                                                                                                                       The population PK model estimated mean volume of distribution of moxetumomab pasudotox-tdfk was 6.5 L (SD 2.4).

 Elimination-                                                                                                                       The mean elimination half-life of moxetumomab pasudotox-tdfk was 1.4 hours (range: 0.8 to 1.8; SD: 0.35).

The population PK model estimated mean systemic clearance of moxetumomab pasudotox-tdfk after the first dose of the first cycle was 25 L/hour (SD: 29.0) and after subsequent dosing was 4 L/hour (SD: 4.4).

Metabolism-                                                                                                                       The metabolic pathway of moxetumomab pasudotox-tdfk in humans is unknown, however, other protein therapeutics generally undergo proteolytic degradation into small peptides and amino acids via catabolic pathways.

Specific Populations-                                                                                                    No clinically significant differences in the pharmacokinetics of moxetumomab pasudotox-tdfk were observed for age (36 to 84 years), sex, race (White and non-White), body weight (42 to 152 kg), mild hepatic impairment (total bilirubin = upper limit of normal [ULN] and AST > ULN, or total bilirubin > 1 to 1.5 times ULN and any AST), mild renal impairment (CLcr 60-89 mL/min; n=40), or moderate renal impairment (CLcr 30-59 mL/min; n=4) based on population PK analysis.

The pharmacokinetics of moxetumomab pasudotox-tdfk in patients with moderate to severe hepatic impairment (total bilirubin > 1.5 ULN) or severe renal impairment (CrCl = 29 mL/min) is unknown.

Anti-Product Antibody Formation-                                                                                   Affecting PK In patients who were ADA-positive with high titers, the presence of ADA post-baseline was associated with statistically significant (p < 0.05) lower PK exposure (Cmax) at later cycles (Cycle 3 and beyond).

USE IN SPECIFIC POPULATIONS- 

 1. Pregnancy 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.    

 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.

2. Lactation 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.

3. Females and Males of Reproductive Potential-                                                           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.

4 Pediatric Use-                                                                                                                 Safety and effectiveness have not been established in pediatric patients.

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.