Doxorubicin Hydrochloride (Page 2 of 7)

3 DOSAGE FORMS AND STRENGTHS

DOXOrubicin HCl Injection, USP: Vials contain 10 mg/5 mL, 20 mg/10 mL, 50 mg/25 mL, and 200 mg/100 mL doxorubicin hydrochloride as a clear red solution.

4 CONTRAINDICATIONS

Doxorubicin is contraindicated in patients with:

• Severe myocardial insufficiency [see Warnings and Precautions (5.1)]
• Recent (occurring within the past 4 to 6 weeks) myocardial infarction [see Warnings and Precautions (5.1)]
• Severe persistent drug-induced myelosuppression [see Warnings and Precautions (5.4)]
• Severe hepatic impairment (defined as Child Pugh Class C or serum bilirubin level greater than 5 mg/dL) [see Warnings and Precautions (5.5)]
• Severe hypersensitivity reaction to doxorubicin including anaphylaxis [see Adverse Reactions (6.2)]

5 WARNINGS AND PRECAUTIONS

5.1 Cardiomyopathy and Arrhythmias

Cardiomyopathy

Doxorubicin can result in myocardial damage, including acute left ventricular failure. The risk of cardiomyopathy is generally proportional to the cumulative exposure. Include prior doses of other anthracyclines or anthracenediones in calculations of total cumulative dosage for doxorubicin. Cardiomyopathy may develop during treatment or up to several years after completion of treatment and can include decrease in LVEF and signs and symptoms of congestive heart failure (CHF). The probability of developing cardiomyopathy is estimated to be 1 to 2% at a total cumulative dose of 300 mg/m² of doxorubicin, 3 to 5% at a dose of 400 mg/m² , 5 to 8% at a dose of 450 mg/m² , and 6 to 20% at a dose of 500 mg/m² , when doxorubicin is administered every 3 weeks. There is an additive or potentially synergistic increase in the risk of cardiomyopathy in patients who have received radiotherapy to the mediastinum or concomitant therapy with other known cardiotoxic agents such as cyclophosphamide and trastuzumab.

Pericarditis and myocarditis have also been reported during or following doxorubicin treatment.

Assess left ventricular cardiac function (e.g., MUGA or echocardiogram) prior to initiation of doxorubicin, during treatment to detect acute changes, and after treatment to detect delayed cardiotoxicity. Increase the frequency of assessments as the cumulative dose exceeds 300 mg/m² . Use the same method of assessment of LVEF at all time points [see Use in Specific Populations (8.4 )].

Consider the use of dexrazoxane to reduce the incidence and severity of cardiomyopathy due to doxorubicin administration in patients who have received a cumulative doxorubicin dose of 300 mg/m² and who will continue to receive doxorubicin.

Arrhythmias

Doxorubicin can result in arrhythmias, including life-threatening arrhythmias, during or within a few hours after doxorubicin administration and at any time point during treatment. Tachyarrhythmias, including sinus tachycardia, premature ventricular contractions, and ventricular tachycardia, as well as bradycardia may occur. Electrocardiographic changes including non-specific ST-T wave changes, atrioventricular and bundle-branch block can also occur. These electrocardiographic changes may be transient and self-limited and may not require dose-modifications of doxorubicin.

5.2 Secondary Malignancies

The risk of developing secondary acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) is increased following treatment with doxorubicin. Cumulative incidences ranged from 0.2% at five years to 1.5% at 10 years in two separate trials involving the adjuvant treatment of women with breast cancer. These leukemias generally occur within 1 to 3 years of treatment.

5.3 Extravasation and Tissue Necrosis

Extravasation of doxorubicin can result in severe local tissue injury manifesting as blistering, ulceration, and necrosis requiring wide excision of the affected area and skin grafting. When given via a peripheral venous line, infuse doxorubicin over 10 minutes or less to minimize the risk of thrombosis or perivenous extravasation. If signs or symptoms of extravasation occur, immediately terminate the injection or infusion [see Dosage and Administration (2.3)]. Extravasation may be present in patients who do not experience a stinging or burning sensation or when blood return is present on aspiration of the infusion needle. If extravasation is suspected, apply ice to the site intermittently for 15 minutes, 4 times a day for 3 days. If appropriate, administer dexrazoxane at the site of extravasation as soon as possible and within the first 6 hours after extravasation.

5.4 Severe Myelosuppression

Doxorubicin can cause myelosuppression. In Study 1, the incidence of severe myelosuppression was: grade 4 leukopenia (0.3%), grade 3 leukopenia (3%), and grade 4 thrombocytopenia (0.1%). A dose-dependent, reversible neutropenia is the predominant manifestation of hematologic toxicity from doxorubicin. When doxorubicin is administered every 21 days, the neutrophil count reaches its nadir 10 to 14 days after administration with recovery usually occurring by the 21st day.

Obtain baseline assessment of blood counts and carefully monitor patients during treatment for possible clinical complications due to myelosuppression.

5.5 Use in Patients with Hepatic Impairment

The clearance of doxorubicin is decreased in patients with elevated serum bilirubin with an increased risk of toxicity [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)]. Reduce the dose of doxorubicin in patients with serum bilirubin levels of 1.2 to 5.0 mg/dL [see Dosage and Administration (2.2)]. Doxorubicin is contraindicated in patients with severe hepatic impairment (defined as Child Pugh Class C or serum bilirubin level greater than 5 mg/dL) [see Contraindications (4)]. Obtain liver tests including SGOT, SGPT, alkaline phosphatase, and bilirubin prior to and during doxorubicin therapy.

5.6 Tumor Lysis Syndrome

Doxorubicin may induce tumor lysis syndrome in patients with rapidly growing tumors. Evaluate blood uric acid levels, potassium, calcium, phosphate, and creatinine after initial treatment. Hydration, urine alkalinization, and prophylaxis with allopurinol to prevent hyperuricemia may minimize potential complications of tumor lysis syndrome.

5.7 Radiation Sensitization and Radiation Recall

Doxorubicin can increase radiation-induced toxicity to the myocardium, mucosa, skin, and liver. Radiation recall, including but not limited to cutaneous and pulmonary toxicity, can occur in patients who receive doxorubicin after prior radiation therapy.

5.8 Embryofetal Toxicity

Doxorubicin can cause fetal harm when administered to a pregnant woman. Doxorubicin was teratogenic and embryotoxic in rats and rabbits at doses lower than the recommended human dose.

If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus [see Use in Specific Populations (8.1)].

Advise female patients of reproductive potential to use highly effective contraception during treatment with doxorubicin and for 6 months after treatment. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking doxorubicin [see Use in Specific Populations (8.1) and (8.6 )].

6 ADVERSE REACTIONS

The following adverse reactions are discussed in more detail in other sections of the labeling.

• Cardiomyopathy and Arrhythmias [see Warnings and Precautions (5.1)]
• Secondary Malignancies [see Warnings and Precautions (5.2)]
• Extravasation and Tissue Necrosis [see Warnings and Precautions (5.3)]
• Severe Myelosuppression [see Warnings and Precautions (5.4)]
• Tumor Lysis Syndrome [see Warnings and Precautions (5.6)]
• Radiation Sensitization and Radiation Recall [see Warnings and Precautions (5.7)]