Paclitaxel Protein-bound Particles For Injectable Suspension (albumin-bound): Package Insert and Label Information

PACLITAXEL PROTEIN-BOUND PARTICLES FOR INJECTABLE SUSPENSION (ALBUMIN-BOUND)- paclitaxel injection, powder, lyophilized, for suspension
Apotex Corp.

Paclitaxel Protein-Bound Particles for Injectable Suspension (albumin-bound)

WARNING: SEVERE MYELOSUPPRESSION

Do not administer paclitaxel protein-bound particles for injectable suspension (albumin-bound) therapy to patients with baseline neutrophil counts of less than 1,500 cells/mm3 [see Contraindications (4)].
Monitor for neutropenia, which may be severe and result in infection or sepsis [see Warnings and Precautions (5.1, 5.3)].
Perform frequent complete blood cell counts on all patients receiving paclitaxel protein-bound particles for injectable suspension (albumin-bound) [see Warnings and Precautions (5.1, 5.3)].

1 INDICATIONS AND USAGE

1.1 Metastatic Breast Cancer

Paclitaxel protein-bound particles for injectable suspension (albumin-bound) is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.

1.2 Non-Small Cell Lung Cancer

Paclitaxel protein-bound particles for injectable suspension (albumin-bound) is indicated for the first-line treatment of locally advanced or metastatic non-small cell lung cancer, in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy.

1.3 Adenocarcinoma of the Pancreas

Paclitaxel protein-bound particles for injectable suspension (albumin-bound) is indicated for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas, in combination with gemcitabine.

2 DOSAGE AND ADMINISTRATION

2.1 Important Administration Instructions

DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS. Paclitaxel protein-bound particles for injectable suspension (albumin-bound) has different dosage and administration instructions from other paclitaxel products.

Closely monitor the infusion site for extravasation or drug infiltration during administration. Limiting the infusion of paclitaxel protein-bound particles for injectable suspension (albumin-bound) to 30 minutes may reduce the risk of infusion-related reactions [see Adverse Reactions (6.2)].

Consider premedication in patients who have had prior hypersensitivity reactions to paclitaxel protein-bound particles for injectable suspension (albumin-bound). Do not re-challenge patients who experience a severe hypersensitivity reaction to paclitaxel protein-bound particles for injectable suspension (albumin-bound) [see Contraindications (4) and Warnings and Precautions (5.5)].

2.2 Recommended Dosage for Metastatic Breast Cancer

After failure of combination chemotherapy for metastatic breast cancer or relapse within 6 months of adjuvant chemotherapy, the recommended regimen for paclitaxel protein-bound particles for injectable suspension (albumin-bound) is 260 mg/m2 administered intravenously over 30 minutes every 3 weeks.

2.3 Recommended Dosage for Non-Small Cell Lung Cancer

The recommended dose of paclitaxel protein-bound particles for injectable suspension (albumin-bound) is 100 mg/m2 administered as an intravenous infusion over 30 minutes on Days 1, 8, and 15 of each 21-day cycle. Administer carboplatin on Day 1 of each 21-day cycle immediately after paclitaxel protein-bound particles for injectable suspension (albumin-bound) [see Clinical Studies (14.2)].

2.4 Recommended Dosage for Adenocarcinoma of the Pancreas

The recommended dose of paclitaxel protein-bound particles for injectable suspension (albumin-bound) is 125 mg/m2 administered as an intravenous infusion over 30-40 minutes on Days 1, 8, and 15 of each 28-day cycle. Administer gemcitabine immediately after paclitaxel protein-bound particles for injectable suspension (albumin-bound) on Days 1, 8, and 15 of each 28-day cycle [see Clinical Studies (14.3)].

2.5 Dosage Modifications for Hepatic Impairment

For patients with moderate or severe hepatic impairment, reduce the starting dose of paclitaxel protein-bound particles for injectable suspension (albumin-bound) as shown in Table 1.

Table 1: Recommendations for Starting Dose in Patients with Moderate and Severe Hepatic Impairment
AST = Aspartate Aminotransferase; MBC = Metastatic Breast Cancer; NSCLC = Non-Small Cell Lung Cancer; ULN = Upper limit of normal.a Dosage recommendations are for the first course of therapy. The need for further dose adjustments in subsequent courses should be based on individual tolerance.b A dose increase to 260 mg/m2 for patients with metastatic breast cancer or 100 mg/m2 for patients with non-small cell lung cancer in subsequent courses should be considered if the patient tolerates the reduced dose for two cycles.c Patients with bilirubin levels above the upper limit of normal were excluded from clinical trials for pancreatic or lung cancer.

AST Levels

Bilirubin Levels

Paclitaxel protein-bound particles for injectable suspension (albumin-bound) Dosea

MBC

NSCLC c

Adenocarcinoma of Pancreasc

Moderate

< 10 x ULN

AND

> 1.5 to ≤ 3 x ULN

200 mg/m2 b

80 mg/m2 b

not recommended

Severe

< 10 x ULN

AND

> 3 to ≤ 5 x ULN

200 mg/m2 b

80 mg/m2 b

not recommended

> 10 x ULN

OR

> 5 x ULN

not recommended

not recommended

not recommended

2.6 Dosage Modifications for Adverse Reactions

Metastatic Breast CancerPatients who experience severe neutropenia (neutrophils less than 500 cells/mm3 for a week or longer) or severe sensory neuropathy during paclitaxel protein-bound particles for injectable suspension (albumin-bound) therapy should have dosage reduced to 220 mg/m2 for subsequent courses of paclitaxel protein-bound particles for injectable suspension (albumin-bound). For recurrence of severe neutropenia or severe sensory neuropathy, additional dose reduction should be made to 180 mg/m2. For Grade 3 sensory neuropathy hold treatment until resolution to Grade 1 or 2, followed by a dose reduction for all subsequent courses of paclitaxel protein-bound particles for injectable suspension (albumin-bound) [see Contraindications (4), Warnings and Precautions (5.1, 5.2) and Adverse Reactions (6.1)].

Non-Small Cell Lung Cancer

Do not administer paclitaxel protein-bound particles for injectable suspension (albumin-bound) on Day 1 of a cycle until absolute neutrophil count (ANC) is at least 1500 cells/mm3 and platelet count is at least 100,000 cells/mm3 [see Contraindications (4), Warnings and Precautions (5.1) and Adverse Reactions (6.1)].
In patients who develop severe neutropenia or thrombocytopenia withhold treatment until counts recover to an absolute neutrophil count of at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an absolute neutrophil count of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle. Upon resumption of dosing, permanently reduce paclitaxel protein-bound particles for injectable suspension (albumin-bound) and carboplatin doses as outlined in Table 2.
Withhold paclitaxel protein-bound particles for injectable suspension (albumin-bound) for Grade 3-4 peripheral neuropathy. Resume paclitaxel protein-bound particles for injectable suspension (albumin-bound) and carboplatin at reduced doses (see Table 2) when peripheral neuropathy improves to Grade 1 or completely resolves [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)].
Table 2: Permanent Dose Reductions for Hematologic and Neurologic Adverse Reactions in NSCLC

Adverse Reaction

Occurrence

Weekly Paclitaxel protein-bound particles for injectable suspension (albumin-bound) Dose (mg/m2)

Every 3-Week Carboplatin Dose (AUC mg•min/mL)

Neutropenic Fever (ANC less than 500/mm3 with fever >38°C) ORDelay of next cycle by more than 7 days for ANC less than 1500/mm3 ORANC less than 500/mm3 for more than 7 days

First

75

4.5

Second

50

3

Third

Discontinue Treatment

Platelet count less than 50,000/mm3

First

75

4.5

Second

Discontinue Treatment

Severe sensory Neuropathy – Grade 3 or 4

First

75

4.5

Second

50

3

Third

Discontinue Treatment

Adenocarcinoma of the PancreasDose level reductions for patients with adenocarcinoma of the pancreas, as referenced in Tables 4 and 5, are provided in Table 3.

Table 3: Dose Level Reductions for Patients with Adenocarcinoma of the Pancreas

Dose Level

Paclitaxel protein-bound particles for injectable suspension (albumin-bound) (mg/m2)

Gemcitabine (mg/m2)

Full dose

125

1000

1st dose reduction

100

800

2nd dose reduction

75

600

If additional dose reduction required

Discontinue

Discontinue

Recommended dose modifications for neutropenia and thrombocytopenia for patients with adenocarcinoma of the pancreas are provided in Table 4.

Table 4: Dose Recommendation and Modifications for Neutropenia and/or Thrombocytopenia at the Start of a Cycle or within a Cycle for Patients with Adenocarcinoma of the Pancreas
ANC = Absolute Neutrophil Count

Cycle Day

ANC (cells/mm3)

Platelet count (cells/mm3)

Paclitaxel protein-bound particles for injectable suspension (albumin-bound) / Gemcitabine

Day 1

< 1500

OR

< 100,000

Delay doses until recovery

Day 8

500 to < 1000

OR

50,000 to < 75,000

Reduce 1 dose level

< 500

OR

< 50,000

Withhold doses

Day 15: If Day 8 doses were reduced or given without modification:

500 to < 1000

OR

50,000 to < 75,000

Reduce 1 dose level from Day 8

< 500

OR

< 50,000

Withhold doses

Day 15: If Day 8 doses were withheld:

≥ 1000

OR

≥ 75,000

Reduce 1 dose level from Day 1

500 to < 1000

OR

50,000 to < 75,000

Reduce 2 dose levels from Day 1

< 500

OR

< 50,000

Withhold doses

Recommended dose modifications for other adverse reactions in patients with adenocarcinoma of the pancreas are provided in Table 5.

Table 5: Dose Modifications for Other Adverse Reactions in Patients with Adenocarcinoma of the Pancreas

Adverse Reaction

Paclitaxel protein-bound particles for injectable suspension (albumin-bound)

Gemcitabine

Febrile Neutropenia: Grade 3 or 4

Withhold until fever resolves and ANC ≥ 1500; resume at next lower dose level

Peripheral Neuropathy: Grade 3 or 4

Withhold until improves to ≤ Grade 1; resume at next lower dose level

No dose reduction

Cutaneous Toxicity: Grade 2 or 3

Reduce to next lower dose level; discontinue treatment if toxicity persists

Gastrointestinal Toxicity: Grade 3 mucositis or diarrhea

Withhold until improves to ≤ Grade 1; resume at next lower dose level

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