1.1 Adjuvant Breast Cancer

Doxorubicin Hydrochloride Injection 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.

1.2 Other Cancers

Doxorubicin Hydrochloride Injection 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 Dosage for Adjuvant Breast Cancer

The recommended dosage of Doxorubicin Hydrochloride Injection is 60 mg/m2 administered as an intravenous bolus on day 1 of each 21-day treatment cycle, in combination with cyclophosphamide, for a total of four cycles.

2.2 Recommended Dosage for Other Cancers

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The recommended dosage of Doxorubicin Hydrochloride Injection when used as a single agent is 60 mg/m2 to 75 mg/m2 intravenously every 21 days.

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The recommended dosage of Doxorubicin Hydrochloride Injection, when administered in combination with other chemotherapy drugs, is 40 mg/m2 to 75 mg/m2 intravenously every 21 to 28 days.

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Consider use of the lower Doxorubicin Hydrochloride Injection dose in the recommended dosage range or longer intervals between cycles for heavily pretreated patients, elderly patients, or obese patients.

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Cumulative doses above 550 mg/m2 are associated with an increased risk of cardiomyopathy [see Warnings and Precautions (5.1)].

2.3 Dosage Modifications for Adverse Reactions

2.4 Dosage Modifications for Hepatic Impairment

Doxorubicin Hydrochloride Injection is contraindicated in patients with severe hepatic impairment (Child-Pugh Class C or serum bilirubin greater than 5 mg/dL) [see Contraindications (4)].

Dosage modifications for Doxorubicin Hydrochloride Injection in patients with elevated serum total bilirubin concentrations [see Warnings and Precautions (5.5), Use in Specific Populations (8.6)] are provided in Table 1.

2.5 Preparation and Administration

Doxorubicin Hydrochloride Injection is a hazardous drug. Follow applicable special handling and disposal procedures.1

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 cause severe local tissue injury manifesting as blistering, ulceration, and necrosis requiring wide excision of the affected area and skin grafting. Extravasation should be considered if a patient experiences a burning or stinging sensation or shows other evidence indicating peri-venous infiltration or extravasation; however, 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.

When given via a peripheral venous line, infuse Doxorubicin Hydrochloride Injection over 10 minutes or less to minimize the risk of thrombosis or perivenous extravasation.

If extravasation is suspected, immediately discontinue the intravenous injection or continuous intravenous infusion [see Dosage and Administration (2.5)]. Apply ice to the site intermittently for 15 minutes, 4 times a day for 3 days. In adults, 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 myelosuppression 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 day 21.

Obtain complete blood counts prior to each treatment and carefully monitor patients during treatment for possible clinical complications due to myelosuppression. Delay next dose of Doxorubicin Hydrochloride Injection if severe myelosuppression has not improved. Consider dose reduction for patients with prolonged myelosuppression based on severity of reaction.

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 (8.6), Clinical Pharmacology (12.3)]. Doxorubicin Hydrochloride Injection 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)]. Reduce the dose of Doxorubicin Hydrochloride Injection in patients with serum bilirubin levels of 1.2 to 5 mg/dL [see Dosage and Administration (2.4)]. Obtain liver tests including ALT, AST, alkaline phosphatase, and bilirubin prior to and during therapy.

5.6 Tumor Lysis Syndrome

Doxorubicin hydrochloride can 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 Potentiation of Radiation Toxicity 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 Embryo-Fetal Toxicity

Based on findings in animals and its mechanism of action, Doxorubicin Hydrochloride Injection can cause fetal harm when administered to a pregnant woman; avoid the use of Doxorubicin Hydrochloride Injection during the 1st trimester. Available human data do not establish the presence or absence of major birth defects and miscarriage related to the use of doxorubicin hydrochloride during the 2nd and 3rd trimesters. Doxorubicin hydrochloride was teratogenic and embryotoxic in rats and rabbits at doses lower than the recommended human dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Doxorubicin Hydrochloride Injection and for 6 months after treatment. Advise males with female partners of reproductive potential to use effective contraception during treatment with Doxorubicin Hydrochloride Injection and for 3 months after treatment. Advise males with pregnant partners to use condoms during treatment with Doxorubicin Hydrochloride Injection and for at least 10 days after the final dose [see Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)].

6.1 Clinical Trials 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.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Doxorubicin Hydrochloride Injection. 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 ALT, increased AST

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 Other Drugs on Doxorubicin Hydrochloride Injection

7.2 Concomitant Use of Trastuzumab

Concomitant use of trastuzumab and doxorubicin hydrochloride results in an increased risk of cardiac dysfunction. Avoid concomitant administration of Doxorubicin Hydrochloride Injection and trastuzumab [see Warnings and Precautions (5.1)].

Patients receiving doxorubicin after stopping treatment with trastuzumab may also be at an increased risk of developing cardiotoxicity. Trastuzumab may persist in the circulation for up to 7 months. Therefore, avoid anthracycline-based therapy for up to 7 months after stopping trastuzumab when possible. If anthracyclines are used before this time, carefully monitor cardiac function.

7.3 Concomitant Use of 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 compared to doxorubicin hydrochloride-based chemotherapy alone.

7.4 Concomitant Use of 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 increased total serum bilirubin, alkaline phosphatase and aspartate aminotransferase.

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

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 infants 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 Hepatic Impairment

The clearance of doxorubicin was reduced in patients with elevated serum total bilirubin levels. Doxorubicin Hydrochloride Injection 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)]. Reduce the dose of Doxorubicin Hydrochloride Injection in patients with serum total bilirubin levels greater than 1.2 mg/dL [See Dosage and Administration (2.4), Warnings and Precautions (5.5)].

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. In four patients, doxorubicin demonstrated dose-independent pharmacokinetics across a dose range of 30 mg/m2 to 70 mg/m2.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Doxorubicin hydrochloride treatment can increase the 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.

14.1 Adjuvant Breast Cancer

The efficacy of doxorubicin hydrochloride-containing regimens for the post-operative, adjuvant treatment of surgically resected breast cancer was evaluated in a meta-analysis conducted by the Early Breast Cancer Trialists Collaborative Group (EBCTCG). The EBCTCG meta-analyses compared cyclophosphamide, methotrexate, and fluorouracil (CMF) to no chemotherapy (19 trials including 7523 patients) and doxorubicin hydrochloride-containing regimens with CMF as an active control (6 trials including 3510 patients). Data from the meta-analysis of trials comparing CMF to no therapy were used to establish the historical treatment effect size for CMF regimens. The major efficacy outcome measures were disease-free survival (DFS) and overall survival (OS).

Of the 3510 women (2157 received doxorubicin hydrochloride-containing regimens and 1353 received CMF treatment) with early breast cancer involving axillary lymph nodes included in the six trials from the meta-analyses, approximately 70% were premenopausal and 30% were postmenopausal.

At the time of the meta-analysis, 1745 first recurrences and 1348 deaths had occurred. The analyses demonstrated that doxorubicin hydrochloride-containing regimens retained at least 75% of the historical CMF adjuvant effect on DFS with a hazard ratio (HR) of 0.91 (95% CI: 0.82, 1.01) and on OS with a HR of 0.91 (95% CI: 0.81, 1.03). Efficacy results are provided in Table 3 and Figures 1 and 2.

Figure 1. Meta-analysis of Disease-Free Survival

Figure 2. Meta-analysis of Overall Survival

Doxorubicin Hydrochloride Injection

Doxorubicin Hydrochloride Injection is a sterile, isotonic solution, available in single-dose ONCO-TAIN® glass vials:

Storage

Store all vials at 2°C to 8°C (36°F to 46°F). Protect from light.

Storage of Doxorubicin Hydrochloride Injection under refrigerated conditions can result in the formation of a gelled product. Place gelled product at room temperature [15ºC to 30ºC (59ºF to 86ºF)] for 2 to 4 hours to return the product to a slightly viscous, mobile solution.

Handling and Disposal

Doxorubicin Hydrochloride Injection is a hazardous drug. Follow applicable special handling and disposal procedures.1

Cardiomyopathy

Advise patients that Doxorubicin Hydrochloride Injection can cause irreversible myocardial damage and to contact a healthcare provider for symptoms of heart failure during or after treatment [see Warnings and Precautions (5.1)].

Secondary Malignancy

Advise patients of the increased risk of treatment-related leukemia [see Warnings and Precautions (5.2)].

Myelosuppression

Advise patients that Doxorubicin Hydrochloride Injection can reduce the absolute neutrophil count resulting in an increased risk of infection and to contact a healthcare provider for new onset fever or symptoms of infection [see Warnings and Precautions (5.4)].

Embryo-Fetal Toxicity

Advise pregnant women and females of reproductive potential of the potential risk to a fetus, and to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.8), Use in Specific Populations (8.1)].

Advise females of reproductive potential to use effective contraception during treatment with Doxorubicin Hydrochloride Injection and for 6 months after treatment [see Warnings and Precautions (5.8), Use in Specific Populations (8.3)].

Advise patients that Doxorubicin Hydrochloride Injection may induce chromosomal damage in sperm, which may lead to loss of fertility and offspring with birth defects. Advise males with female partners of reproductive potential to use effective contraception during treatment with Doxorubicin Hydrochloride Injection and for 3 months after treatment [see Warnings and Precautions (5.8), Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)].

Advise males with pregnant partners to use condoms during treatment with Doxorubicin Hydrochloride Injection and for at least 10 days after the final dose [see Use in Specific Populations (8.3)].

Lactation

Advise females not to breastfeed during treatment with Doxorubicin Hydrochloride Injection and for 10 days after the final dose [see Use in Specific Populations (8.2)].

Infertility

Advise females and males of the potential loss of fertility from Doxorubicin Hydrochloride Injection [see Use in Specific Populations (8.3)].

Gastrointestinal and Dermatologic Adverse Reactions

Advise patients that Doxorubicin Hydrochloride Injection can cause nausea, vomiting, diarrhea, mouth/oral pain and sores and to contact a healthcare provider should they develop any severe symptoms that prevent them from eating and drinking [see Adverse Reactions (6)]. Advise patients that Doxorubicin Hydrochloride Injection can cause alopecia [see Adverse Reactions (6.1)].

Administration

Advise patients that Doxorubicin Hydrochloride Injection can cause their urine to appear red for 1 to 2 days after administration.