Idarubicin

12.1 Mechanism of Action Idarubicin hydrochloride has antimitotic and cytotoxic activity through forming complexes with the DNA, inhibiting nucleic acid synthesis, inhibiting topoisomerase II activity, and producing DNA-damaging free radicals.

1 INDICATIONS AND USAGE IDAMYCIN PFS is indicated for the treatment of adult patients with acute myeloid leukemia (AML) as a component of a combination chemotherapy regimen. IDAMYCIN PFS is an anthracycline topoisomerase inhibitor indicated for the treatment of adult patients with acute myeloid leukemia (AML) as a component of a combination chemotherapy regimen. (1)

2 DOSAGE AND ADMINISTRATION Induction Therapy • 12 mg/m 2 intravenously over 10 to 15 minutes on days 1, 2, and 3 of induction in combination with cytarabine 100 mg/m 2 by continuous intravenous infusion daily for 7 days or cytarabine 25 mg/m 2 intravenous bolus followed by cytarabine 200 mg/m 2 continuous intravenous infusion daily for 5 days. (2.1) • IDAMYCIN PFS can be given as part of a combination regimen with other chemotherapeutic drugs. (2.1) • Renal Impairment: Assess renal function prior to therapy. Reduce dosage in renal impairment. ( 2.3 , 8.6 ) • Hepatic Impairment: Assess hepatic function prior to therapy. Avoid or reduce dosage in hepatic impairment. ( 2.4 , 8.7 ) See full prescribing information for preparation and administration instructions. (2.5 , 2.6) 2.1 Recommended Dosage Administer IDAMYCIN PFS 12 mg/m 2 intravenously over 10 to 15 minutes on days 1, 2, and 3 of induction in combination with cytarabine. The cytarabine may be given as 100 mg/m 2 by continuous intravenous infusion daily for 7 days or as cytarabine 25 mg/m 2 intravenous bolus followed by cytarabine 200 mg/m 2 continuous intravenous infusion daily for 5 days. If a response is not achieved with the first induction cycle, a second induction cycle may be administered. Other dosage regimens may be used for a second induction cycle. Individualize the dose and dosing schedule of IDAMYCIN PFS based on the specific regimen administered, disease state, response to treatment, and patient risk factors. 2.2 Dosage Modifications for Adverse Reactions Cardiomyopathy Discontinue IDAMYCIN PFS in patients who develop signs or symptoms of cardiomyopathy [see Warnings and Precautions (5.1) ] . Myelosuppression If patients develop severe myelosuppression, reduce the dose of IDAMYCIN PFS by 25% or as clinically indicated in subsequent cycles [see Warnings and Precautions (5.4)] . Mucositis If patients develop severe mucositis with IDAMYCIN PFS, reduce the dose by 25% in subsequent cycles. If a second cycle is planned, delay administration in patients who develop severe mucositis until this adverse reaction has resolved [see Adverse Reactions (6.1) ] . 2.3 Recommended IDAMYCIN PFS Dosage in Patients with Renal Impairment In patients with renal impairment, reduce the dose of IDAMYCIN PFS as described in Table 1 [see Use in Specific Populations (8.6) ] . Table 1: Recommended IDAMYCIN PFS Dosage for Patients with Renal Impairment Renal Impairment/Estimated GFR Dosage Modification GFR greater than or equal to 30 mL/min No adjustment needed GFR less than 30 mL/min Reduce the dose by 33% Hemodialysis Reduce the dose by 33% 2.4 Recommended IDAMYCIN PFS Dosage in Patients with Hepatic Impairment In patients with hepatic impairment, reduce the dose of IDAMYCIN PFS as described in Table 2 [see Use in Specific Populations (8.7) ] . Table 2: Recommended IDAMYCIN PFS Dosage for Patients with Hepatic Impairment Serum Bilirubin Dosage Less than or equal to 2.6 mg/dL No adjustment needed Greater than 2.6 mg/dL and less than 5 mg/dL Reduce the dose by 50% Greater than 5 mg/dL Avoid Use 2.5 Preparation • IDAMYCIN PFS is a hazardous drug. Follow applicable special handling and disposal procedures. 1 • Do not mix IDAMYCIN PFS or administer as an infusion with other drugs or heparin. • Avoid prolonged contact with any solution of an alkaline pH, as this will result in degradation of IDAMYCIN PFS. • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. • Withdraw the volume of IDAMYCIN PFS needed based on the required dose. • Do not further dilute prior to administration (see section 2.6 Administration). • Discard unused portion. 2.6 Administration • IDAMYCIN PFS is for intravenous infusion only. • Prior to administration, flush the intravenous catheter used for IDAMYCIN PFS administration to ensure patency and to minimize the risk of extravasation. • Administer IDAMYCIN PFS over 10 to 15 minutes into the tubing of a freely running intravenous infusion of 0.9% Sodium Chloride Injection or 5% Dextrose Injection. • Closely monitor the infusion site for extravasation or drug infiltration during administration. Manage cases of extravasation as per institutional guidelines. • Immediately discontinue the infusion if extravasation occurs [see Warnings and Precautions (5.3) ] .

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Cardiomyopathy [see Warnings and Precautions (5.1) ] • Secondary Malignancies [see Warnings and Precautions (5.2) ] • Severe Local Tissue Necrosis with Extravasation [see Warnings and Precautions (5.3) ] • Severe Myelosuppression [see Warnings and Precautions (5.4) ] • Tumor Lysis Syndrome [see Warnings and Precautions (5.5) ] • Hypersensitivity [see Warnings and Precautions (5.6) ] Most common adverse reactions (≥30%) are infection, nausea/vomiting, alopecia, abdominal pain/diarrhea, hemorrhage, mucositis, dermatologic, mental status changes, and pulmonary disorders. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials and Postmarketing Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of IDAMYCIN PFS in combination with cytarabine has been evaluated in four controlled clinical studies with 823 patients with AML randomized to receive idarubicin hydrochloride (n=401) or daunorubicin (n=422) [see Clinical Studies (14) ] . Southeastern Cancer Study Group (SEG) Table 3 below lists the adverse reactions that occurred in patients with AML who received idarubicin hydrochloride in the Southeastern Cancer Study Group (SEG) study. Table 3: Adverse Reactions (≥5%) in Patients with AML Who Received Idarubicin Hydrochloride as Induction Therapy in the SEG Trial Adverse Reactions Idarubicin with Cytarabine (N=110) Daunorubicin with Cytarabine (N=118) All Grades % All Grades % Infection 95 97 Nausea/Vomiting 82 80 Alopecia 77 72 Abdominal Pain/Diarrhea 73 68 Hemorrhage 63 65 Mucositis 50 55 Dermatologic 46 40 Mental Status Changes 41 34 Pulmonary Disorders 39 39 Fever 26 28 Headache 20 24 Cardiac Disorder 16 24 Peripheral Neuropathy 7 9 Clinically relevant adverse reactions in <5% of patients who received idarubicin hydrochloride included pulmonary allergy, seizure, and cerebellar adverse reactions. Other Clinical Trials The following additional adverse reactions associated with the use of idarubicin hydrochloride were identified in clinical studies or postmarketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiac • Asymptomatic declines in Left Ventricular Ejection Fraction (LVEF) • Chest pain • Congestive heart failure • Myocardial infarction • Serious arrhythmias including atrial fibrillation Dermatologic • Bullous erythrodermatous rash (palms and soles) • Generalized rash • Radiation recall (skin reaction) • Urticaria Gastrointestinal • Severe enterocolitis with perforation Hepatic • Increased ALT/AST Renal • Renal impairment