Idarubicin

5 WARNINGS AND PRECAUTIONS • Myelosuppression : Severe myelosuppression resulting in severe infection, septic shock, hemorrhage, or death may occur. Obtain complete blood counts prior to each treatment and closely monitor patients during treatment for possible clinical complications due to myelosuppression. (5.4) • Tumor Lysis Syndrome : During treatment, monitor blood chemistries and manage promptly. Treat as clinically indicated. (5.5) • Hypersensitivity : Monitor patients for hypersensitivity reactions and manage as clinically indicated. (5.6) • Renal Impairment : Assess renal function prior to and during treatment. Reduce the dose in patients on dialysis or those with GFR <30 mL/min. ( 2.3 , 5.7 , 8.6 ) • Hepatic Impairment : Obtain liver tests prior to and during therapy. Reduce dose in patients with serum bilirubin levels of 2.6 to 5 mg/dL. Avoid use in patients with serum bilirubin greater than 5 mg/dL. ( 2.4 , 5.8 , 8.7 ) • Embryo-Fetal Toxicity : Can cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception. ( 5.9 , 8.1 , 8.3 ) 5.1 Cardiomyopathy IDAMYCIN PFS can cause myocardial damage, including left ventricular failure, or congestive heart failure (CHF). In pediatric patients, anthracycline-induced cardiomyopathy included impaired left ventricular systolic performance, reduced contractility, congestive heart failure, or death. Cardiomyopathy may develop during treatment with IDAMYCIN PFS or up to several years after completion of treatment. Cases of pericarditis and myocarditis have also been reported at a lower incidence and may not be dose related. The risk of cardiomyopathy is generally proportional to the cumulative exposure to anthracycline drugs. Include prior doses of other anthracyclines or anthracenediones in calculations of total cumulative dosage for idarubicin hydrochloride. In adult patients, at cumulative doses exceeding 90 mg/m 2 of idarubicin hydrochloride, there is an increased incidence of drug-induced congestive heart failure. The tolerable limit may be lower in patients who received radiation therapy to the mediastinum. Concomitant use of cardiotoxic drugs may increase the risk of idarubicin-induced cardiac toxicity or may result in cardiotoxicity at a lower cumulative anthracycline dose. Calculate the lifetime cumulative anthracycline exposure prior to each cycle of IDAMYCIN PFS. IDAMYCIN PFS use is not recommended in patients whose lifetime anthracycline exposure has reached the maximum cumulative limit. Assess left ventricular cardiac function (e.g., MUGA or echocardiogram) prior to initiation of IDAMYCIN PFS. Perform serial cardiac monitoring, which may include electrocardiograms and/or determination of systolic ejection fraction, in all patients during treatment to detect acute changes and after treatment to detect delayed cardiotoxicity. Increase the frequency of assessments as the cumulative anthracycline dose increases or in patients with risk factors for cardiac toxicity. Consider long-term periodic evaluation of cardiac function in these patients. Adults 65 years of age and older, or with pre-existing cardiac disease, may have an increased risk of anthracycline-induced cardiac toxicity, or may experience cardiotoxicity at a lower cumulative anthracycline dose. Discontinue IDAMYCIN PFS in patients who develop signs or symptoms of cardiomyopathy. 5.2 Secondary Malignancies The risk of developing secondary AML and myelodysplastic syndrome (MDS) is increased following treatment with IDAMYCIN PFS. AML and MDS have occurred in patients treated with anthracycline topoisomerase inhibitors when used in combination with other antineoplastic agents or radiation therapy. Monitor patients long-term for the development of secondary malignancies. 5.3 Severe Local Tissue Necrosis with Extravasation Extravasation of IDAMYCIN PFS at the site of intravenous administration can cause severe local tissue injury including blistering, ulceration, thrombophlebitis, and necrosis requiring wide excision of the affected area and skin grafting. Monitor patients during the IDAMYCIN PFS infusion for signs and symptoms of extravasation (including erythematous streaking, burning, or stinging sensations, thrombosis) or perivenous infiltration. If extravasation occurs during administration, immediately discontinue the intravenous injection or continuous intravenous infusion of IDAMYCIN PFS and manage per institutional guidelines [see Dosage and Administrations (2.6)]. 5.4 Severe Myelosuppression Severe myelosuppression resulting in severe infection, septic shock, hemorrhage, or death may occur during treatment with IDAMYCIN PFS, and some patients may require blood product transfusions. Obtain complete blood counts prior to each treatment and closely monitor patients during treatment for possible clinical complications due to myelosuppression. Delay next dose of IDAMYCIN PFS if severe myelosuppression has not improved. Consider dose reduction for patients with prolonged myelosuppression [see Dosage and Administrations (2.2) ] . Discontinue IDAMYCIN PFS in patients who develop severe myelosuppression. 5.5 Tumor Lysis Syndrome IDAMYCIN PFS may induce tumor lysis syndrome. Patients at risk of tumor lysis syndrome are those with rapidly growing tumors or high tumor burden prior to treatment. During and after initial treatment, monitor blood chemistries and manage abnormalities promptly. Hydration, urine alkalinization, and prophylaxis with allopurinol to prevent hyperuricemia may minimize potential complications of tumor lysis syndrome. 5.6 Hypersensitivity IDAMYCIN PFS can cause hypersensitivity reactions. Clinical signs and symptoms of hypersensitivity may include, but are not limited to, rash and urticaria [see Adverse Reactions (6.1) ] . Monitor patients for signs and symptoms of hypersensitivity during treatment with IDAMYCIN PFS and manage as clinically indicated. 5.7 Use in Patients with Renal Impairment Renal impairment may result in increased risk of toxicity in patients treated with IDAMYCIN PFS [see Use in Specific Populations (8.6) ] . Assess renal function prior to and during treatment with IDAMYCIN PFS. Reduce the dose of IDAMYCIN PFS in patients on dialysis or those with GFR <30 mL/min [see Dosage and Administration (2.3)]. 5.8 Use in Patients with Hepatic Impairment Hepatic impairment may result in increased risk of toxicity in patients treated with IDAMYCIN PFS [see Use in Specific Populations (8.7) ] . Obtain liver tests including ALT, AST, alkaline phosphatase, and bilirubin prior to and during therapy. Reduce the dose of IDAMYCIN PFS in patients with serum bilirubin levels of 2.6 to 5 mg/dL. Avoid use of IDAMYCIN PFS in patients with serum bilirubin greater than 5 mg/dL [see Dosage and Administration (2.4) ]. 5.9 Embryo-Fetal Toxicity Based on findings from animal reproductive studies and its mechanism of action [see Clinical Pharmacology (12.1) ] , IDAMYCIN PFS can cause fetal harm when administered to pregnant women. Idarubicin hydrochloride was embryotoxic and teratogenic in rats at doses of 1.2 mg/m 2 /day or 0.1 times the human dose, which was not maternally toxic. Idarubicin hydrochloride was embryotoxic but not teratogenic in rabbits at doses of 2.4 mg/m 2 /day or 0.2 times the human dose, which was maternally toxic. Advise women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with IDAMYCIN PFS and for 6.5 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception for 3.5 months after the last dose [see Use in Specific Populations (8.1 , 8.3) and Nonclinical Toxicology (13.1) ].

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

8 USE IN SPECIFIC POPULATIONS • Lactation : Advise not to breastfeed. (8.2) • Infertility : May impair fertility. (8.3) 8.1 Pregnancy Risk Summary Based on findings from animal reproduction studies and its mechanism of action, IDAMYCIN PFS can cause fetal harm when administered to a pregnant woman [see Warnings and Precautions (5.9) ] . There are no available data on the use of IDAMYCIN PFS in pregnant women to evaluate for a drug-associated risk. Idarubicin hydrochloride was embryotoxic and teratogenic in rats at doses of 1.2 mg/m 2 /day or 0.1 times the human dose. Idarubicin hydrochloride was embryotoxic but not teratogenic in rabbits at doses of 2.4 mg/m 2 /day or 0.2 times the human dose [see Data ] . Advise women of the potential risk to the fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Idarubicin hydrochloride was embryotoxic and teratogenic in the rat at a dose of 1.2 mg/m 2 /day or 0.1 times the human dose, which was not maternally toxic. Idarubicin hydrochloride was embryotoxic but not teratogenic in the rabbit even at a dose of 2.4 mg/m 2 /day or 0.2 times the human dose, which was maternally toxic. 8.2 Lactation Risk Summary There are no data on the presence of idarubicin hydrochloride or its metabolites in human milk, the effects on the breastfed child or the effects on milk production. Because of the potential for serious adverse reactions in the breastfed child, including myelosuppression, cardiac toxicity and malignancy, advise women not to breastfeed during treatment with IDAMYCIN PFS and for 14 days after the last dose. 8.3 Females and Males of Reproductive Potential Based on mechanism of action and findings in animals, IDAMYCIN PFS can cause fetal harm [see Use in Specific Populations (8.1) ] . Pregnancy Testing Verify the pregnancy status of female patients of reproductive potential prior to initiating therapy with IDAMYCIN PFS. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with IDAMYCIN PFS and for 6.5 months after the last dose. Males Based on the genotoxicity potential, advise males with female partners of reproductive potential to use effective contraception during treatment with IDAMYCIN PFS and for 3.5 months after the last dose. Infertility Based on animal studies and mechanism of action, IDAMYCIN PFS may impair fertility in males and females of reproductive potential [see Nonclinical Toxicology (13.1) ] . It is not known if these effects are reversible. 8.4 Pediatric Use The safety and effectiveness of IDAMYCIN PFS in pediatric patients have not been established. Pediatric patients may be at greater risk for anthracycline-induced acute manifestations of cardiotoxicity or late cardiovascular dysfunction. The safety and effectiveness of idarubicin hydrochloride were assessed but not established in two open label clinical studies in pediatric patients aged 1 to <17 years with leukemia and solid tumors. The pharmacokinetics of idarubicin hydrochloride in these pediatric patients were within range of that observed in adult patients given a similar dose based on body surface area. Idarubicin hydrochloride and idarubicinol were detected in CSF samples obtained in these patients; the clinical relevance of these findings is unknown. 8.5 Geriatric Use Patients over 60 years of age who were undergoing induction therapy experienced congestive heart failure, serious arrhythmias, chest pain, myocardial infarction, and asymptomatic declines in LVEF more frequently than younger patients [see Adverse Reactions (6.1) ] . 8.6 Renal Impairment Reduce dosage of IDAMYCIN PFS in patients with GFR less than 30 mL/min and in patients on hemodialysis [see Dosage and Administration (2.3) ] . Renal function should be evaluated prior to and during treatment with IDAMYCIN PFS. The effect of renal impairment on idarubicin hydrochloride or idarubicinol pharmacokinetics is unknown [see Clinical Pharmacology (12.3) ] . However, renal impairment can affect the disposition of idarubicin hydrochloride based on a mechanistic understanding of idarubicin hydrochloride elimination. Treatment was not given if creatinine serum levels exceeded 2 mg/dL in multiple clinical trials. 8.7 Hepatic Impairment Reduce dosage of IDAMYCIN PFS in patients with serum bilirubin levels greater than 2.6 mg/dL and less than 5 mg/dL [see Dosage and Administration (2.4) ] . Do not administer IDAMYICN PFS in patients with serum bilirubin levels greater than 5 mg/dL. Liver function should be evaluated prior to and during treatment with IDAMYCIN PFS. The effect of hepatic impairment on idarubicin hydrochloride or idarubicinol pharmacokinetics is unknown [see Clinical Pharmacology (12.3) ] . However, hepatic impairment can affect the disposition of idarubicin hydrochloride based on a mechanistic understanding of idarubicin hydrochloride elimination.