Motixafortide

APHEXDA for injection contains motixafortide, which is a hematopoietic stem cell mobilizer. The chemical name of the synthetic motixafortide acetate, the active pharmaceutical ingredient is N-(4-Fluoro-benzoyl)-L-arginyl-L-arginyl-[L-3-naphthyl)alanyl]-L-cysteinyl-L-tyrosyl 5 -L-citrullinyl-L-lysyl-D-lysyl-L-prolyl-L-tyrosyl 10 -L‑arginyl-L-citrullinyl-L-cysteinyl-L-arginineamide, cyclic (4-13)-disulfide, acetate salt. Motixafortide acetate is a synthetic, cyclic peptide composed of a sequence of amino acids with the following structure: Cit: Citrulline Nal: Naphthylalanine Fba: 4-Florobenzoic acid Counter Ion: Acetate Molecular weight: 2159.6 g/mol (as the free base) APHEXDA is supplied as a sterile white to off-white, preservative-free lyophilized powder in single-dose vials. Each vial contains 73 mg of motixafortide (provided as motixafortide acetate) for reconstitution with 2 mL 0.45% saline, delivering 62 mg motixfortide per 1.7 mL. Motixafortide is present as a salt with 4 to 8.5 molar equivalents of acetate. The inactive ingredients include 26 mg of mannitol and hydrochloric acid for pH adjustment. Reconstitution with 2 mL of 0.45% sodium chloride for injection (or 1 mL water for injection + 1 mL 0.9% sodium chloride for injection) yields a clear solution of 36.5 mg/mL motixafortide, pH 5.8 to 7.5. sequence CITimage NALimage FBAimage

APHEXDA 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. 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. ( 1 )

APHEXDA (motixafortide) for injection is supplied as a white to off-white lyophilized powder in a single-dose vial for reconstitution. Each vial delivers 62 mg motixafortide free base. NDC 82737-073-01 (Carton containing one vial). Store at 2°C to 8°C (36°F to 46°F) in original carton to protect from light. Discard prepared reconstituted solution after 24 hours storage under refrigeration 2°C to 8°C (36°F to 46°F) or at room temperature 20°C to 25°C (68°F to 77°F) protected from light.

2 DOSING AND ADMINISTRATION Initiate APHEXDA treatment after filgrastim has been administered daily for 4 days. ( 2.1 ) Recommended dosage is 1.25 mg/kg actual body weight by subcutaneous injection 10 to 14 hours prior to initiation of apheresis. ( 2.2 ) A second dose of APHEXDA can be administered 10 to 14 hours prior to a third apheresis. ( 2.2 ) See Full Prescribing Information for instructions on preparation and administration. 2.1 Important Dosing Information ​Premedicate all patients before each dose of APHEXDA to reduce the risk of hypersensitivity and injection site reactions: Administer diphenhydramine (12.5 mg intravenously or 25 mg to 50 mg orally, or another H1-antihistamine), an H2 blocker (e.g., famotidine), and a leukotriene inhibitor (e.g., montelukast) approximately 30 to 60 minutes before injection of APHEXDA. The addition of an analgesic medication (e.g., acetaminophen) to the premedication regimen is recommended. Administer filgrastim 10 mcg/kg subcutaneously once daily for 4 days prior to the first dose of APHEXDA and on each day prior to each apheresis. 2.2 Recommended Dosage The recommended dosage of APHEXDA is 1.25 mg/kg administered via slow (approximately 2 minutes) subcutaneous injection 10 to 14 hours prior to the initiation of the first apheresis. Dosing is based on actual body weight. A second dose of APHEXDA can be administered 10 to 14 hours before a third apheresis, if necessary. 2.3 Preparation and Administration Use aseptic technique to prepare and administer APHEXDA: More than one vial may be needed for a full dose. Calculate the dose, the total volume of reconstituted APHEXDA solution required, and number of APHEXDA vials required based on patient’s actual body weight. Remove the APHEXDA vial(s) from the refrigerator and allow to reach room temperature at 20°C to 25°C (68°F to 77°F) for at least 30 minutes. Reconstitute each vial with 2 mL of 0.45% Sodium Chloride Injection, USP at room temperature (20°C to 25°C (68°F to 77°F)) resulting in a concentration of 36.5 mg/mL of APHEXDA and permitting withdrawal of up to 1.7 mL (62 mg). Alternatively, you can reconstitute each vial with 1 mL of Sterile Water for Injection, USP and 1 mL of 0.9% Sodium Chloride Injection, USP. Gently swirl and invert for up to 3 minutes slowly until completely dissolved. Inspect the reconstituted solution for discoloration and particulate matter. The reconstituted solution should appear clear and colorless. Do not use if the reconstituted solution is discolored, is cloudy, or contains visible particulates. If needed, store the reconstituted APHEXDA solution refrigerated at 2°C to 8°C (36°F to 46°F) or at room temperature at 20°C to 25°C (68°F to 77°F) for up to 24 hours protected from light. Withdraw the required injection volume of APHEXDA from the vial(s) into an appropriately sized syringe. Each injection volume should not exceed 2 mL. Divide doses requiring greater than 2 mL into multiple syringes to allow different injection sites. Administration Administer injection into the abdomen, the back or side of the upper arms, or the thighs. Rotate injection sites. An injection should never be given into scar tissue or areas that are reddened, inflamed, or swollen. If injecting into the abdomen, avoid a 5 cm diameter circle around the navel. If more than one injection is needed for a single dose of APHEXDA, the injection sites should be at least 2 cm apart from previous injection locations. Discard unused portion of the drug. Monitor patients for one hour after administration [see Warnings and Precautions ( 5.1 ) ].

APHEXDA is contraindicated in patients with a history of serious hypersensitivity reactions to motixafortide [see Warnings and Precautions (5.1) ] . History of serious hypersensitivity to APHEXDA. ( 4 )

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. ( 2.1 , 2.3 , 5.1 ) Injection Site Reactions: The addition of analgesic premedication (e.g., acetaminophen) is recommended. ( 5.2 ) Tumor Cell Mobilization in Patients with Leukemia: APHEXDA may mobilize leukemic cells and should not be used in leukemia patients. ( 5.3 ) Leukocytosis: Increased circulating leukocytes have been observed. Monitor white blood cell counts during APHEXDA use. ( 5.4 ) 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. ( 5.5 ) Embryo-fetal Toxicity: Can cause fetal harm. Advise women of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.6 , 8.1 , 8.3 ) 5.1 Anaphylactic Shock and Hypersensitivity Reactions Anaphylactic shock occurred in 0.7% of APHEXDA-treated patients in clinical studies (n=407). The time to anaphylactic shock was between 5 minutes and 30 minutes after drug administration. Hypersensitivity reactions occurred in 7.6% of APHEXDA-treated patients in the GENESIS study. In addition, pruritus, flushing, urticaria, rash, erythema, vomiting, nausea and chills have been reported. Premedicate all patients prior to each dose of APHEXDA 30-60 minutes prior to administration with a triple-drug premedication regimen that includes an H1-antihistamine, an H2 blocker, and a leukotriene inhibitor [see Dosage and Administration (2.1) ]. Patients receiving concomitant negative chronotropic drugs (e.g., beta blockers) may be more at risk for hypotension in case of hypersensitivity reaction. When appropriate, beta blockers should be replaced with non-chronotropic drugs. Administer APHEXDA only in a setting where personnel and therapies are immediately available for the treatment of anaphylaxis and other systemic reactions. Monitor patients for signs or symptoms of hypersensitivity reactions for one hour following administration of APHEXDA and manage reactions promptly. 5.2 Injection Site Reactions Injection site reactions were reported in 73% of patients receiving APHEXDA in the GENESIS trial. Symptoms of injection site reactions included pain, erythema, pruritus, bruising, discomfort, induration, mass, nodule, rash, swelling, and urticaria. Among 92 patients treated with APHEXDA, the highest severity of the reactions was severe in 9%. Premedicate with an analgesic medication (e.g., acetaminophen) prior to each APHEXDA dose. Use analgesic medication and local treatments postdose, as needed. 5.3 Tumor Cell Mobilization in Patients with Leukemia For the purpose of hematopoietic stem cell (HSC) mobilization, APHEXDA may cause mobilization of leukemic cells and subsequent contamination of the apheresis product. Therefore, APHEXDA is not intended for HSC mobilization and harvest in patients with leukemia. 5.4 Leukocytosis Administration of APHEXDA in conjunction with filgrastim increases circulating leukocytes as well as HSC populations. Monitor white blood cell counts during APHEXDA use. 5.5 Potential for Tumor Cell Mobilization When APHEXDA is used in combination with filgrastim for HSC mobilization, tumor cells may be released from the marrow and subsequently collected in the leukapheresis product. The effect of potential reinfusion of tumor cells has not been well-studied. 5.6 Embryo-fetal Toxicity Based on its mechanism of action, APHEXDA can cause fetal harm when administered to a pregnant woman. Animal models link dysfunction in CXCR4/SDF-1 signaling to adverse outcomes in mammalian embryo-fetal development and suggest risks to normal placental development. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with APHEXDA and for 8 days after the final dose [ see Use in Specific Populations (8.1, 8.3 ) ].

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 [see Warnings and Precautions (5.1) ] . Advise patients that APHEXDA may cause injection site reactions, such as pain, redness, and swelling [see Warnings and Precautions (5.2) , Adverse Reactions (6.1 , 6.2) ] . Advise females of reproductive potential to use effective contraceptive methods during APHEXDA treatment and for 8 days after the administration of APHEXDA [see Warnings and Precautions (5.6) , Use in Specific Populations (8.1 , 8.3) ] . 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 [see Warnings and Precautions (5.6) , Use in Specific Populations (8.1 , 8.3) ]. Advise women that breastfeeding is not recommended during treatment with APHEXDA and for 8 days following the last dose [see Use in Specific Populations (8.2) ] .

Carcinogenicity studies with motixafortide have not been conducted. Motixafortide was not genotoxic in an in vitro bacterial mutation assay (Ames test), in an in vitro chromosomal aberration test using V79 Chinese hamster cells, or in an in vivo bone marrow micronucleus test in mice after intravenous injection at doses up to 4 mg/kg (12 mg/m 2 ). Fertility studies have not been conducted with motixafortide. No histopathological evidence of toxicity to male or female reproductive organs was observed in 28-day repeat-dose toxicity studies in rats and dogs.

Risk Summary Based on its mechanism of action, APHEXDA can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] . There are no available data with APHEXDA use in pregnant women informing the risk of embryo-fetal toxicity. Animal models link dysfunction in CXCR4/SDF-1 signaling to adverse outcomes in mammalian embryo-fetal development and suggest risks to normal placental development (see Data ) . No animal studies have been conducted to evaluate the effect of motixafortide on reproduction and fetal development. Advise pregnant women of the potential risk to a fetus. 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%, respectively. Data Animal Data Animal reproduction studies have not been conducted with motixafortide to evaluate its effect on reproduction and embryo-fetal development. Disruption of CXCR4/SDF-1 signaling in mice and other models caused increased embryo-fetal lethality, and impairment of vascularization, cardiac anomalies, reduced hematopoiesis, impaired bone marrow myelopoiesis, disorganized neural layers in cerebellum, and reduced neural innervation of limbs. CXCR4/SDF-1 levels have been shown to play a key role in stimulating trophoblast proliferation and differentiation necessary for appropriate placental growth and function in humans.

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

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.

The following clinically significant adverse reactions are discussed in other sections of the labeling: Anaphylactic Shock and Hypersensitivity Reactions [see Warnings and Precautions (5.1) ] Injection Site Reactions [see Warnings and Precautions (5.2) ] Potential for Tumor Cell Mobilization in Patients in Leukemia [see Warnings and Precautions (5.3) ] Leukocytosis [see Warnings and Precautions (5.4) ] Potential for Tumor Cell Mobilization [see Warnings and Precautions (5.5) ] Most common adverse reactions (incidence >20%) are injection site reactions, injection site pain, injection site erythema, injection site pruritus, pruritus, flushing, and back pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact BioLineRx at 1-800-574-9978 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because 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 of APHEXDA was evaluated in the GENESIS study based on data from 92 patients with multiple myeloma who received at least one dose of APHEXDA 1.25 mg/kg subcutaneously and filgrastim and 42 patients who received placebo and filgrastim for mobilization of hematopoietic stem cells for collection and apheresis [see Clinical Studies (14) ]. The premedication regimen changed during the conduct of the trial as evidence of hypersensitivity reactions was noted. Of the 92 patients who received at least one dose of APHEXDA, 14 patients received the triple-drug premedication regimen and 78 did not receive the triple-drug premedication regimen (either received no premedication or another premedication regimen). Serious adverse reactions occurred in 5.4% of patients receiving APHEXDA in combination with filgrastim. Serious adverse reactions included vomiting, injection site reaction, hypersensitivity reaction, injection site cellulitis, hypokalemia and hypoxia. One patient did not receive the 5th dose of filgrastim due to an elevated white blood cell count following administration of APHEXDA. The most common adverse reactions occurring in GENESIS (>20% and at least 2% higher than the filgrastim + placebo arm) were injection site reactions (pain, erythema and pruritus), pruritus, flushing, and back pain. Table 1 summarizes the common adverse reactions in GENESIS. Table 1: Common Adverse Reactions in Patients with Multiple Myeloma During Hematopoietic Stem Cell Mobilization and Apheresis in GENESIS a APHEXDA and Filgrastim n=92 % Placebo and Filgrastim n=42 % Injection site reactions c All Grades a Grade > 3 b All Grades a Grade > 3 b Injection site reactions 73 8 5 0 Injection site pain 53 7 5 0 Injection site erythema 27 0 0 0 Injection site pruritus 24 0 0 0 Pruritus 38 11 0 0 Flushing d 33 7 0 0 Rash e 16 0 5 0 Urticaria 14 1.1 0 0 Erythema 12 0 0 0 Back pain f 21 0 17 0 Paresthesia g 19 0 17 0 Hypokalemia 15 4.3 12 0 Nausea 14 0 12 0 (a) Adverse reactions that occurred in ≥10% in APHEXDA-treated patients and ≥2% more than placebo-treated patients. (b) All reactions were grade 3. (c) Injection site reactions includes: injection site bruising, injection site discomfort, injection site erythema, injection site induration, injection site mass, injection site nodule, injection site pain, injection site pruritus, injection site rash, injection site swelling, injection site urticaria, injection site cellulitis and injection related reaction. (d) Flushing includes hot flush. (e) Rash includes: rash erythematous, rash maculo-papular, rash papular and rash pruritic. (f) Back pain includes spinal pain and sacral pain. (g) Paresthesia includes: paresthesia oral, hypoesthesia, hypoesthesia oral and burning sensation. Clinically relevant adverse reactions that occurred in the APHEXDA arm only in <10% of patients include dermatitis exfoliative generalized, ear swelling, pyrexia, chills, dizziness, tremor and hypertension.