1.1 Adjuvant Breast Cancer

Doxorubicin hydrochloride, USP is indicated as a component of multi-agent adjuvant chemotherapy for treatment of women with axillary lymph node involvement following resection of primary breast cancer [see Clinical Studies (14)].

1.2 Other Cancers

Doxorubicin hydrochloride, USP is indicated for the treatment of

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acute lymphoblastic leukemia

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acute myeloblastic leukemia

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Hodgkin lymphoma

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non-Hodgkin lymphoma (NHL)

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metastatic breast cancer

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metastatic Wilms' tumor

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metastatic neuroblastoma

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metastatic soft tissue sarcoma

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metastatic bone sarcoma

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metastatic ovarian carcinoma

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metastatic transitional cell bladder carcinoma

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metastatic thyroid carcinoma

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metastatic gastric carcinoma

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metastatic bronchogenic carcinoma

2.1 Recommended Dose

2.2 Dose Modifications

2.3 Preparation and Administration

2.4 Procedures for Proper Handling and Disposal

Handle and dispose of doxorubicin hydrochloride, USP consistent with recommendations for the handling and disposal of hazardous drugs.1

Treat accidental contact with the skin or eyes immediately by copious lavage with water, or soap and water, or sodium bicarbonate solution. Do not abrade the skin by using a scrub brush. Seek medical attention.

Doxorubicin hydrochloride for injection, USP: Vials contain 10 mg and 50 mg doxorubicin hydrochloride as a red-orange lyophilized powder.

Doxorubicin hydrochloride is contraindicated in patients with:

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Severe myocardial insufficiency [see Warnings and Precautions (5.1)]

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Recent (occurring within the past 4-6 weeks) myocardial infarction [see Warnings and Precautions (5.1)]

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Severe persistent drug-induced myelosuppression [see Warnings and Precautions (5.4)]

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Severe hepatic impairment (defined as Child Pugh Class C or serum bilirubin level greater than 5 mg/dL) [see Warnings and Precautions (5.5)]

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Severe hypersensitivity reaction to doxorubicin hydrochloride including anaphylaxis [see Adverse Reactions (6.2)]

5.1 Cardiomyopathy and Arrhythmias

5.2 Secondary Malignancies

The risk of developing secondary acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) is increased following treatment with doxorubicin hydrochloride. 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  hydrochloride  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 hydrochloride 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 hydrochloride. When doxorubicin hydrochloride 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 hydrochloride in patients with serum bilirubin levels of 1.2 to 5 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 hydrochloride therapy.

5.6 Tumor Lysis Syndrome

Doxorubicin hydrochloride 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 hydrochloride 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 hydrochloride after prior radiation therapy.

5.8 Embryofetal Toxicity

Doxorubicin hydrochloride can cause fetal harm when administered to a pregnant woman. Doxorubicin hydrochloride 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 hydrochloride 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 hydrochloride [see Use in Specific Populations (8.1) and (8.6)].

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

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Cardiomyopathy and Arrhythmias [see Warnings and Precautions (5.1)]

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Secondary Malignancies [see Warnings and Precautions (5.2)]

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Extravasation and Tissue Necrosis [see Warnings and Precautions (5.3)]

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Severe Myelosuppression [see Warnings and Precautions (5.4)]

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Tumor Lysis Syndrome [see Warnings and Precautions (5.6)]

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Radiation Sensitization and Radiation Recall [see Warnings and Precautions (5.7)]

6.1 Clinical Trial Experience in Breast Cancer

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 clinical practice.

The safety data below were collected from 1492 women who received doxorubicin hydrochloride at a dose of 60 mg/m2 and cyclophosphamide at a dose of 600 mg/m2 (AC) every 3 weeks for 4 cycles for the adjuvant treatment of axillary lymph node positive breast cancer. The median number of cycles received was 4. Selected adverse reactions reported in this study are provided in Table 1. No treatment-related deaths were reported in patients on either arm of the study.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of doxorubicin hydrochloride. Because these reactions are 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-cardiogenic shock

Cutaneous-Skin and nail hyperpigmentation, oncolysis, rash, itching, photosensitivity, urticaria, acral erythema, palmar plantar erythrodysesthesia

Gastrointestinal-Nausea, mucositis, stomatitis, necrotizing colitis, typhlitis, gastric erosions, gastrointestinal tract bleeding, hematochezia, esophagitis, anorexia, abdominal pain, dehydration, diarrhea, hyperpigmentation of the oral mucosa

Hypersensitivity-Anaphylaxis

Laboratory Abnormalities-Increased alanine aminotransferase, increased aspartate aminotransferase

Neurological-Peripheral sensory and motor neuropathy, seizures, coma

Ocular-Conjunctivitis, keratitis, lacrimation

Vascular-Phlebosclerosis, phlebitis/thrombophlebitis, hot flashes, thromboembolism

Other-Malaise/asthenia, fever, chills, weight gain

7.1 Effect of CYP3A4 Inhibitors, Inducers and P-gp

Doxorubicin is a major substrate of cytochrome P450 CYP3A4 and CYP2D6, and P-glycoprotein (P-gp). Clinically significant interactions have been reported with inhibitors of CYP3A4, CYP2D6, and/or P-gp (e.g., verapamil), resulting in increased concentration and clinical effect of doxorubicin. Inducers of CYP3A4 (e.g., phenobarbital, phenytoin, St. John's Wort) and P-gp inducers may decrease the concentration of doxorubicin. Avoid concurrent use of doxorubicin hydrochloride with inhibitors and inducers of CYP3A4, CYP2D6, or P-gp.

7.2 Trastuzumab

Concurrent use of trastuzumab and doxorubicin hydrochloride results in an increased risk of cardiac dysfunction. Avoid concurrent administration of doxorubicin and trastuzumab. The appropriate interval for administering doxorubicin following trastuzumab therapy has not been determined [see Warnings and Precautions (5.1)].

7.3 Paclitaxel

Paclitaxel, when given prior to doxorubicin hydrochloride, increases the plasma-concentrations of doxorubicin and its metabolites. Administer doxorubicin hydrochloride prior to paclitaxel if used concomitantly.

7.4 Dexrazoxane

Do not administer dexrazoxane as a cardioprotectant at the initiation of doxorubicin hydrochloride  containing chemotherapy regimens. In a randomized trial in women with metastatic breast cancer, initiation of dexrazoxane with doxorubicin hydrochloride-based chemotherapy resulted in a significantly lower tumor response rate (48% vs. 63%; p=0.007) and shorter time to progression than in women who received doxorubicin hydrochloride-based chemotherapy alone.

7.5 6-Mercaptopurine

Doxorubicin hydrochloride may potentiate 6-mercaptopurine-induced hepatotoxicity. In 11 patients with refractory leukemia treated with 6-mercaptopurine (500 mg/m2 intravenously daily for 5 days per cycle every 2-3 weeks) and doxorubicin hydrochloride (50 mg/m2 intravenous once per cycle every 2-3 weeks) alone or with vincristine and prednisone, all developed hepatic dysfunction manifested by elevations of total serum bilirubin, alkaline phosphatase and aspartate aminotransferase.

8.1 Pregnancy

Pregnancy Category D

8.3 Nursing Mothers

Doxorubicin has been detected in the milk of at least one lactating patient [see Clinical Pharmacology (12.3)]. Because of the potential for serious adverse reactions in nursing infants from doxorubicin hydrochloride, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

Based on postmarketing reports, pediatric patients treated with doxorubicin hydrochloride are at risk for developing late cardiovascular dysfunction. Risk factors include young age at treatment (especially < 5 years), high cumulative doses and receipt of combined modality therapy. Long-term periodic cardiovascular monitoring is recommended for all pediatric patients who have received doxorubicin hydrochloride. Doxorubicin hydrochloride, as a component of intensive chemotherapy regimens administered to pediatric patients, may contribute to prepubertal growth failure and may also contribute to gonadal impairment, which is usually temporary.

There are no recommended dose adjustments based on age. Doxorubicin clearance was increased in patients aged 2 years to 20 years as compared to adults, while doxorubicin clearance was similar in children less than 2 years as compared to adults [see Clinical Pharmacology (12.3)].

8.5 Geriatric Use

Clinical experience in patients who were 65 years of age and older who received doxorubicin hydrochloride-based chemotherapy regimens for metastatic breast cancer showed no overall differences in safety and effectiveness compared with younger patients.

8.6 Females and Males of Reproductive Potential

8.7 Hepatic Impairment

The clearance of doxorubicin was reduced in patients with elevated serum bilirubin levels. Reduce the dose of doxorubicin hydrochloride in patients with serum bilirubin levels greater than 1.2 mg/dL [See Dosage and Administration (2.2) and Warnings and Precautions (5.5)]. Doxorubicin hydrochloride is contraindicated in patients with severe hepatic impairment (defined as Child Pugh Class C or serum bilirubin levels greater than 5 mg/dL) [see Contraindications (4)].

12.1 Mechanism of Action

The cytotoxic effect of doxorubicin hydrochloride on malignant cells and its toxic effects on various organs are thought to be related to nucleotide base intercalation and cell membrane lipid binding activities of doxorubicin. Intercalation inhibits nucleotide replication and action of DNA and RNA polymerases. The interaction of doxorubicin with topoisomerase II to form DNA-cleavable complexes appears to be an important mechanism of doxorubicin hydrochloride cytocidal activity.

12.3 Pharmacokinetics

Pharmacokinetic studies conducted in patients with various types of tumors have shown that doxorubicin follows multiphasic disposition after intravenous injection. The distribution half-life is approximately 5 minutes, while the terminal half-life is 20 to 48 hours. In four patients, doxorubicin demonstrated dose-independent pharmacokinetics across a dose range of 30 to 70 mg/m2.

Distribution

Steady-state distribution volume ranges from 809 to 1214 L/m2. Binding of doxorubicin and its major metabolite, doxorubicinol, to plasma proteins is about 75% and is independent of plasma concentration of doxorubicin up to 1.1 mcg/mL.

Doxorubicin was measured in the milk of one lactating patient after therapy with 70 mg/m2 of doxorubicin hydrochloride given as a 15-minute intravenous infusion. The peak milk concentration at 24 hours after treatment was 4.4-fold greater than the corresponding plasma concentration. Doxorubicin was detectable in the milk up to 72 hours.

Doxorubicin does not cross the blood brain barrier.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Doxorubicin hydrochloride treatment results in an increased risk of secondary malignancies based on postmarketing reports [see Warnings and Precautions (5.2)]. Doxorubicin hydrochloride was mutagenic in the in vitro Ames assay, and clastogenic in multiple in vitro assays (CHO cell, V79 hamster cell, human lymphoblast, and SCE assays) and the in vivo mouse micronucleus assay.

Doxorubicin hydrochloride decreased fertility in female rats at the doses of 0.05 and 0.2 mg/kg/day (approximately 0.005 and 0.02 times the recommended human dose, based on body surface area).

A single intravenous dose of 0.1 mg/kg doxorubicin hydrochloride (approximately 0.01 times the recommended human dose based on body surface area) was toxic to male reproductive organs in animal studies, producing testicular atrophy, diffuse degeneration of the seminiferous tubules, and oligospermia/hypospermia in rats. Doxorubicin hydrochloride induces DNA damage in rabbit spermatozoa and dominant lethal mutations in mice.