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 (CLCR) 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 CLCR 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)].

The following (Cockcroft-Gault) formula may be used to estimate CLCR:

           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.

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 subcutaneous 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 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)].

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 subcutaneous. 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 subcutaneous 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. 

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

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/m2 (approximately 10 times the recommended human dose of 0.24 mg/kg when compared on a mg/m2 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 × 106 cells/L in the comparator arm and 15 × 106 cells/L in the plerixafor arm. On the day of the first apheresis, median peripheral blood CD34+ counts were 64 × 106 cells/L in the comparator arm and 77 × 106 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 CLCR 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 (CLCR 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)].

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.

12.2 Pharmacodynamics

Data on the fold increase in peripheral blood CD34+ cell count (cells/mcL) by apheresis day were evaluated in two placebo-controlled clinical studies in patients with NHL and MM (Study 1 and Study 2, respectively). The fold increase in CD34+ cell count (cells/mcL) over the 24-hour period starting from the day prior to the first apheresis and ending the next morning just before the first apheresis is summarized in Table 3. During this 24-hour period, a single dose of plerixafor or placebo was administered 10 to 11 hours prior to apheresis.

In pharmacodynamic studies of plerixafor in healthy volunteers, peak mobilization of CD34+ cells was observed between 6 and 9 hours after administration. In pharmacodynamic studies of plerixafor in conjunction with filgrastim in healthy volunteers, a sustained elevation in the peripheral blood CD34+ count was observed from 4 to 18 hours after plerixafor administration with a peak CD34+ count between 10 and 14 hours.

QT/QTc Prolongation

There is no indication of a QT/QTc prolonging effect of plerixafor in single doses up to 0.40 mg/kg. In a randomized, double-blind, crossover study, 48 healthy subjects were administered a single subcutaneous dose of plerixafor (0.24 mg/kg and 0.40 mg/kg) and placebo. Peak concentrations for 0.40 mg/kg plerixafor were approximately 1.8-fold higher than the peak concentrations following the 0.24 mg/kg single subcutaneous dose.

12.3 Pharmacokinetics

The single-dose pharmacokinetics of plerixafor 0.24 mg/kg were evaluated in patients with NHL and MM following pretreatment with filgrastim (10 mcg/kg once daily for 4 consecutive days). Plerixafor exhibits linear kinetics between the 0.04 mg/kg to 0.24 mg/kg dose range. The pharmacokinetics of plerixafor was similar across clinical studies in healthy subjects who received plerixafor alone and NHL and MM patients who received plerixafor in combination with filgrastim.

A population pharmacokinetic analysis incorporated plerixafor data from 63 subjects (NHL patients, MM patients, subjects with varying degrees of renal impairment, and healthy subjects) who received a single subcutaneous dose (0.04 mg/kg to 0.24 mg/kg) of plerixafor. A two-compartment disposition model with first order absorption and elimination was found to adequately describe the plerixafor concentration-time profile. Significant relationships between clearance and creatinine clearance (CLCR), as well as between central volume of distribution and body weight were observed. The distribution half-life (t1/2α) was estimated to be 0.3 hours and the terminal population half-life (t1/2β) was 5.3 hours in patients with normal renal function.

The population pharmacokinetic analysis showed that the mg/kg-based dosage results in an increased plerixafor exposure (AUC0-24h) with increasing body weight. In order to compare the pharmacokinetics and pharmacodynamics of plerixafor following 0.24 mg/kg-based and fixed (20 mg) doses, a follow-up trial was conducted in patients with NHL (N=61) who were treated with 0.24 mg/kg or 20 mg of plerixafor. The trial was conducted in patients weighing 70 kg or less. The fixed 20 mg dose showed 1.43-fold higher exposure (AUC0-10h) than the 0.24 mg/kg dose (Table 4). The fixed 20 mg dose also showed numerically higher response rate (5.2% [60% vs 54.8%] based on the local lab data and 11.7% [63.3% vs 51.6%] based on the central lab data) in attaining the target of ≥5 × 106 CD34+ cells/kg than the mg/kg-based dose. However, the median time to reach ≥5 × 106 CD34+ cells/kg was 3 days for both treatment groups, and the safety profile between the groups was similar. Based on these results, further analysis was conducted by FDA reviewers and a body weight of 83 kg was selected as an appropriate cut-off point to transition patients from fixed to weight based dosing.

There is limited experience with the 0.24 mg/kg dose of plerixafor in patients weighing above 160 kg. Therefore, the dose should not exceed that of a 160 kg patient (i.e., 40 mg/day if CLCR is greater than 50 mL/min and 27 mg/day if CLCR is less than or equal to 50 mL/min) [see Dosage and Administration (2.1, 2.3)].

Absorption

Peak plasma concentrations occurred at approximately 30 to 60 minutes after a subcutaneous dose.

Distribution

Plerixafor is bound to human plasma proteins up to 58%. The apparent volume of distribution of plerixafor in humans is 0.3 L/kg demonstrating that plerixafor is largely confined to, but not limited to, the extravascular fluid space.

Metabolism

The metabolism of plerixafor was evaluated with in vitro assays. Plerixafor is not metabolized as shown in assays using human liver microsomes or human primary hepatocytes and does not exhibit inhibitory activity in vitro towards the major drug metabolizing cytochrome P450 enzymes (1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4/5). In in vitro studies with human hepatocytes, plerixafor does not induce CYP1A2, CYP2B6, or CYP3A4 enzymes. These findings suggest that plerixafor has a low potential for involvement in cytochrome P450­-dependent drug-drug interactions.

Elimination

The major route of elimination of plerixafor is urinary. Following a 0.24 mg/kg dose in healthy volunteers with normal renal function, approximately 70% of the dose was excreted in the urine as the parent drug during the first 24 hours following administration. In studies with healthy subjects and patients, the terminal half-life in plasma ranges between 3 and 5 hours. At concentrations similar to what are seen clinically, plerixafor did not act as a substrate or inhibitor of P-glycoprotein in an in vitro study with MDCKII and MDCKII-MDR1 cell models.

Special Populations

Renal impairment

Following a single 0.24 mg/kg subcutaneous dose, plerixafor clearance was reduced in subjects with varying degrees of renal impairment and was positively correlated with CLCR. The mean AUC0­ 24h of plerixafor in subjects with mild (CLCR 51 to 80 mL/min), moderate (CLCR 31 to 50 mL/min), and severe (CLCR <31 mL/min) renal impairment was 7%, 32%, and 39% higher than healthy subjects with normal renal function, respectively. Renal impairment had no effect on Cmax. A population pharmacokinetic analysis indicated an increased exposure (AUC0-24h) in patients with moderate and severe renal impairment compared to patients with CLCR >50 mL/min. These results support a dose reduction of one-third in patients with moderate to severe renal impairment (CLCR ≤50 mL/min) in order to match the exposure in patients with normal renal function. The population pharmacokinetic analysis showed that the mg/kg-based dosage results in an increased plerixafor exposure (AUC0-24h) with increasing body weight; therefore, if CLCR is ≤50 mL/min the dose should not exceed 27 mg/day [see Dosage and Administration (2.3)].

Since plerixafor is primarily eliminated by the kidneys, coadministration of plerixafor with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of plerixafor or the coadministered drug. The effects of coadministration of plerixafor with other drugs that are renally eliminated or are known to affect renal function have not been evaluated.

Race

Clinical data show similar plerixafor pharmacokinetics for Caucasians and African Americans, and the effect of other racial/ethnic groups has not been studied.

Gender

Clinical data show no effect of gender on plerixafor pharmacokinetics.

Age

Clinical data show no effect of age on plerixafor pharmacokinetics.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies with plerixafor have not been conducted.

Plerixafor was not genotoxic in an in vitro bacterial mutation assay (Ames test in Salmonella), an in vitro chromosomal aberration test using V79 Chinese hamster cells, or an in vivo bone marrow micronucleus test in rats after subcutaneous doses up to 25 mg/kg (150 mg/m2).

The effect of plerixafor on human fertility is unknown. The effect of plerixafor on male fertility was not studied in designated reproductive toxicology studies. The staging of spermatogenesis measured in a 28-day repeated dose toxicity study in rats revealed no abnormalities considered to be related to plerixafor. No histopathological evidence of toxicity to male or female reproductive organs was observed in 28-day repeated dose toxicity studies.

No adverse effects on estrus or reproductive indices were observed in an investigative fertility study in female rats administered plerixafor at doses up to 90 mg/m2 (15 mg/kg/day) or approximately 10 times the recommended human dose of 0.24 mg/kg when compared on a mg/m2 basis.