Drug Interaction Studies

No drug-drug interaction studies have been conducted with ELZONRIS.

BRIEF SUMMARY

TAGRAXOFUSP-erzs- (Dec 2018)

Indn-        To treat  blastic plasmacytoid dendritis cell neoplasm (EPDCN)                                     

Comp-        Injection: 1,000 mcg in 1 mL in a single-dose vial.      Administer ntravenously at 12 mcg/kg over 15 minutes once daily on days 1 to 5 of a 21-day cycle. 

ADR-       Most common adverse reactions (incidence = 30%) are capillary leak syndrome, nausea, fatigue, peripheral edema, pyrexia and weight increase. Most common laboratory abnormalities (incidence = 50%) are decreases in albumin, platelets, hemoglobin,calcium, and sodium, and increases in glucose, ALT and AST. 

CI-        None.

WARNINGS-

 Hypersensitivity: Monitor patients for signs/symptoms and treat appropriately. 

 Hepatotoxicity: Monitor ALT and AST. Interrupt if the transaminases rise to greater than 5 times the upper limit of normal.

Pat Infm-

Capillary Leak Syndrome-                                                                                             Advise patients of the risk of capillary leak syndrome (CLS), and to contact their health care professional for signs and symptoms associated with CLS including new or worsening edema, weight gain, shortness of breath, and/or hypotension after infusion.   

 Advise patients to weigh themselves daily 

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U.S. FDA APPROVED  DRUGS DURING 2018

Sr.No-  58

ADVERSE REACTIONS

 Most common adverse reactions (incidence = 30%) are capillary leak syndrome, nausea, fatigue, peripheral edema, pyrexia and weight increase. Most common laboratory abnormalities (incidence = 50%) are decreases in albumin, platelets, hemoglobin,calcium, and sodium, and increases in glucose, ALT and AST. 

CONTRAINDICATIONS                                                                                               None.

WARNINGS AND PRECAUTIONS

 Hypersensitivity: Monitor patients for signs/symptoms and treat appropriately. 

 Hepatotoxicity: Monitor ALT and AST. Interrupt ELZONRIS if the transaminases rise to greater than 5 times the upper limit of normal.

 PATIENT COUNSELING INFORMATION

Capillary Leak Syndrome

Advise patients of the risk of capillary leak syndrome (CLS), and to contact their health care professional for signs and symptoms associated with CLS including new or worsening edema, weight gain, shortness of breath, and/or hypotension after infusion.

Advise patients to weigh themselves daily 

Hypersensitivity

Advise patients of the risk of hypersensitivity reactions, and to contact their healthcare professional for signs and symptoms associated with hypersensitivity reactions including rash, flushing, wheezing and swelling of the face

Hepatic Toxicity

Advise patients to report symptoms that may indicate elevated liver enzymes including fatigue, anorexia and/or right upper abdominal discomfort 

Contraception

Advise females to avoid pregnancy and to use acceptable contraceptive methods during ELZONRIS treatment and for at least 1 week after the last dose of ELZONRIS.

Lactation

Advise women not to breastfeed 

Manufactured and Distributed by: Stemline Therapeutics, Inc. New York, NY 10022 US License No. 2088

 CLINICAL PHARMACOLOGY

1. Mechanism of Action

Tagraxofusp-erzs is a CD123-directed cytotoxin composed of recombinant human interleukin-3 (IL-3) and truncated diphtheria toxin (DT) fusion protein that inhibits protein synthesis and causes cell death in CD123- expressing cells.

2. Pharmacokinetics

Following administration of tagraxofusp-erzs 12 mcg/kg via 15-minute infusion in patients with BPDCN, the mean (SD) area under the plasma drug concentration over time curve (AUC) was 231 (123) hr·mcg/L and maximum plasma concentration (Cmax) was 162 (58.1) mcg/L.

Distribution

Mean (SD) volume of distribution of tagraxofusp-erzs is 5.1 (1.9) L in patients with BPDCN.

Elimination

Mean (SD) clearance is 7.1 (7.2) L/hr in patients with BPDCN. Mean (SD) terminal half-life of tagraxofusperzs is 0.7 (0.3) hours. 

Anti-Product Antibody Formation Affecting Pharmacokinetics

Pharmacokinetic data obtained following doses given in Cycle 3 showed increased titers of anti-drug antibodies and reduced free ELZONRIS concentration in most plasma samples.

Following administration of tagraxofusperzs 12 mcg/kg via 15-minute infusion in patients with pre-existing anti-drug antibodies, the mean (SD) volume of distribution of tagraxofusp-erzs is 21.2 (25.4) L, clearance is 13.9 (19.4) L/hr, AUC is 151 (89.2) hr·mcg/L and Cmax is 80.0 (82.2) mcg/L.

Specific Populations

No clinically significant differences in the pharmacokinetics of tagraxofusp-erzs were observed based on age (22 to 84 years), sex, mild to moderate renal impairment (eGFR 30 to 89 mL/min/1.73 m2 , estimated by MDRD), mild (total bilirubin = ULN and AST >ULN, or total bilirubin 1 to 1.5 times ULN and any AST) or moderate (total bilirubin >1.5 to 3 times ULN and any AST) hepatic impairment or body weight after adjusting dose by body weight.

The effect of severe renal impairment (eGFR 15 to 29 mL/min/1.73 m2 ), or severe hepatic impairment (total bilirubin >3 times ULN and any AST) on tagraxofusp-erzs pharmacokinetics is unknown.

Drug Interaction Studies No drug-drug interaction studies have been conducted with ELZONRIS.

USE IN SPECIFIC POPULATIONS

1 Pregnancy Risk Summary

Based on its mechanism of action, ELZONRIS has the potential for adverse effects on embryo-fetal development 

There are no available data on ELZONRIS use in pregnant women to inform a drug-associated risk of adverse developmental outcomes.

Animal reproduction or developmental toxicity studies have not been conducted with tagraxofusp-erzs. Advise pregnant women of the potential risk to the fetus.

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

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

2.Lactation Risk Summary

No data are available regarding the presence of ELZONRIS in human milk, the effects on the breastfed child, or the effects on milk production.

Because of the potential for serious adverse reactions in breastfed children from ELZONRIS, breast feeding is not recommended during treatment and for 1 week after the last dose.

3. Females and Males of Reproductive Potential

Based on its mechanism of action, ELZONRIS may cause fetal harm when administered to a pregnant woman 

Pregnancy Testing: Conduct pregnancy testing in females of reproductive potential within 7 days prior to initiating ELZONRIS treatment.

Contraception: Advise females to use acceptable contraceptive methods during ELZONRIS treatment and for at least 1 week after the last dose of ELZONRIS.

4. Pediatric Use

The safety and effectiveness of ELZONRIS for treatment of BPDCN have been established in pediatric patients 2 years of age and older (no data for pediatric patients less than 2 years of age).

Use of ELZONRIS in these age groups is supported by evidence from an adequate and well-controlled study of ELZONRIS in adults with BPDCN and additional safety data from three pediatric patients with BPDCN, including 1 child (2 years to < 12 years old) and 2 adolescents (12 years to < 17 years old), treated with ELZONRIS at the recommended dosage.

The safety profile of ELZONRIS in the pediatric patients was similar to that seen in the adults. Efficacy for pediatric patients is extrapolated from the results of STML-401-0114 

5 Geriatric Use-

 Of the 94 patients who received ELZONRIS at the labeled dose in STML-401-0114, 23% were 75 years and older. The older patients experienced a higher incidence of altered mental status (including confusional state, delirium, mental status changes, dementia, and encephalopathy) than younger patients.