Plerixafor

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# Overview
Plerixafor is an hematopoietic that is FDA approved for the treatment of non-Hodgkin's lymphoma and multiple myeloma.   Common adverse reactions include diarrhea, nausea, fatigue, injection site reactions, headache, arthralgia, dizziness, and vomiting.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
Plerixafor is indicated in combination with granulocyte-colony stimulating factor (G-CSF) to mobilize hematopoietic stem cells (HSCs) to the peripheral blood for collection and subsequent autologous transplantation in patients with non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM).
- Dosage: 0.24 mg/kg body weight by subcutaneous (SC) injection

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Plerixafor in adult patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Plerixafor in adult patients.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
Safety and efficacy not established in pediatric patients

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Plerixafor in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Plerixafor in pediatric patients.

# Contraindications
History of hypersensitivity to plerixafor. Anaphylactic shock has occurred with use of plerixafor.

# Warnings
- 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. 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.
- 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.
- Administration of plerixafor in conjunction with G-CSF increases circulating leukocytes as well as HSC populations. Monitor white blood cell counts during plerixafor use.
- Thrombocytopenia has been observed in patients receiving plerixafor. Monitor platelet counts in all patients who receive plerixafor and then undergo apheresis.
- When plerixafor is used in combination with G-CSF 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.
- 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. Evaluate individuals receiving plerixafor in combination with G-CSF who report left upper abdominal pain and/or scapular or shoulder pain for splenic integrity.
- plerixafor may cause fetal harm when administered to a pregnant woman. Plerixafor is teratogenic in animals. There are no adequate and well-controlled studies in pregnant women using plerixafor. Advise women of childbearing potential to avoid becoming pregnant while receiving treatment with plerixafor. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

# Adverse Reactions

## 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 G-CSF 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 G-CSF 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 G-CSF group and 292 patients were treated in the placebo and G-CSF group. Patients received daily morning doses of G-CSF 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.
- 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.

## Postmarketing 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.
- Immune System Disorders: Anaphylactic reactions, including anaphylactic shock
- Psychiatric disorders: Abnormal dreams and nightmares

# Drug Interactions
Based on in vitro data, plerixafor is not a substrate, inhibitor or inducer of human cytochrome P450 isozymes. Plerixafor is not likely to be implicated in in vivo drug-drug interactions involving cytochrome P450s. 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.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): D
- Plerixafor may cause fetal harm when administered to a pregnant woman. Plerixafor is teratogenic in animals.
- Plerixafor administered to pregnant rats induced embryo-fetal toxicities including fetal death, increased resorptions and post-implantation 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 or 10 times the AUC in subjects with normal renal function who received a single dose of 0.24 mg/kg).
Pregnancy Category (AUS): 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Plerixafor in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Plerixafor during labor and delivery.

### Nursing Mothers
- It is not known whether plerixafor is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from plerixafor, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

### Pediatric Use
- The safety and efficacy of plerixafor in pediatric patients have not been established in controlled clinical studies.

### Geriatic 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  50 mL/min is recommended.

### Gender
- Clinical data show no effect of gender on plerixafor pharmacokinetics.

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

### Renal Impairment
- In patients with moderate and severe renal impairment (CLCR  50 mL/min), reduce the dose of plerixafor by one-third to 0.16 mg/kg.

### Hepatic Impairment
There is no FDA guidance on the use of Plerixafor in patients with hepatic impairment.

### Females of Reproductive Potential and Males
- The effect of plerixafor on human fertility is unknown.  The effect of plerixafor on male or female 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.

### Immunocompromised Patients
There is no FDA guidance one the use of Plerixafor in patients who are immunocompromised.

# Administration and Monitoring

### Administration
Subcutaneous

### Monitoring
There is limited information regarding Plerixafor Monitoring in the drug label.

# IV Compatibility
There is limited information regarding the compatibility of Plerixafor and IV administrations.

# 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.

# Pharmacology

## Mechanism of Action
- Plerixafor is an inhibitor of the CXCR4 chemokine receptor and blocks binding of its cognate ligand, stromal cell-derived factor-1 (SDF-1).  SDF-1 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-1 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.

## Structure
The structural formula is:

## 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 G-CSF 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.
- 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.

## Pharmacokinetics
The single-dose pharmacokinetics of plerixafor 0.24 mg/kg were evaluated in patients with NHL and MM following pre-treatment with G-CSF (10 micrograms/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 were similar across clinical studies in healthy subjects who received plerixafor alone and NHL and MM patients who received plerixafor in combination with G-CSF.
- 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 SC 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 (t1/2) was estimated to be 0.3 hours and the terminal population half-life (t1/2) 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 (AUC024h) with increasing body weight. 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 > 50 mL/min and 27 mg/day if CLCR is  50 mL/min).
- Peak plasma concentrations occurred at approximately 30  60 minutes after a SC dose.
- 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.
- 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.
- 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.

## Nonclinical Toxicology
- 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).

# Clinical Studies
The efficacy and safety of plerixafor in conjunction with G-CSF in non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM) were evaluated in two placebo-controlled studies (Studies 1 and 2).  Patients were randomized to receive either plerixafor 0.24 mg/kg or placebo on each evening prior to apheresis. Patients received daily morning doses of G-CSF 10 micrograms/kg for 4 days prior to the first dose of plerixafor or placebo and on each morning prior to apheresis. Two hundred and ninety-eight (298) NHL patients were included in the primary efficacy analyses for Study 1. The mean age was 55 years (range 2975) and 58 years (range 2275) in the plerixafor and placebo groups, respectively, and 93% of subjects were Caucasian. In study 2, 302 patients with MM were included in the primary efficacy analyses. The mean age (58years) and age range (2875) were similar in the plerixafor and placebo groups, and 81% of subjects were Caucasian.
- In Study 1, 59% of NHL patients who were mobilized with plerixafor and G-CSF collected  5  106 CD34+ cells/kg from the peripheral blood in four or fewer apheresis sessions, compared with 20% of patients who were mobilized with placebo and G-CSF (p < 0.001). Other CD34+ cell mobilization outcomes showed similar findings (Table 4).
- The median number of days to reach  5  106 CD34+ cells/kg was 3 days for the plerixafor group and not evaluable for the placebo group. Table 5 presents the proportion of patients who achieved  5  106 CD34+ cells/kg by apheresis day.
- In Study 2, 72% of MM patients who were mobilized with plerixafor and G-CSF collected  6  106 CD34+ cells/kg from the peripheral blood in two or fewer apheresis sessions, compared with 34% of patients who were mobilized with placebo and G-CSF (p < 0.001). OtherCD34+ cell mobilization outcomes showed similar findings (Table 6).
- The median number of days to reach  6  106 CD34+ cells/kg was 1 day for the plerixafor group and 4 days for the placebo group. Table 7 presents the proportion of patients who achieved  6  106 CD34+ cells/kg by apheresis day.
- Multiple factors can influence time to engraftment and graft durability following stem cell transplantation. For transplanted patients in the Phase 3 studies, time to neutrophil and platelet engraftment and graft durability were similar across the treatment groups.

# How Supplied
- Single-use vial containing 1.2 mL of a 20 mg/mL solution

## Storage
Store at 25C (77F)

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
- Advise patients of the potential for anaphylactic reactions, including signs and symptoms such as urticaria, periorbital swelling, dyspnea, or hypoxia during and following plerixafor injection and to report these symptoms immediately to a health care professional.
- Advise patients to inform a health care professional immediately if symptoms of vasovagal reactions such as orthostatic hypotension or syncope occur during or shortly after their plerixafor injection.
- Advise patients who experience itching, rash, or reaction at the site of injection to notify a health care professional, as these symptoms have been treated with over-the-counter medications during clinical trials.
- Advise patients that plerixafor may cause gastrointestinal disorders, including diarrhea, nausea, vomiting, flatulence, and abdominal pain. Patients should be told how to manage specific gastrointestinal disorders and to inform their health care professional if severe events occur following plerixafor injection.
- Advise female patients with reproductive potential to use effective contraceptive methods during plerixafor use.

# Precautions with Alcohol
Alcohol-Plerixafor interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- Mozobil 

# Look-Alike Drug Names
There is limited information regarding Plerixafor Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price