Plerixafor

1 INDICATIONS AND USAGE Plerixafor injection is indicated in combination with filgrastim to mobilize hematopoietic stem cells (HSCs) to the peripheral blood for collection and subsequent autologous transplantation in patients with non-Hodgkin’s lymphoma (NHL) or multiple myeloma (MM). Plerixafor injection, a hematopoietic stem cell mobilizer, is indicated in combination with filgrastim to mobilize hematopoietic stem cells (HSCs) to the peripheral blood for collection and subsequent autologous transplantation in patients with non-Hodgkin’s lymphoma or multiple myeloma. ( 1 )

2 DOSAGE AND ADMINISTRATION Initiate Plerixafor Injection treatment after the patient has received filgrastim once daily for 4 days. ( 2.1 ) Repeat Plerixafor Injection dose up to 4 consecutive days. ( 2.1 ) Dose based on patient weight Less than or equal to 83 kg: 20 mg dose or select dose based on 0.24 mg/kg actual body weight. ( 2.1 ) Greater than 83 kg: select dose based on 0.24 mg/kg actual body weight. ( 2.1 ) Administer by subcutaneous injection approximately 11 hours prior to initiation of apheresis. ( 2.1 ) Renal impairment: If creatinine clearance is ≤50 mL/min, decrease dose by one-third to 0.16 mg/kg. ( 2.3 ) 2.1 Recommended Dosage and Administration Begin treatment with Plerixafor Injection after the patient has received filgrastim once daily for 4 days [see Dosage and Administration ( 2.2 )]. Administer Plerixafor Injection approximately 11 hours prior to initiation of each apheresis for up to 4 consecutive days. The recommended dose of Plerixafor Injection by subcutaneous injection is based on body weight: 20 mg fixed dose or 0.24 mg/kg of body weight for patients weighing less than or equal to 83 kg. [see Clinical Pharmacology ( 12.3 )] 0.24 mg/kg of body weight for patients weighing greater than 83 kg Use the patient's actual body weight to calculate the volume of Plerixafor Injection to be administered. Each vial delivers 1.2 mL of 20 mg per mL solution, and the volume to be administered to patients should be calculated from the following equation: 0.012 × patient's actual body weight (in kg) = volume to be administered (in mL) In clinical studies, Plerixafor Injection dose has been calculated based on actual body weight in patients up to 175% of ideal body weight. Plerixafor Injection dose and treatment of patients weighing more than 175% of ideal body weight have not been investigated. Based on increasing exposure with increasing body weight, the Plerixafor Injection dose should not exceed 40 mg/day [see Clinical Pharmacology ( 12.3 )]. Vials should be inspected visually for particulate matter and discoloration prior to administration and should not be used if there is particulate matter or if the solution is discolored. Discard unused portion. 2.2 Recommended Concomitant Medications Administer daily morning doses of filgrastim 10 mcg/kg for 4 days prior to the first evening dose of Plerixafor Injection and on each day prior to apheresis [see Clinical Studies ( 14 )]. 2.3 Dose Modifications in Renal Impairment In patients with moderate and severe renal impairment (estimated creatinine clearance (CL CR ) less than or equal to 50 mL/min), reduce the dose of Plerixafor Injection by one-third based on body weight category as shown in Table 1 . If CL CR is less than or equal to 50 mL/min the dose should not exceed 27 mg/day, as the mg/kg based dosage results in increased plerixafor exposure with increasing body weight [see Clinical Pharmacology ( 12.3 )]. Similar systemic exposure is predicted if the dose is reduced by one-third in patients with moderate and severe renal impairment compared with subjects with normal renal function [see Clinical Pharmacology ( 12.3 )]. Table 1: Recommended Dosage of Plerixafor Injection in Patients with Renal Impairment Estimated Creatinine Clearance (mL/min) Dose Body Weight less than or equal to 83 kg Body Weight greater than 83 kg and less than 160 kg greater than 50 20 mg or 0.24 mg/kg once daily 0.24 mg/kg once daily (not to exceed 40 mg/day) less than or equal to 50 13 mg or 0.16 mg/kg once daily 0.16 mg/kg once daily (not to exceed 27 mg/day) The following (Cockcroft-Gault) formula may be used to estimate CL CR : Males: Creatinine clearance (mL/min) = weight (kg) × (140 – age in years) 72 × serum creatinine (mg/dL) Females: Creatinine clearance (mL/min) = 0.85 × value calculated for males There is insufficient information to make dosage recommendations in patients on hemodialysis.

2.1 Recommended Dosage and Administration Begin treatment with Plerixafor Injection after th …

3 DOSAGE FORMS AND STRENGTHS Injection: 24 mg per 1.2 mL (20 mg per mL) sterile, clear, colorless to pale-yellow solution in a single-dose vial. Injection: 24 mg per 1.2 mL (20 mg per mL) in a single-dose vial. ( 3 )

4 CONTRAINDICATIONS Plerixafor Injection is contraindicated in patients with a history of hypersensitivity to plerixafor [see Warnings and Precautions ( 5.1 )] . Anaphylactic shock has occurred with use of Plerixafor Injection. History of hypersensitivity to Plerixafor Injection. ( 4 )

6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed elsewhere in the labeling: • Anaphylactic shock and hypersensitivity reactions [see Warnings and Precautions ( 5.1 )] • Potential for tumor cell mobilization in leukemia patients [see Warnings and Precautions ( 5.2 )] • Increased circulating leukocytes and decreased platelet counts [see Warnings and Precautions ( 5.3 )] • Potential for tumor cell mobilization [see Warnings and Precautions ( 5.4 )] • splenic enlargement [see Warnings and Precautions ( 5.5 )] Most common adverse reactions (≥ 10%): diarrhea, nausea, fatigue, injection site reactions, headache, arthralgia, dizziness, and vomiting. To report SUSPECTED ADVERSE REACTIONS, contact Gland Pharma at 864-879-9994 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 most common adverse reactions (≥ 10%) reported in patients who received Plerixafor Injection in conjunction with filgrastim regardless of causality and more frequent with Plerixafor Injection than placebo during HSC mobilization and apheresis were diarrhea, nausea, fatigue, injection site reactions, headache, arthralgia, dizziness, and vomiting. Safety data for Plerixafor Injection in combination with filgrastim were obtained from two randomized placebo-controlled studies (301 patients) and 10 uncontrolled studies (242 patients). Patients were primarily treated with Plerixafor Injection at daily doses of 0.24 mg/kg SC. Median exposure to Plerixafor Injection in these studies was 2 days (range 1 to 7 days). In the two randomized studies in patients with NHL and MM, a total of 301 patients were treated in the Plerixafor Injection and filgrastim group and 292 patients were treated in the placebo and filgrastim group. Patients received daily morning doses of filgrastim 10 mcg/kg for 4 days prior to the first dose of Plerixafor Injection 0.24 mg/kg SC or placebo and on each morning prior to apheresis. The adverse reactions that occurred in ≥ 5% of the patients who received Plerixafor Injection regardless of causality and were more frequent with Plerixafor Injection than placebo during HSC mobilization and apheresis are shown in Table 2. Table 2: Adverse Reactions in ≥ 5% of Non-Hodgkin’s Lymphoma and Multiple Myeloma Patients Receiving Plerixafor Injection and More Frequent than Placebo during HSC Mobilization and Apheresis Percent of Patients (%) Plerixafor Injection and Filgrastim (n = 301) Placebo and Filgrastim (n = 292) All Grades a Grade 3 Grade 4 All Grades Grade 3 Grade 4 Gastrointestinal disorders Diarrhea 37 < 1 0 17 0 0 Nausea 34 1 0 22 0 0 Vomiting 10 < 1 0 6 0 0 Flatulence 7 0 0 3 0 0 General disorders and administration site conditions Injection site reactions 34 0 0 10 0 0 Fatigue 27 0 0 25 0 0 Musculoskeletal and connective tissue disorders Arthralgia 13 0 0 12 0 0 Nervous system disorders Headache 22 < 1 0 21 1 0 Dizziness 11 0 0 6 0 0 Psychiatric disorders Insomnia 7 0 0 5 0 0 a Grades based on criteria from the World Health Organization (WHO) In the randomized studies, 34% of patients with NHL or MM had mild to moderate injection site reactions at the site of subcutaneous administration of Plerixafor Injection. These included erythema, hematoma, hemorrhage, induration, inflammation, irritation, pain, paresthesia, pruritus, rash, swelling, and urticaria. Mild to moderate allergic reactions were observed in less than 1% of patients within approximately 30 min after Plerixafor Injection administration, including one or more of the following: urticaria (n = 2), periorbital swelling (n = 2), dyspnea (n = 1) or hypoxia (n = 1). Symptoms generally responded to treatments (e.g., antihistamines, corticosteroids, hydration or supp …

8 USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed. ( 8.2 ) 8.1 Pregnancy Risk Summary Limited available data with Plerixafor Injection use in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes. In animal reproduction studies, subcutaneous administration of plerixafor to pregnant rats during organogenesis at doses 10 times the maximum recommended human doses resulted in embryo-fetal mortality, structural abnormalities, and alterations to growth [see Data ] . Advise pregnant women of the potential risk to the fetus. Advise women of reproductive potential to avoid becoming pregnant while receiving treatment with Plerixafor Injection [see Warnings and Precautions ( 5.6 )] . 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. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The background risk of major birth defects and miscarriages for the indicated population is unknown. Data Animal Data Plerixafor administered to pregnant rats induced embryo-fetal toxicity, including fetal death, increased resorptions and postimplantation loss, decreased fetal weights, anophthalmia, shortened digits, cardiac interventricular septal defect, ringed aorta, globular heart, hydrocephaly, dilatation of olfactory ventricles, and retarded skeletal development. Embryo-fetal toxicities occurred mainly at a dose of 90 mg/m 2 (approximately 10 times the recommended human dose of 0.24 mg/kg when compared on a mg/m 2 basis). 8.2 Lactation Risk Summary There are no data on the presence of plerixafor in human milk, the effect on the breastfed child, or the effect on milk production. Because of the potential serious adverse reactions in the breastfed child, advise females that breastfeeding is not recommended during treatment with Plerixafor Injection and for one week after the final dose. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating Plerixafor Injection [see Use in Specific Populations ( 8.1 )] . Contraception Females Plerixafor Injection can cause embryo-fetal harm when administered to pregnant women [see Use in Specific Populations ( 8.1 )] . Advise females of reproductive potential to use effective contraception during treatment with Plerixafor Injection and for one week after the final dose. Males Males treated with Plerixafor Injection should use effective contraception during treatment and for one week after cessation of treatment. 8.4 Pediatric Use The safety and effectiveness of Plerixafor Injection have not been established in pediatric patients. Effectiveness was not demonstrated in a single phase 1/2 randomized, open-label, comparative study of Plerixafor Injection plus standard regimens for mobilization of hematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation. Forty-five pediatric patients ages 1 to <17 years with solid tumors or lymphoma were randomized 2:1 to Plerixafor Injection in addition to standard mobilization regimens (N=30) or standard mobilization regimens alone (N=15) (comparator arm). No new safety signals were observed in pediatric patients in this trial. The day prior to the first apheresis, median peripheral blood CD34+ counts were 35 × 10 6 cells/L in the comparator arm and 15 × 10 6 cells/L in the Plerixafor Injection arm. On the day of the first apheresis, median peripheral blood CD34+ counts were 64 × 10 6 cells/L in the comparator arm and 77 × 10 6 cells/L in the Plerixafor Injection arm. Plerixafor exposure, shown as AUC, in pediatric patients aged 12 to 18 years was within the range of values previously observed in adults, while the AUC of plerixafor in pediatric patients aged 2 to 12 years was 67% to 87% of that observed in adults, given the same …

12.1 Mechanism of Action Plerixafor is an inhibitor of the CXCR4 chemokine receptor and blocks binding of its cognate ligand, stromal cell-derived factor-1α (SDF-1α). SDF-1α and CXCR4 are recognized to play a role in the trafficking and homing of human hematopoietic stem cells (HSCs) to the marrow compartment. Once in the marrow, stem cell CXCR4 can act to help anchor these cells to the marrow matrix, either directly via SDF-1α or through the induction of other adhesion molecules. Treatment with plerixafor resulted in leukocytosis and elevations in circulating hematopoietic progenitor cells in mice, dogs and humans. CD34+ cells mobilized by plerixafor were capable of engraftment with long-term repopulating capacity up to one year in canine transplantation models.

11 DESCRIPTION Plerixafor injection, USP is a sterile, preservative-free, clear, colorless to pale-yellow, isotonic solution for subcutaneous injection. Each mL of the sterile solution contains 20 mg of plerixafor, USP. Each single-dose vial is filled to deliver 1.2 mL of the sterile solution that contains 24 mg of plerixafor and 5.9 mg of sodium chloride in Water for Injection adjusted to a pH of 6.0 to 7.5 with hydrochloric acid and with sodium hydroxide, if required. Plerixafor is a hematopoietic stem cell mobilizer with a chemical name 1,1’-[1,4-phenylenebis(methylene)]-bis-1,4,8,11-tetraaza cyclotetradecane. It has the molecular formula C 28 H 54 N 8 . The molecular weight of plerixafor is 502.79 g/mol. The structural formula is provided in Figure 1. Figure 1: Structural Formula Plerixafor, USP is a white to off-white crystalline solid. It is hygroscopic. Plerixafor has a typical melting point of 131.5°C. The partition coefficient of plerixafor between 1-octanol and pH 7 aqueous buffer is <0.1. plerixaforinjstructure

10 OVERDOSAGE Based on limited data at doses above the recommended dose of 0.24 mg/kg SC, the frequency of gastrointestinal disorders, vasovagal reactions, orthostatic hypotension, and/or syncope may be higher.

16 HOW SUPPLIED/STORAGE AND HANDLING Plerixafor Injection is a sterile, preservative-free, clear, colorless to pale-yellow solution supplied in a 2 mL clear glass vial as follows: NDC Plerixafor Injection (20 mg per mL) Package Factor 25021-416-01 24 mg per 1.2 mL Single-Dose Vial 1 vial per carton Storage Conditions Store at 20o to 25oC (68o to 77oF). [See USP Controlled Room Temperature.] Discard unused portion. Sterile, Nonpyrogenic, Preservative-free. The container closure is not made with natural rubber latex.