DOXORUBICIN HYDROCHLORIDE

DOXORUBICIN HYDROCHLORIDE- doxorubicin hydrochloride injectable, liposomal
Zydus Pharmaceuticals USA Inc.

BOXED WARNING

WARNING: CARDIOMYOPATHY and INFUSION-RELATED REACTIONS

  • Doxorubicin hydrochloride liposomal infusion can cause myocardial damage, including acute left ventricular failure. The risk of cardiomyopathy was 11% when the cumulative anthracycline dose was between 450 mg/m2 to 550 mg/m2. Assess left ventricular cardiac function prior to initiation of doxorubicin hydrochloride liposomal infusion and during and after treatment [see Warnings and Precautions (5.1)].
  • Serious, life-threatening, and fatal infusion-related reactions can occur with doxorubicin hydrochloride liposomal infusion. Acute infusion-related reactions occurred in 11% of patients with solid tumors. Withhold doxorubicin hydrochloride liposomal infusion for infusion-related reactions and resume at a reduced rate. Discontinue doxorubicin hydrochloride liposomal infusion for serious or life-threatening infusion-related reactions [see Warnings and Precautions (5.2)].

1 INDICATIONS AND USAGE

1.1 Ovarian Cancer

Doxorubicin hydrochloride liposomal infusion is indicated for the treatment of patients with ovarian cancer whose disease has progressed or recurred after platinum-based chemotherapy.

1.2 AIDS-Related Kaposi’s Sarcoma

Doxorubicin hydrochloride liposomal infusion is indicated for the treatment of AIDS-related Kaposi’s sarcoma in patients after failure of prior systemic chemotherapy or intolerance to such therapy.

1.3 Multiple Myeloma

Doxorubicin hydrochloride liposomal infusion, in combination with bortezomib, is indicated for the treatment of patients with multiple myeloma who have not previously received bortezomib and have received at least one prior therapy.

2 DOSAGE AND ADMINISTRATION

2.1 Important Use Information

Do not substitute doxorubicin hydrochloride liposomal infusion for other doxorubicin hydrochloride products.

Do not administer as an undiluted suspension or as an intravenous bolus [see Warnings and Precautions (5.2)].

2.2 Ovarian Cancer

The recommended dose of doxorubicin hydrochloride liposomal infusion is 50 mg/m2 intravenously over 60 minutes every 28 days until disease progression or unacceptable toxicity.

2.3 AIDS-Related Kaposi’s Sarcoma

The recommended dose of doxorubicin hydrochloride liposomal infusion is 20 mg/m2 intravenously over 60 minutes every 21 days until disease progression or unacceptable toxicity.

2.4 Multiple Myeloma

The recommended dose of doxorubicin hydrochloride liposomal infusion is 30 mg/m2 intravenously over 60 minutes on day 4 of each 21-day cycle for eight cycles or until disease progression or unacceptable toxicity. Administer doxorubicin hydrochloride liposomal infusion after bortezomib on day 4 of each cycle [see Clinical Studies (14.3)].

2.5 Dose Modifications for Adverse Reactions

Do not increase doxorubicin hydrochloride liposomal infusion after a dose reduction for toxicity.

Table 1: Recommended Dose Modifications for Hand-Foot Syndrome, Stomatitis, or Hematologic Adverse Reactions
Toxicity Dose Adjustment
Hand-Foot Syndrome (HFS)
Grade 1: Mild erythema, swelling, or desquamation not interfering with daily activities
  • If no previous Grade 3 or 4 HFS: no dose adjustment.
  • If previous Grade 3 or 4 HFS: delay dose up to 2 weeks, then decrease dose by 25%.
Grade 2: Erythema, desquamation, or swelling interfering with, but not precluding normal physical activities; small blisters or ulcerations less than 2 cm in diameter
  • Delay dosing up to 2 weeks or until resolved to Grade 0-1.
  • Discontinue doxorubicin hydrochloride liposomal infusion if no resolution after 2 weeks.
  • If resolved to Grade 0-1 within 2 weeks:
o And no previous Grade 3 or 4 HFS: continue treatment at previous dose. o And previous Grade 3 or 4 toxicity: decrease dose by 25%.
Grade 3: Blistering, ulceration, or swelling interfering with walking or normal daily activities; cannot wear regular clothing
  • Delay dosing up to 2 weeks or until resolved to Grade 0-1, then decrease dose by 25%.
  • Discontinue doxorubicin hydrochloride liposomal infusion if no resolution after 2 weeks.
Grade 4: Diffuse or local process causing infectious complications, or a bed ridden state or hospitalization
  • Delay dosing up to 2 weeks or until resolved to Grade 0-1, then decrease dose by 25%.
  • Discontinue doxorubicin hydrochloride liposomal infusion if no resolution after 2 weeks.
Stomatitis
Grade 1: Painless ulcers, erythema, or mild soreness
  • If no previous Grade 3 or 4 toxicity: no dose adjustment.
  • If previous Grade 3 or 4 toxicity: delay up to 2 weeks then decrease dose by 25%.
Grade 2: Painful erythema, edema, or ulcers, but can eat
  • Delay dosing up to 2 weeks or until resolved to Grade 0-1.
  • Discontinue doxorubicin hydrochloride liposomal infusion if there is no resolution after 2 weeks.
  • If resolved to Grade 0-1 within 2 weeks:
o And no previous Grade 3 or 4 stomatitis: resume treatment at previous dose. o And previous Grade 3 or 4 toxicity: decrease dose by 25%.
Grade 3: Painful erythema, edema, or ulcers, and cannot eat
  • Delay dosing up to 2 weeks or until resolved to Grade 0-1. Decrease dose by 25% and return to original dose interval.
  • If after 2 weeks there is no resolution, discontinue doxorubicin hydrochloride liposomal infusion.
Grade 4: Requires parenteral or enteral support
  • Delay dosing up to 2 weeks or until resolved to Grade 0-1. Decrease dose by 25% and return to original dose interval.
  • If after 2 weeks there is no resolution, discontinue doxorubicin hydrochloride liposomal infusion.
Neutropenia or Thrombocytopenia
Grade 1 No dose reduction
Grade 2 Delay until ANC ≥ 1,500 and platelets ≥ 75,000; resume treatment at previous dose
Grade 3 Delay until ANC ≥ 1,500 and platelets ≥ 75,000; resume treatment at previous dose
Grade 4 Delay until ANC ≥ 1,500 and platelets ≥ 75,000; resume at 25% dose reduction or continue previous dose with prophylactic granulocyte growth factor
Table 2: Recommended Dose Modifications of Doxorubicin Hydrochloride Liposomal Infusion for Toxicity When Administered in Combination With Bortezomib
Toxicity Doxorubicin Hydrochloride Liposomal Infusion
Fever ≥38°C and ANC <1,000/mm3
  • Withhold dose for this cycle if before Day 4;
  • Decrease dose by 25%, if after Day 4 of previous cycle.
On any day of drug administration after Day 1 of each cycle:
  • Platelet count <25,000/mm3
  • Hemoglobin <8 g/dL
  • ANC <500/mm3
  • Withhold dose for this cycle if before Day 4;
  • Decrease dose by 25%, if after Day 4 of previous cycle AND if bortezomib is reduced for hematologic toxicity.
Grade 3 or 4 non-hematologic drug related toxicity Do not dose until recovered to Grade <2, then reduce dose by 25%.

For neuropathic pain or peripheral neuropathy, no dosage adjustments are required for doxorubicin hydrochloride liposomal infusion. Refer to bortezomib manufacturer’s prescribing information.

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