IDARUBICIN: 5,038 Adverse Event Reports & Safety Profile

DESCRIPTION Idarubicin Hydrochloride Injection, USP contains idarubicin hydrochloride, USP and is a sterile, semi-synthetic, preservative-free solution (PFS) antineoplastic anthracycline for intravenous use. Chemically, idarubicin hydrochloride, USP is 5, 12-Naphthacenedione, 9-acetyl-7-[(3-amino-2,3,6-trideoxy-α-L- lyxo -hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,9,11-trihydroxyhydrochloride, (7S- cis ). The structural formula is as follows: C 26 H 27 NO 9

• HCl M.W.

533.95 Idarubicin Hydrochloride Injection, USP is a sterile, clear, orange-red, isotonic parenteral preservative-free solution, available in 5 mL (5 mg), 10 mL (10 mg) and 20 mL (20 mg) single-dose-only vials. Each mL contains idarubicin hydrochloride USP, 1 mg (equivalent to 0.93 mg idarubicin free base) and the following inactive ingredients: glycerin USP, 25 mg and q.s. water for injection, USP. Hydrochloric acid and/or sodium hydroxide is used to adjust pH to a target of 3.5.

Structural

Formula

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)

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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) ]</span> . Myelosuppression If patients develop severe myelosuppression, reduce the dose of IDAMYCIN PFS by 25% or as clinically indicated in subsequent cycles <span class="opacity-50 text-xs">[see Warnings and Precautions (5.4)]</span> . 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 <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> .

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 <span class="opacity-50 text-xs">[see Use in Specific Populations (8.6) ]</span> .

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 <span class="opacity-50 text-xs">[see Use in Specific Populations (8.7) ]</span> .

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) ] .

None. None. (4)

ADVERSE REACTIONS Approximately 550 patients with AML have received idarubicin in combination with cytarabine in controlled clinical trials worldwide. In addition, over 550 patients with acute leukemia have been treated in uncontrolled trials utilizing idarubicin as a single agent or in combination. The table below lists the adverse experiences reported in U.S.

Study

2 (see CLINICAL STUDIES ) and is representative of the experiences in other studies. These adverse experiences constitute all reported or observed experiences, including those not considered to be drug related. Patients undergoing induction therapy for AML are seriously ill due to their disease, are receiving multiple transfusions, and concomitant medications including potentially toxic antibiotics and antifungal agents. The contribution of the study drug to the adverse experience profile is difficult to establish.

Induction Phase

Percentage of Patients Adverse Experiences IDR (N=110) DNR (N=118)

Infection

95% 97% Nausea & Vomiting 82% 80% Hair Loss 77% 72% Abdominal Cramps/Diarrhea 73% 68% Hemorrhage 63% 65% Mucositis 50% 55% Dermatologic 46% 40% Mental Status 41% 34% Pulmonary-Clinical 39% 39% Fever (not elsewhere classified) 26% 28% Headache 20% 24% Cardiac-Clinical 16% 24% Neurologic-Peripheral Nerves 7% 9% Pulmonary Allergy 2% 4% Seizure 4% 5% Cerebellar 4% 4% Abbreviations: IDR=Idarubicin; DNR=Daunorubicin The duration of aplasia and incidence of mucositis were greater on the IDR arm than the DNR arm, especially during consolidation in some U.S. controlled trials (see CLINICAL STUDIES ). The following information reflects experience based on U.S. controlled clinical trials.

Myelosuppression

Severe myelosuppression is the major toxicity associated with idarubicin therapy, but this effect of the drug is required in order to eradicate the leukemic clone. During the period of myelosuppression, patients are at risk of developing infection and bleeding which may be life-threatening or fatal.

Gastrointestinal

Nausea and/or vomiting, mucositis, abdominal pain and diarrhea were reported frequently, but were severe (equivalent to WHO Grade 4) in less than 5% of patients. Severe enterocolitis with perforation has been reported rarely. The risk of perforation may be increased by instrumental intervention. The possibility of perforation should be considered in patients who develop severe abdominal pain and appropriate steps for diagnosis and management should be taken.

Dermatologic

Alopecia was reported frequently and dermatologic reactions including generalized rash, urticaria and a bullous erythrodermatous rash of the palms and soles have occurred. The dermatologic reactions were usually attributed to concomitant antibiotic therapy. Local reactions including hives at the injection site have been reported. Recall of skin reaction due to prior radiotherapy has occurred with idarubicin administration. Hepatic and Renal Changes in hepatic and renal function tests have been observed. These changes were usually transient and occurred in the setting of sepsis and while patients were receiving potentially hepatotoxic and nephrotoxic antibiotics and antifungal agents. Severe changes in renal function (equivalent to WHO Grade 4) occurred in no more than 1% of patients, while severe changes in hepatic function (equivalent to WHO Grade 4) occurred in less than 5% of patients.

Cardiac

Congestive heart failure (frequently attributed to fluid overload), serious arrhythmias including atrial fibrillation, chest pain, myocardial infarction and asymptomatic declines in LVEF have been reported in patients undergoing induction therapy for AML. Myocardial insufficiency and arrhythmias were usually reversible and occurred in the setting of sepsis, anemia and aggressive intravenous fluid administration. The events were reported more frequently in patients over age 60 years and in those with pre-existing cardiac disease. To report SUSPECTED ADVERSE REACTIONS, contact Meitheal Pharmaceuticals, Inc. at 1-844-824-8426 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

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 <span class="opacity-50 text-xs">[see Dosage and Administrations (2.6)]</span>.

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 <span class="opacity-50 text-xs">[see Dosage and Administrations (2.2) ]</span> . 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 <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . 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 <span class="opacity-50 text-xs">[see Use in Specific Populations (8.6) ]</span> . 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 &lt;30 mL/min <span class="opacity-50 text-xs">[see Dosage and Administration (2.3)]</span>.

5.8 Use in Patients with Hepatic Impairment Hepatic impairment may result in increased risk of toxicity in patients treated with IDAMYCIN PFS <span class="opacity-50 text-xs">[see Use in Specific Populations (8.7) ]</span> . 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.4) ]</span>.

5.9 Embryo-Fetal Toxicity Based on findings from animal reproductive studies and its mechanism of action <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.1) ]</span> , 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 <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1 , 8.3) and Nonclinical Toxicology (13.1) ]</span>.

PRECAUTIONS General Therapy with idarubicin requires close observation of the patient and careful laboratory monitoring. Hyperuricemia secondary to rapid lysis of leukemic cells may be induced. Appropriate measures must be taken to prevent hyperuricemia and to control any systemic infection before beginning therapy. Extravasation of idarubicin can cause severe local tissue necrosis. Extravasation may occur with or without an accompanying stinging or burning sensation even if blood returns well on aspiration of the infusion needle. If signs or symptoms of extravasation occur the injection or infusion should be terminated immediately and restarted in another vein (see DOSAGE AND ADMINISTRATION ).

Laboratory Tests

Frequent complete blood counts and monitoring of hepatic and renal function tests are recommended. Carcinogenesis, Mutagenesis, Impairment of Fertility Formal long-term carcinogenicity studies have not been conducted with idarubicin. Idarubicin and related compounds have been shown to have mutagenic and carcinogenic properties when tested in experimental models (including bacterial systems, mammalian cells in culture and female Sprague-Dawley rats). In male dogs given 1.8 mg/m 2 /day 3 times/week (about one seventh the weekly human dose on a mg/m 2 basis) for 13 weeks, or 3 times the human dose, testicular atrophy was observed with inhibition of spermatogenesis and sperm maturation with few or no mature sperm. These effects were not readily reversed after a recovery of 8 weeks. Pregnancy (See WARNINGS ).

Nursing

Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from idarubicin, mothers should discontinue nursing prior to taking this drug and do not breastfeed during treatment and for 14 days after last dose.

Pediatric Use

Safety and effectiveness in children have not been established.

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 ).