Plerifor

Plerifor

plerixafor

Manufacturer:

Camber

Distributor:

Camber
Full Prescribing Info
Contents
Plerixafor.
Description
Each ml contains 20 mg of Plerixafor.
Action
Pharmacology: Pharmacodynamics: Plerixafor, a hematopoietic stem cell mobilizer, 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 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 for up to 1 year in canine transplantation models.
Pharmacokinetics: A population pharmacokinetic analysis incorporated plerixafor data from 63 subjects (patients with NHL, patients with multiple myeloma, subjects with varying degrees of renal impairment, and healthy subjects) who received a single subcutaneous dose (0.04 to 0.24 mg/kg) of plerixafor. A 2-compartment disposition model with first order absorption and elimination was found to adequately describe the plerixafor concentration-time profile. Significant relationships between clearance and CrCl, as well as between central volume of distribution and body weight were observed.
The population pharmacokinetic analysis showed that the mg/kg-based dosage results in an increased plerixafor exposure (AUC0-24h) 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 CrCl is more than 50 mL/min and 27 mg/day if CrCl is 50 mL/min or less).
Absorption: Peak plasma concentrations occurred at approximately 30 - 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 CYP-450-dependent drug-drug interactions.
Excretion: 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. The distribution half-life was estimated to be 0.3 hours and the terminal population half-life was 5.3 hours in patients with normal renal function.
Special populations: Renal function 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 CrCl. The mean AUC0-24h of plerixafor in subjects with mild (CrCl 51 to 80 mL/min), moderate (CrCl 31 to 50 mL/min), and severe (CrCl of less than 31 mL/min) renal impairment was 7%, 32%, and 39%, respectively, 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 CrCl of greater than 50 mL/min. These results support a dose reduction of one-third in patients with moderate to severe renal impairment (CrCl 50 mL/min or less) 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 CrCl is 50 mL/min or less, the dose should not exceed 27 mg/day.
Indications/Uses
Peripheral stem cell collection and transplantation: 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.
Dosage/Direction for Use
General dosing considerations: Dose adjustment in patients with a creatinine clearance (CrCl) of 50 mL/min or less is recommended (see Renal Function Impairment).
Adults: Peripheral stem cell collection and transplantation: Usual Dosage: 0.24 mg/kg body weight by subcutaneous injection. Begin treatment with plerixafor injection after the patient has received G-CSF once daily for 4 days. Administer plerixafor injection approximately 11 hours prior to initiation of each apheresis for up to 4 consecutive days.
Maximum dose: 40 mg/day.
Concomitant therapy: Administer daily morning doses of G-CSF 10 mcg/kg for 4 days prior to the first evening dose of plerixafor and on each day prior to apheresis.
Renal Impairment: See Table 1.

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Preparation for administration: Use the patient's actual body weight to calculate the volume of plerixafor 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. (See Equation.)

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In clinical studies, plerixafor dose has been calculated based on actual body weight in patients up to 175% of ideal body weight. Plerixafor dose and treatment of patients weighing more than 175% of ideal body weight have not been investigated.
Overdosage
Based on limited data at doses above usual dosage (0.24 mg/kg SC), the frequency of gastrointestinal disorders, vasovagal reactions, orthostatic hypotension, and/or syncope may be higher.
Contraindications
History of hypersensitivity to Plerixafor.
Special Precautions
Leukemia: 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.
Hematologic effects: Leukocytosis: 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: Thrombocytopenia has been observed in patients receiving plerixafor. Monitor platelet counts in all patients who receive plerixafor and then undergo apheresis.
Tumor cell mobilization: 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.
Splenic enlargement: 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. Evaluate individuals receiving plerixafor in combination with G-CSF who report left upper abdominal pain and/or scapular or shoulder pain for splenic integrity.
Hypersensitivity reactions: Serious hypersensitivity reactions, included anaphylactic-type reactions, some of which 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 administration for at least 30 minutes and until clinically stable following completion of each administration. Only administer 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 administration in less than 1 % of patients.
Renal function Impairment: In patients with moderate and severe renal impairment (CrCl 50 mL/min or less), reduce the dose of plerixafor by one-third to 0.16 mg/kg.
Pediatric: The safety and effectiveness of plerixafor in children have not been established in controlled clinical studies.
Use In Pregnancy & Lactation
Pregnancy: Pregnancy risk factor D.
Plerixafor may cause fetal harm when administered to a pregnant women. 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, apprise the patient of the potential hazard to the fetus.
Lactation: 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 reaction in breast-feeding infants from plerixafor, make a decision whether to discontinue breast-feeding or the drug, taking into the account the importance of the drug to the mother.
Adverse Reactions
Common adverse reaction: The most common adverse reactions (at least 10 %) reported in patients who received plerixafor in conjunction with G-CSF regardless of causality and more frequently with plerixafor than placebo during HSC mobilization and apheresis were diarrhea, nausea, fatigue, injection-site reactions, headache, arthralgia, dizziness, and vomiting.
Adverse reactions (5% or more): See Table 2.

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Hyperleukocytosis: 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.
Injection-site reactions: In the randomized studies, 34 % of patients with NHL or multiple myeloma 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.
Other adverse reactions (less than 5 %): Other adverse reactions that occurred in less than 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.
Other adverse reactions (less than 1 %): Mild to moderate systemic reactions were observed in less than 1% of patients approximately 30 minutes after plerixafor administration. Reactions included 1 or more of the following: urticaria (n = 2), periorbital swelling (n = 2), dyspnea (n = 1), or hypoxia (n = 1). Symptoms generally responded to treatments (eg, 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 of 0.24 mg/kg or less. The majority of these events occurred within 1 hour of plerixafor administration. Because of the potential for these reactions, appropriate precautions.
Drug Interactions
Nephrotoxic drugs: Because 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 concentration of plerixafor or the coadministered drug. The effect of coadministration of plerixafor with other drugs that are renally eliminated or are known to affect renal function have not been evaluated.
Storage
Store below 30°C and protect from moisture.
ATC Classification
L03AX16 - plerixafor ; Belongs to the class of other immunostimulants.
Presentation/Packing
Inj (vial) 24 mg/1.2 mL (clear colorless to pale yellow solution free from visible particles) x 2 mL x 1's.
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