Mozobil Mozifor Plerixafor Injection 24mg

[Product Name] Plerixafor Injection

[English Name] Plerixafor Injection

[Specification] 1.2 mL: 24 mg; 1 vial/box

[Manufacturer] Hetero (India)

[Indications]

Plerixafor Injection, in combination with Granulocyte Colony-Stimulating Factor (G-CSF), is indicated for the mobilization of hematopoietic stem cells (HSCs) into the peripheral blood for collection and subsequent autologous transplantation in patients with non-Hodgkin lymphoma (NHL).

[Dosage and Administration]

Prior to administration, the vial should be inspected for particulate matter and discoloration; if particulate matter or discoloration is present, the product must not be used.

Treatment with this product should begin after the patient has received G-CSF once daily for 4 days. This product should be administered 11 hours prior to the start of each apheresis session, for up to 4 consecutive days.

The recommended subcutaneous dosage of this product is determined by body weight:

For patients weighing ≤ 83 kg: a fixed dose of 20 mg, or 0.24 mg/kg of body weight.

For patients weighing > 83 kg: 0.24 mg/kg of body weight.

The volume of this product to be administered should be calculated based on the patient's actual body weight. Each vial contains 1.2 mL of solution at a concentration of 20 mg/mL; the volume to be administered to the patient is calculated using the following formula:

0.012 × Actual Body Weight (kg) = Volume to be Administered (mL)

The patient's body weight should be measured within one week prior to the first dose of Plerixafor to determine the appropriate dosage. In clinical studies, Plerixafor doses were calculated based on up to 175% of the patient's ideal body weight. The dosage and treatment outcomes for patients whose actual body weight exceeds 175% of their ideal body weight have not been studied. Ideal body weight is determined using the following formulas:

Males (kg): 50 + 2.3 × ((Height (cm) × 0.394) - 60); Females (kg): 45.5 + 2.3 × ((Height (cm) × 0.394) - 60).

Given that exposure increases with increasing body weight, the dosage of this product must not exceed 40 mg per day. **Recommended Concomitant Medication**

Administer G-CSF 10 mcg/kg subcutaneously once daily for 4 consecutive days prior to the first dose of this product, and on each morning prior to apheresis.

**Dosing in Patients with Renal Impairment**

In patients with moderate to severe renal impairment (estimated creatinine clearance [CLcr] ≤ 50 mL/min), reduce the dose of this product by one-third based on body weight (see Table 1). If CLcr is ≤ 50 mL/min, the dose should not exceed 27 mg/day, as doses calculated on a mg/kg basis result in increased plerixafor exposure with increasing body weight (see [Pharmacokinetics]). If the dose is reduced by one-third, systemic drug exposure in patients with moderate to severe renal impairment is similar to that in patients with normal renal function (see [Pharmacokinetics]).

**Males:**

Creatinine Clearance (mL/min) = [Body Weight (kg) × (140 – Age [years])] ÷ [72 × Serum Creatinine (mg/dL)]

**Females:**

Creatinine Clearance (mL/min) = 0.85 × Value calculated for males

There is insufficient information to recommend a dosage for patients undergoing dialysis.

**Pediatric Patients**

Experience with the use of this product in pediatric patients is limited. The safety and efficacy of this product in children under 18 years of age have not been established.

**Geriatric Patients (>65 years)**

No dose adjustment is required for geriatric patients with normal renal function. Dose adjustment is recommended for geriatric patients with a creatinine clearance ≤ 50 mL/min (see "Renal Impairment" above). In general, because the incidence of decreased renal function increases with age, care should be taken in selecting the dose for geriatric patients.

**[Adverse Reactions]**

The adverse reactions described in this prescribing information are derived from clinical trials and post-marketing reports. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in one clinical trial cannot be directly compared to rates observed in another clinical trial, and may not reflect the rates observed in clinical practice. The following serious adverse reactions are discussed in the Warnings and Precautions section of this prescribing information:

Anaphylactic shock and anaphylactic reactions

Potential for tumor cell mobilization in patients with leukemia

Increased circulating leukocytes and decreased platelet counts

Potential for tumor cell mobilization

Splenomegaly

1. Clinical Trials Experience

Summary of Adverse Reactions from International Clinical Studies

The most common adverse reactions (≥10%) reported in patients receiving this product in combination with G-CSF (regardless of causality)—and occurring at a higher incidence in patients receiving this product during HSC mobilization and collection compared to those receiving placebo—included diarrhea, nausea, fatigue, injection site reactions, headache, arthralgia, dizziness, and vomiting.

Safety data for this product in combination with G-CSF were derived from two placebo-controlled, randomized Phase 3 studies (301 patients) and ten uncontrolled Phase 2 studies (242 patients). Patients were primarily treated with daily subcutaneous injections of 0.24 mg/kg of Plerixafor. In these studies, the median duration of exposure to Plerixafor was 2 days (range: 1 to 7 days).

In two randomized, controlled studies involving patients with Non-Hodgkin Lymphoma (NHL) and Multiple Myeloma (MM), a total of 301 patients were treated in the Plerixafor-plus-G-CSF group, while the placebo-plus-G-CSF group included 292 patients. Patients received G-CSF at a dose of 10 µg/kg daily in the morning, starting 4 days prior to the first subcutaneous injection of 0.24 mg/kg of this product (or placebo) and continuing daily prior to each hematopoietic stem cell collection. Adverse reactions that occurred in ≥25% of patients receiving this product (regardless of causality)—and at a higher incidence in patients receiving this product during stem cell mobilization and collection compared to those receiving placebo—are listed below.

In the randomized, controlled studies, 34% of NHL and MM patients experienced mild to moderate injection site reactions at the site of the subcutaneous Plerixafor injection. These reactions included erythema, hematoma, hemorrhage, induration, inflammation, irritation, pain, paresthesia, pruritus, rash, swelling, and urticaria. Less than 1% of patients experienced mild to moderate hypersensitivity reactions within 30 minutes of receiving this product, including one or more of the following: urticaria (n=2), periorbital edema (n=2), dyspnea (n=1), or hypoxia (n=1). Symptoms were relieved by treatment (e.g., antihistamines, corticosteroids, hydration, or supplemental oxygen) or resolved spontaneously.

Vasovagal reactions, orthostatic hypotension, and/or syncope may occur following subcutaneous injection. In studies involving patients with tumors and healthy volunteers, less than 1% of subjects experienced vasovagal reactions following subcutaneous injection of this product (at doses ≤ 0.24 mg/kg). Most events occurred within 1 hour after administration. Appropriate precautions should be taken due to the potential for these reactions.

Other adverse reactions reported in <5% of patients during HSC mobilization and collection in randomized controlled studies—but considered related to this product—include abdominal pain, hyperhidrosis, abdominal distension, dry mouth, erythema, gastric discomfort, fatigue, oral hypoesthesia, constipation, dyspepsia, and musculoskeletal pain.

Leukocytosis: In clinical trials, a leukocyte count of 100,000/µL or higher was observed on the day prior to or on the day of HSC collection in 7% of patients treated with this product and 1% of patients treated with placebo. No complications or clinical symptoms of leukostasis were observed.

Summary of Adverse Reactions in Chinese Clinical Studies

In a Phase II clinical study (EFC12482) conducted in Chinese patients with NHL, 51 patients were actually exposed to treatment with this product plus G-CSF, while another 49 patients received placebo plus G-CSF. Table 3 lists adverse reactions that occurred in the Plerixafor group with an incidence of ≥1%—and at a higher incidence than in the control group—during the period from Day 4 of G-CSF mobilization through 24 hours after the final HSC collection, and which were considered related to this product.

2. Post-marketing Experience

In addition to the adverse reactions reported in clinical trials, the following adverse reactions have been reported during the post-marketing period for this product. Because these adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or to establish a causal relationship to drug exposure.

Blood and Lymphatic System Disorders: Splenomegaly and splenic rupture

Immune System Disorders: Allergic reactions, including anaphylactic shock

Psychiatric Disorders: Abnormal dreams and nightmares

[ Contraindications ]

This product is contraindicated in patients with a known hypersensitivity to any of its components.

[ Composition ]

The active ingredient of this product is plerixafor. Chemical Name: 1,1'-[1,4-phenylenebis(methylene)]bis-1,4,8,11-tetraazacyclotetradecane. Molecular Formula: C28H54N8. Molecular Weight: 502.79. Excipients: Sodium chloride, Water for Injection (pH adjusted to 6.0–7.5 with hydrochloric acid and/or sodium hydroxide, as needed).

[ Description ]

This product is a clear, colorless to pale yellow liquid.

[ Precautions ]

1. Anaphylactic Shock and Allergic Reactions

Serious allergic reactions, including anaphylaxis, have occurred in patients receiving this product; some of these were life-threatening and accompanied by clinically significant hypotension and shock (see [Adverse Reactions]). Patients should be monitored for signs and symptoms of allergic reactions during and for at least 30 minutes after administration of this product, until clinical stability is achieved following each dose. This product should be administered only in settings where personnel and therapies for the immediate treatment of anaphylaxis and other hypersensitivity reactions are available.

In clinical studies, mild to moderate allergic reactions were observed in less than 1% of patients within 30 minutes after administration of this product (see [Adverse Reactions]).

2. Mobilization of Tumor Cells in Patients with Leukemia

In the process of mobilizing HSCs, plerixafor may cause the mobilization of leukemia cells and subsequent contamination of the apheresis product. Therefore, the use of plerixafor for HSC mobilization and collection in patients with leukemia is not recommended. 3. Hematologic Effects

Leukocytosis

When used in combination with G-CSF, this product may increase circulating leukocyte and HSC counts. Leukocyte counts should be monitored during treatment with this product. For patients with peripheral neutrophil counts exceeding 50 × 10⁹/L, the decision to administer this product should be based on the patient's clinical status.

Thrombocytopenia

Thrombocytopenia has been observed in patients receiving this product. Platelet counts should be monitored in all patients receiving this product and undergoing HSC collection.

4. Potential for Tumor Cell Mobilization

When this product is used in combination with G-CSF for HSC mobilization, tumor cells may be released from the bone marrow and subsequently collected in the leukapheresis product. The potential effects of reinfusing tumor cells have not been adequately studied.

5. Splenomegaly and Splenic Rupture

In extended-duration studies in rats (2 to 4 weeks) involving daily subcutaneous administration of plerixafor at doses approximately 4 times the recommended human dose (based on body surface area), increases in absolute and relative spleen weights associated with extramedullary hematopoiesis were observed. The effect of plerixafor on spleen size in patients has not been specifically evaluated in clinical studies. Cases of splenomegaly and splenic rupture have been reported following the administration of this product in combination with the growth factor G-CSF. Patients receiving this product in combination with G-CSF who experience left upper quadrant abdominal pain and/or scapular or shoulder pain should undergo an assessment for splenic integrity.

6. Embryo-Fetal Toxicity

This product may cause fetal harm when administered to pregnant women. Plerixafor has been shown to be teratogenic in animals. There are no adequate and well-controlled studies of this product in pregnant women. Women of childbearing potential are advised to use effective contraception during treatment with this product. If this product is used during pregnancy, or if the patient becomes pregnant while taking this product, the patient should be apprised of the potential hazard to the fetus (see "Use in Specific Populations: Pregnancy and Lactation").

7. QT/QTc Interval Prolongation

No QT/QTc interval prolongation effect was observed with this product at single doses up to 0.40 mg/kg. In a randomized, double-blind, crossover study, 48 subjects received a single subcutaneous injection of plerixafor (0.24 mg/kg and 0.40 mg/kg) or placebo. The peak concentration following a single subcutaneous dose of 0.40 mg/kg of this product was approximately 1.8 times the peak concentration observed after a single subcutaneous dose of 0.24 mg/kg.

8. Effects on Ability to Drive and Use Machines

This product may affect the ability to drive and use machines. Some patients have experienced dizziness, fatigue, or vasovagal reactions; therefore, caution should be exercised when driving or operating machinery.

[Pharmacological Action]

Plerixafor is a chemokine receptor CXCR4 inhibitor that blocks the binding of CXCR4 to its cognate ligand (stromal cell-derived factor-1α, SDF-1α). Studies suggest that SDF-1α and CXCR4 play a role in the directed migration and homing of human hematopoietic stem cells (HSCs) to the bone marrow. Once within the bone marrow, stem cell CXCR4 helps anchor these cells within the bone marrow stroma, either directly via SDF-1α or indirectly by inducing other adhesion factors. Plerixafor induces leukocytosis and an increase in the number of circulating hematopoietic progenitor cells in mice, dogs, and humans. In canine transplant models, CD34+ cells mobilized by plerixafor demonstrated engraftment potential and long-term regenerative capacity spanning up to one year.

[Storage]

Storage Temperature: 2°C to 8°C (Refrigerate; do not freeze).

Protect from Light: Store in the original carton to protect from light.

Do Not Freeze: Freezing may cause precipitation or structural degradation of the drug; if the product becomes frozen, it must not be used.

Specifications and Parameters

Product Name: Plerixafor Injection (Mozobil) 1.2 mL: 24 mg | Mozobil / Mozifor / Plerixafor Injection 24 mg/1.2 mL (20 mg/mL)

Common Name: Plerixafor Injection

Composition: Plerixafor

Dosage Form: Solution for Injection

Specification: 24 mg/1.2 mL; 1 vial per box

Manufacturer: Hetero Drugs Ltd., India

Indications: This product, in combination with Granulocyte Colony-Stimulating Factor (G-CSF), is indicated for the mobilization of hematopoietic stem cells (HSCs) into the peripheral blood for collection and subsequent autologous transplantation in patients with non-Hodgkin lymphoma (NHL).

Dosage and Administration: Recommended Dosage and Administration

Prior to administration, the vial should be inspected visually for particulate matter and discoloration. If particulate matter or discoloration is present, the product must not be used.

Treatment with this product should begin after the patient has received G-CSF once daily for 4 days. This product should be administered 11 hours prior to the start of each apheresis session, for up to 4 consecutive days.

The recommended subcutaneous dosage is determined by the patient's body weight:

For patients weighing ≤ 83 kg: A fixed dose of 20 mg, OR 0.24 mg/kg of body weight.

For patients weighing > 83 kg: 0.24 mg/kg of body weight.

The volume of this product to be administered is calculated based on the patient's actual body weight. Each vial contains 1.2 mL of solution at a concentration of 20 mg/mL; the volume to be administered to the patient is calculated using the following formula:

0.012 × Patient's Actual Body Weight (kg) = Volume to be Administered (mL)

The patient's body weight should be measured within one week prior to the first dose of Plerixafor to determine the appropriate dosage. In clinical studies, the Plerixafor dose was calculated based on up to 175% of the patient's ideal body weight. The dosage and treatment outcomes for patients whose actual body weight exceeds 175% of their ideal body weight have not been studied. Use the following formulas to determine ideal body weight:

Males (kg): 50 + 2.3 × ((Height (cm) × 0.394) - 60); Females (kg): 45.5 + 2.3 × ((Height (cm) × 0.394) - 60).

Since exposure increases with increasing body weight, the dose of this product must not exceed 40 mg/day. Recommended Concomitant Medication:

G-CSF 10 μg/kg should be administered daily in the morning for 4 consecutive days prior to the first dose of this product, and on each day prior to apheresis.

Dosing in Patients with Renal Impairment:

In patients with moderate to severe renal impairment (estimated creatinine clearance [CLcr] ≤ 50 mL/min), the dose of this product should be reduced by one-third based on body weight (see Table 1). If CLcr is ≤ 50 mL/min, the dose must not exceed 27 mg/day, as doses calculated on a mg/kg basis result in increased plerixafor exposure with increasing body weight (see [Pharmacokinetics]). When the dose is reduced by one-third, systemic drug exposure in patients with moderate to severe renal impairment is similar to that in patients with normal renal function (see [Pharmacokinetics]).

Males:

Creatinine Clearance (mL/min) = [Body Weight (kg) × (140 - Age (years))] / [72 × Serum Creatinine (mg/dL)]

Females:

Creatinine Clearance (mL/min) = 0.85 × Value calculated for males

There is insufficient information to recommend a dosage for patients undergoing dialysis.

Pediatric Patients:

Experience with the use of this product in pediatric patients is limited. The safety and efficacy of this product in children under 18 years of age have not been established.

Geriatric Patients (>65 years of age):

No dose adjustment is required for geriatric patients with normal renal function. Dose adjustment is recommended for geriatric patients with a creatinine clearance ≤ 50 mL/min (see "Renal Impairment" above). In general, because the incidence of decreased renal function increases with age, care should be taken in selecting the dose for geriatric patients.