PLERIXAFOR

Plerixafor injection 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. 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- tetraazacyclo-tetradecane. 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 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. structure

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)

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/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.

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)

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. (6) To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 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 in conjunction with filgrastim regardless of causality and more frequent with plerixafor than placebo during HSC mobilization and apheresis were diarrhea, nausea, fatigue, injection site reactions, headache, arthralgia, dizziness, and vomiting. Safety data for plerixafor 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 at daily doses of 0.24 mg/kg SC. Median exposure to plerixafor 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 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 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 regardless of causality and were more frequent with plerixafor 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 and More Frequent than Placebo during HSC Mobilization and Apheresis Percent of Patients (%) Plerixafor 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. 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 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 supplemental oxygen) or resolved spontaneously. Vasovagal reactions, orthostatic hypotension, and/or syncope can occur following subcutaneous injections. In plerixafor oncology and healthy volunteer clinical studies, less than 1% of subjects experienced vasovagal reactions following subcutaneous administration of plerixafor doses ≤ 0.24 mg/kg. The majority of these events occurred within 1 hour of plerixafor administration. Because of the potential for these reactions, appropriate precautions should be taken. Other adverse reactions in the randomized studies that occurred in < 5% of patients but were reported as related to plerixafor during HSC mobilization and apheresis included abdominal pain, hyperhidrosis, abdominal distention, dry mouth, erythema, stomach discomfort, malaise, hypoesthesia oral, constipation, dyspepsia, and musculoskeletal pain. Hyperleukocytosis: In clinical trials, white blood cell counts of 100,000/mcL or greater were observed, on the day prior to or any day of apheresis, in 7% of patients receiving plerixafor and in 1% of patients receiving placebo. No complications or clinical symptoms of leukostasis were observed. 6.2 Post-marketing Experience In addition to adverse reactions reported from clinical trials, the following adverse reactions have been reported from post-marketing experience with plerixafor. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System: Splenomegaly and splenic rupture Immune System Disorders: Anaphylactic reactions, including anaphylactic shock Psychiatric Disorders: Abnormal dreams and nightmares