BRIEF SUMMARY

MOTIXAFORMIDE- (Aug 2023)

Indn-   use with Filgrastim (G- CSF) to mobilize homotopoietic stem cells to the peripheral  blood collection and subsequent autologous  transplantation in patients with multiple  myloma    

Comp-  For Injection: 62 mg as a lyophilized powder in a single-dose vial for reconstitution.  • Recommended dosage is 1.25 mg/kg actual body weight by subcutaneous injection 10 to 14 hours prior to initiation of apheresis.

ADR-  Most common adverse reactions (incidence >20%) are injection site reactions, injection site pain, injection site erythema, injection site pruritus, pruritus, flushing, and back pain.

CI-   History of serious hypersensitivity reaction to APHEXDA.

WARNINGS-

 • Anaphylactic Shock and Hypersensitivity Reactions: Premedicate all patients with a combination of an H1-antihistamine, an H2 blocker, and a leukotriene inhibitor prior to each  dose

Pat Inform-

Advise patients of the risk of anaphylactic and hypersensitivity reactions (such as pruritus, flushing, urticaria, rash, vomiting, nausea and chills) during and after  injection and to immediately report such signs and symptoms to healthcare professionals

• Advise patients that it may cause injection site reactions, such as pain, redness, and swelling

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U.S.  APPROVED DRUGS DURING 2023                                        

Serial No 36

Name-                      APHEXDA

Acive  Ingredient -  Motixafortide

Pharmacological clssificiation-        To  use with Filgrastim (G- CSF) to mobilize                                                                    hemotopoietic stem cells to the peripheral                                                                      blood collection and subsequent autologous                                                               transplantation in patients with multiple                                                                         myloma                                                                                         

Date of Approval                               9/18/23  

HIGHLIGHTS OF PRESCRIBING INFORMATION-

These highlights do not include all the information needed to u                                    APHEXDA safely and effectively.

See full prescribing information for APHEXDA. APHEXDATM (motixafortide) for injection, for subcutaneous use

Initial U.S. Approval: 2023

INDICATIONS AND USAGE

 APHEXDA, a hematopoietic stem cell mobilizer, is indicated in combination with filgrastim (G-CSF) to mobilize hematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation in patients with multiple myeloma.

DOSAGE AND ADMINISTRATION-

 • Initiate APHEXDA treatment after filgrastim has been administered daily for 4 days.

 • Recommended dosage is 1.25 mg/kg actual body weight by subcutaneous injection 10 to 14 hours prior to initiation of apheresis.

 • A second dose of APHEXDA can be administered 10 to 14 hours prior to a third apheresis.

 • See Full Prescribing Information for instructions on preparation and administration.

ADVERSE REACTIONS-

 Most common adverse reactions (incidence >20%) are injection site reactions, injection site pain, injection site erythema, injection site pruritus, pruritus, flushing, and back pain.

CONTRAINDICATIONS-

 History of serious hypersensitivity reaction to APHEXDA.

WARNINGS AND PRECAUTIONS-

 • Anaphylactic Shock and Hypersensitivity Reactions: Premedicate all patients with a combination of an H1-antihistamine, an H2 blocker, and a leukotriene inhibitor prior to each APHEXDA dose

Administer APHEXDA in a setting where personnel and therapies are available for immediate treatment. Observe for signs and symptoms and manage promptly.

 • Injection Site Reactions: The addition of analgesic premedication (e.g., acetaminophen) is recommended.

 • Tumor Cell Mobilization in Patients with Leukemia: APHEXDA may mobilize leukemic cells and should not be used in leukemia patients.

 • Leukocytosis: Increased circulating leukocytes have been observed. Monitor white blood cell counts during APHEXDA use.

 • Potential for Tumor Cell Mobilization: Tumor cells may be released from marrow during HSC mobilization with APHEXDA and filgrastim. Effect of reinfusion of tumor cells is unknown.

 • Embryo-fetal Toxicity: Can cause fetal harm. Advise women of reproductive potential of the potential risk to a fetus and to use effective contraception. -

DOSAGE AND ADMINISTRATION-

 • Initiate APHEXDA treatment after filgrastim has been administered daily for 4 days.       • Recommended dosage is 1.25 mg/kg actual body weight by subcutaneous injection 10 to 14 hours prior to initiation of apheresis.                                                                            • A second dose of APHEXDA can be administered 10 to 14 hours prior to a third apheresis.

DOSAGE FORMS AND STRENGTH

 For Injection: 62 mg as a lyophilized powder in a single-dose vial for reconstitution.-

 PATIENT COUNSELING INFORMATION

• Advise patients of the risk of anaphylactic and hypersensitivity reactions (such as pruritus, flushing, urticaria, rash, vomiting, nausea and chills) during and after APHEXDA injection and to immediately report such signs and symptoms to healthcare professionals

• Advise patients that APHEXDA may cause injection site reactions, such as pain, redness, and swelling

• Advise females of reproductive potential to use effective contraceptive methods during APHEXDA treatment and for 8 days after the administration of APHEXDA

• Advise females of reproductive potential of the potential risk to a fetus. Advise females to contact their healthcare provider if they become pregnant or if pregnancy is suspected during treatment with APHEXDA

• Advise women that breastfeeding is not recommended during treatment with APHEXDA and for 8 days following the last dose [

. Manufactured for: BioLineRx Ltd TM Modi’in, Israel Distributed by: BioLineRx USA Inc TM 77 Fourth Avenue Waltham, MA 024

 CLINICAL PHARMACOLOGY-

1. Mechanism of Action

Motixafortide is an inhibitor of the C-X-C Motif Chemokine Receptor 4 (CXCR4) and blocks the binding of its cognate ligand, stromal-derived factor-1a (SDF-1a)/C-X-C Motif Chemokine Ligand 

2. Pharmacodynamics-

In vitro studies showed that the concentration for half-maximal inhibition (IC50) of motixafortide towards CXCR4 ranges from 0.42 – 4.5 nM, the binding affinity (KD) is 7.9 pM and the dissociation rate (Kd) from the CXCR4 receptor is 3.38e-5 s-1 with receptor occupancy maintained over >72 hours.

.3 Pharmacokinetics-

The pharmacokinetics of motixafortide were evaluated using both noncompartmental and population PK approaches in various populations, including healthy volunteers, patients with acute myeloid leukemia, and patients with multiple myeloma.

Absorption-

After subcutaneous injection as either a single or repeated dose at 0.24 to 2 mg/kg, motixafortide appeared in plasma with time to maximum concentration occurring at approximately 0.25 to 1.17 hours.

Distribution-

Motixafortide is highly bound to human plasma proteins (>99%). The estimated volume of distribution of the central compartment in a typical subject is 27 L. 5

Metabolism-

Motixafortide undergoes non-specific degradation into small peptides and individual amino acids and their derivatives by catabolic pathways. Catabolism can occur in both blood and liver microsomes. In in vitro studies using human and animal biomaterials, no prominent unique human metabolites were identified.

Elimination-

 Motixafortide has an effective half-life in human plasma of approximately 2 hours. The elimination kinetics were similar in healthy subjects and patients with multiple myeloma. Apparent total clearance of motixafortide for a typical subject is 46.5 L/h. No mass balance studies were conducted in humans.

Specific Populations -

Renal Impairment -                                                                                                         Based on the population PK analysis, in patients with mildly to moderately decreased renal function, the pharmacokinetic profile of motixafortide was not significantly affected. While the effect of severe renal impairment on the clearance of motixafortide has not been evaluated, a significant effect is not anticipated.

Hepatic Impairment-                                                                                                   Motixafortide is catabolized in both the liver and blood, and animal data suggest that the main excretion pathway of its metabolites is via the kidneys and biliary excretion is minimal.

Drug Interaction Studies-

In vitro studies showed a lack of significant (>25%) cytochrome P450 (CYP) inhibition in human hepatocytes, a lack of CYP induction potential in human hepatocytes, and a low potential for transporter-mediated interactions.

 USE IN SPECIFIC POPULATIONS

.1 Pregnancy 6 Reference ID: 5240885 Risk Summary Based on its mechanism of action, APHEXDA can cause fetal harm when administered to a pregnant woman 

The background risk of major birth defects and miscarriages for the indicated population is unknown.

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

2. Lactation Risk Summary -

There are no data on the presence of motixafortide in human milk, the effects on the breastfed child, or the effects on milk production.

Because of the potential serious adverse reactions in the breastfed child, advise females that breastfeeding is not recommended during the treatment with APHEXDA treatment and for 8 days after the final dose.

3. Females and Males of Reproductive Potential

Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating APHEXDA.

Contraception-

Females APHEXDA can cause fetal harm when administered to pregnant women 

Advise females of reproductive potential to use effective 7 Reference ID: 5240885 contraception during treatment with APHEXDA and for 8 days after the final dose

.

4. Pediatric Use -

The safety and effectiveness of APHEXDA have not been established in pediatric patients.

5. Geriatric Use

Of the total number of patients in the GENESIS study, 33.8% were =65 years old, while 1.25% were =75 years old in the APHEXDA arm. No overall differences in safety or effectiveness were observed between these patients and younger patients.