Plerixafor

Plerixafor 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, 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 )

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

Plerixafor 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. History of hypersensitivity to plerixafor. ( 4 )

Anaphylactic Shock and Serious Hypersensitivity Reactions have occurred. Monitor patients during and after completion of plerixafor administration. ( 5.1 ) Tumor Cell Mobilization in Leukemia Patients: Plerixafor may mobilize leukemic cells and should not be used in leukemia patients. ( 5.2 ) Hematologic Effects: Increased circulating leukocytes and decreased platelet counts have been observed. Monitor blood cell counts and platelet counts during plerixafor use. ( 5.3 ) Potential for Tumor Cell Mobilization: Tumor cells may be released from marrow during HSC mobilization with plerixafor and filgrastim. Effect of reinfusion of tumor cells is unknown. ( 5.4 ) Splenic Rupture: Evaluate patients who report left upper abdominal and/or scapular or shoulder pain. ( 5.5 ) Embryo-Fetal Toxicity: Can cause fetal harm. Advise women not to become pregnant when taking plerixafor. ( 5.6 , 8.1 )

5.1 Anaphylactic Shock and Hypersensitivity Reactions Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening with clinically significant hypotension and shock have occurred in patients receiving plerixafor [see Adverse Reactions (6.2) ] . Observe patients for signs and symptoms of hypersensitivity during and after plerixafor administration for at least 30 minutes and until clinically stable following completion of each administration. Only administer Plerixafor when personnel and therapies are immediately available for the treatment of anaphylaxis and other hypersensitivity reactions. In clinical studies, mild or moderate allergic reactions occurred within approximately 30 minutes after plerixafor administration in less than 1% of patients [see Adverse Reactions (6.1) ] .

5.2 Tumor Cell Mobilization in Leukemia Patients For the purpose of HSC mobilization, plerixafor may cause mobilization of leukemic cells and subsequent contamination of the apheresis product. Therefore, plerixafor is not intended for HSC mobilization and harvest in patients with leukemia.

5.3 Hematologic Effects Leukocytosis Administration of plerixafor in conjunction with filgrastim increases circulating leukocytes as well as HSC populations. Monitor white blood cell counts during plerixafor use [see Adverse Reactions (6.1) ] . Thrombocytopenia Thrombocytopenia has been observed in patients receiving plerixafor. Monitor platelet counts in all patients who receive plerixafor and then undergo apheresis.

5.4 Potential for Tumor Cell Mobilization When plerixafor 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.

5.5 Splenic Enlargement and Rupture Higher absolute and relative spleen weights associated with extramedullary hematopoiesis were observed following prolonged (2 to 4 weeks) daily plerixafor SC administration in rats at doses approximately 4-fold higher than the recommended human dose based on body surface area. The effect of plerixafor on spleen size in patients was not specifically evaluated in clinical studies. Cases of splenic enlargement and/or rupture have been reported following the administration of plerixafor in conjunction with growth factor filgrastim. Evaluate individuals receiving plerixafor in combination with filgrastim who report left upper abdominal pain and/or scapular or shoulder pain for splenic integrity.

5.6 Embryo-Fetal Toxicity Based on findings from animal reproduction studies, plerixafor can cause fetal harm when administered to a pregnant woman. Plerixafor administration to pregnant rats during organogenesis resulted in embryo-fetal mortality, structural abnormalities, and alterations to growth at exposures approximately 10 times the exposure at the recommended human dose. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use an effective form of contraception during treatment with plerixafor and for one week after the final dose [see Use in Specific Populations (8.1) ] .

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 Fresenius Kabi USA, LLC at 1-800-551-7176 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 micrograms/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 Grades based on criteria from the World Health Organization (WHO) 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 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 Postmarketing Experience In addition to adverse reactions reported from clinical trials, the following adverse reactions have been reported from postmarketing 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

Lactation: Advise not to breastfeed. ( 8.2 )

8.1 Pregnancy Risk Summary Limited available data with plerixafor 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 [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 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 [see Use in Specific Populations (8.1) ] . Contraception Females Plerixafor 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 and for one week after the final dose. Males Males treated with plerixafor should use effective contraception during treatment and for one week after cessation of treatment.

8.4 Pediatric Use The safety and effectiveness of plerixafor have not been established in pediatric patients. Effectiveness was not demonstrated in a single phase 1/2 randomized, open-label, comparative study of plerixafor 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 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 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 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 adult dose (0.24 mg/kg).

8.5 Geriatric Use Of the total number of subjects in controlled clinical studies of plerixafor, 24% were 65 and over, while 0.8% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Since plerixafor is mainly excreted by the kidney, no dose modifications are necessary in elderly individuals with normal renal function. In general, care should be taken in dose selection for elderly patients due to the greater frequency of decreased renal function with advanced age. Dosage adjustment in elderly patients with CL CR less than or equal to 50 mL/min is recommended [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) ] .

8.6 Renal Impairment In patients with moderate and severe renal impairment (CL CR less than or equal to 50 mL/min), reduce the dose of plerixafor by one-third to 0.16 mg/kg [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) ] .

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.