CLASSES

Colony-stimulating Factors

DEA CLASS

Rx

DESCRIPTION

Hematopoietic stem-cell mobilizer
Used in combination with a granulocyte-colony stimulating factor to mobilize hematopoietic stem cells prior to an autologous stem-cell transplant in patients with non-Hodgkin lymphoma or multiple myeloma
Serious hypersensitivity reactions have occurred; monitor patients during and after the subcutaneous injection

COMMON BRAND NAMES

Mozobil

HOW SUPPLIED

Mozobil Subcutaneous Inj Sol: 1mL, 20mg

DOSAGE & INDICATIONS

MAXIMUM DOSAGE

<= 83 kg and estimated creatinine clearance (CrCl) > 50 mL/min: 0.24 mg/kg (actual body weight) per dose or a fixed 20-mg dose subcutaneously once daily for up to 4 consecutive days.
> 83 kg and estimated CrCl > 50 mL/min: 0.24 mg/kg (actual body weight) per dose up to a maximum of 40 mg per dose subcutaneously once daily for up to 4 consecutive days.

<= 83 kg and estimated creatinine clearance (CrCl) > 50 mL/min: 0.24 mg/kg (actual body weight) per dose or a fixed 20-mg dose subcutaneously once daily for up to 4 consecutive days.
> 83 kg and estimated CrCl > 50 mL/min: 0.24 mg/kg (actual body weight) per dose up to a maximum of 40 mg per dose subcutaneously once daily for up to 4 consecutive days.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

DOSING CONSIDERATIONS

Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Estimated creatinine clearance (CrCl) > 50 mL/min: No dosage adjustment is necessary.
Estimated CrCl <= 50 mL/min:
weight of 83 kg or less: fixed 13-mg dose or 0.16 mg/kg actual body weight subcutaneously once daily for up to 4 consecutive days.
weight greater than 83 kg: 0.16 mg/kg actual body weight (maximum dose, 27 mg) subcutaneously once daily for up to 4 consecutive days.
Hemodialysis: dosage recommendations in patients on hemodialysis are not provided by the manufacturer.

ADMINISTRATION

Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

STORAGE

Mozobil:
- Discard product if it contains particulate matter, is cloudy, or discolored
- Discard unused portion. Do not store for later use.
- Store at 77 degrees F; excursions permitted to 59-86 degrees F

CONTRAINDICATIONS / PRECAUTIONS

Serious and life-threatening hypersensitivity reactions, including anaphylactic reactions, hypotension, and shock, have been reported with plerixafor therapy. Use is contraindicated in patients with a history of plerixafor hypersensitivity. Monitor patients for signs and symptoms of hypersensitivity for at least 30 minutes during and after each plerixafor administration.

Do not use plerixafor for hematopoietic stem-cell (HSC) mobilization and harvest in patients with leukemia. Tumor cells including leukemic cells may be released from the marrow and subsequently collected in the leukapheresis product after HSC mobilization with plerixafor and granulocyte-colony stimulating factor.

Use plerixafor with caution in patients with renal disease as it is excreted primarily by the kidney. Concomitant use of plerixafor and other agents that reduce renal function or compete for active tubular secretion may result in increased levels of either agent. A dosage reduction is required in patients with moderate or severe renal impairment (creatinine clearance <= 50 ml/min); additionally, the plerixafor dose should not exceed 27 mg/day in these patients.

Thrombocytopenia has been reported with plerixafor use. Monitor platelet counts in all patients receiving plerixafor who then undergo apheresis.

Leukocytosis may occur with plerixafor plus granulocyte colony-stimulating factor use; therefore, monitor white blood cell counts during therapy.

The safety and effectiveness of plerixafor has not been established in adolescents, children, infants, and neonates. Adding plerixafor to standard regimens for hematopoietic stem-cell mobilization was not superior to standard regimens alone for peripheral blood collection prior to an autologous transplantation in pediatric patients ages 1 to less than 17 years of age in a randomized (2:1), open-label, phase 1/2 trial (n = 45). No new safety information was reported in this trial.

Plerixafor may cause fetal harm if administered during pregnancy based on data from animal studies. Females of reproductive potential should avoid pregnancy during and after plerixafor therapy. If plerixafor is used during pregnancy, the woman should be apprised of the potential hazard to the fetus. In pregnant rats, plerixafor administration resulted in 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; the majority of these toxicities occurred at doses 10-times the recommended human dose.

Counsel patients about the reproductive risk and contraception requirements during plerixafor treatment. Pregnancy testing is recommended for females of reproductive potential prior to starting plerixafor therapy. These patients should avoid pregnancy and use effective contraception during plerixafor therapy and for 1 week after the final dose. Patients who become pregnant while receiving plerixafor should be apprised of the potential hazard to the fetus.

Advise patients that breast-feeding is not recommended during plerixafor treatment and for 1 week after the last dose due to the potential for serious adverse reactions in the breastfed child. There are no data on the presence of plerixafor in human milk, the effects on the breast-fed child, or the effects on milk production.

ADVERSE REACTIONS

vomiting / Early / 0-1.0
diarrhea / Early / 0-1.0
nausea / Early / 1.0-1.0
headache / Early / 0-1.0
anaphylactic shock / Rapid / 0-1.0
anaphylactoid reactions / Rapid / 0-1.0
splenic rupture / Delayed / Incidence not known

bleeding / Early / 0-34.0
hematoma / Early / 0-34.0
constipation / Delayed / 0-5.0
erythema / Early / 0-5.0
orthostatic hypotension / Delayed / 0-1.0
dyspnea / Early / 0-1.0
hypotension / Rapid / 0-1.0
hypoxia / Early / 0-1.0
thrombocytopenia / Delayed / Incidence not known
splenomegaly / Delayed / Incidence not known

pruritus / Rapid / 0-34.0
injection site reaction / Rapid / 34.0-34.0
skin irritation / Early / 0-34.0
paresthesias / Delayed / 0-34.0
rash / Early / 0-34.0
fatigue / Early / 27.0-27.0
arthralgia / Delayed / 13.0-13.0
dizziness / Early / 11.0-11.0
flatulence / Early / 7.0-7.0
insomnia / Early / 7.0-7.0
dyspepsia / Early / 0-5.0
abdominal pain / Early / 0-5.0
xerostomia / Early / 0-5.0
hypoesthesia / Delayed / 0-5.0
musculoskeletal pain / Early / 0-5.0
hyperhidrosis / Delayed / 0-5.0
malaise / Early / 0-5.0
syncope / Early / 0-1.0
urticaria / Rapid / 0-1.0
leukocytosis / Delayed / 10.0
nightmares / Early / Incidence not known

DRUG INTERACTIONS

There are no drug interactions associated with Plerixafor products.

PREGNANCY AND LACTATION

Plerixafor may cause fetal harm if administered during pregnancy based on data from animal studies. Females of reproductive potential should avoid pregnancy during and after plerixafor therapy. If plerixafor is used during pregnancy, the woman should be apprised of the potential hazard to the fetus. In pregnant rats, plerixafor administration resulted in 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; the majority of these toxicities occurred at doses 10-times the recommended human dose.

Counsel patients about the reproductive risk and contraception requirements during plerixafor treatment. Pregnancy testing is recommended for females of reproductive potential prior to starting plerixafor therapy. These patients should avoid pregnancy and use effective contraception during plerixafor therapy and for 1 week after the final dose. Patients who become pregnant while receiving plerixafor should be apprised of the potential hazard to the fetus.

MECHANISM OF ACTION

Plerixafor competitively inhibits the binding of stromal-derived factor-1 (SDF-1 or CXCL12) to its receptor, CXC receptor-4 (CXCR4), allowing hematopoietic stem cells (HSC) to mobilize into the peripheral blood. Chemokines, specifically the CXC chemokine family, are key regulators of HSC mobilization. The chemokine SDF-1, which contains a CXC sequence, is constitutively expressed by multiple tissues, including bone marrow stromal cells. Its receptor, CXCR4 is a transmembrane G-protein-coupled receptor also present on multiple sites, including CD34+ cells. Physiologically, the interaction between SDF-1 and CXCR4 results in chemotaxis, increased survival of HSCs, and the homing of HSCs in the bone marrow environment. Homing of HSCs is caused by SDF-1 located on the surface of endothelial cells and bound to heparan sulphates, interacting with CXCR4 located on HSCs. Engagement of CXCR4, induces a cascade that leads to adhesion and arrest of HSCs. Transendothelial migration and migration to the hematopoietic niche are enhanced by SDF-1 and the gradient caused by the continuous production of SDF-1 by stromal cells. The final anchoring of HSCs in the bone marrow environment occurs as a result of interactions with stromal cells and extracellular matrix, and the continued production of SDF-1. Plerixafor selectively inhibits the binding of SDF-1 to CXCR4, preventing this cascade, and allowing HSCs to mobilize into the peripheral blood, thereby increasing the yield of HSCs for collection.

PHARMACOKINETICS

Plerixafor is administered subcutaneously. It is up to 58% bound to plasma proteins, has an apparent volume of distribution of 0.3 L/kg, and is predominantly confined to the extravascular space. Plerixafor is not metabolized using human liver microsomes or human primary hepatocytes. The major route of plerixafor elimination is in the urine. In healthy volunteers, approximately 70% of the parent drug was excreted in the urine within 24 hours of a single dose of plerixafor 0.24 mg/kg. The terminal half-life of plerixafor was 3 to 5 hours in healthy subjects and patients. Following a single dose of plerixafor 0.24 mg/kg administered 10 to 11 hours before apheresis, mean peripheral blood CD34+ cell counts were increased by 6.1-fold (standard deviation (SD) of +/- 5.4) and 6.4-fold (SD of +/- 6.8) over a 24-hour period in patients with non-Hodgkin lymphoma and multiple myeloma, respectively, in 2 placebo-controlled studies. All patients received pretreatment with filgrastim (G-CSF) and G-CSF was given prior to apheresis. In healthy volunteers who received plerixafor in conjunction with G-CSF, peak CD34+ cell mobilization occurred at 10 and 14 hours after plerixafor administration. The median time to reach 5 × 106 CD34+ cells/kg or greater was 3 days for non-Hodgkin lymphoma patients (weighing 70 kg or less) who received fixed-dose plerixafor (20 mg) or weight-based plerixafor (0.24 mg/kg) in a population pharmacokinetic analysis (n = 61).
 
Affected cytochrome P450 isoenzymes and drug transporters: none
Based on in vitro assays, plerixafor is not a substrate, inhibitor, or inducer of human CYP450 isozymes or a substrate or inhibitor of P-glycoprotein (P-gp) at therapeutic concentrations. Therefore, plerixafor is not likely to be affected by concomitant administration of CYP450 inhibitors and inducers or P-gp inhibitors or inducers; it is also not likely to influence the exposure of other drugs. In vitro, plerixafor did not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4/5; induce CYP1A2, CYP2B6, or CYP3A4; or act as a P-gp substrate or inhibitor.