1.1 Adjuvant Breast Cancer

DOXOrubicin hydrochloride injection, USP is indicated as a c omponent of multi-a gent adjuvant chemotherapy for treat ment of wo men with axillary lymph node involve ment following resection of pri mary breast cancer [see Clinical Studies (14.1 ) ].

1.2 Other Cancers

DOXOrubicin hydrochloride injection, USP is indicated for the treat ment of

• acute ly mphoblastic leu ke mia
• acute m yeloblastic leuke mia
• Hodgkin lympho ma
• non-Hodgkin ly mpho ma (NHL)
• metastatic breast cancer
• metastatic Wil ms’ tumor
• metastatic neurobla stoma
• metastatic s oft tissue sa rco ma
• metastatic bone sarco ma
• metastatic o varian car cino ma
• metastatic t ransitional c ell bladder carcino ma
• metastatic t hyroid carcinoma
• metastatic gastric carcinoma
• metastatic bronchogenic carcinoma

2.1 Recommended Dose

Adjuvant Breast Cancer

The recommended dose of doxorubicin hydrochloride 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 [see Clinical Studies (14)].

Metastatic Disease, Leukemia, or Lymphoma

• The recommended dose of doxorubicin hydrochloride when used as a single agent is 60 to 75 mg/m2 intravenously every 21 days.
• The recommended dose of doxorubicin hydrochloride, when administered in combination with other chemotherapy drugs, is 40 to 75 mg/m2 intravenously every 21 to 28 days.
• Consider use of the lower doxorubicin dose in the recommended dose range or longer intervals between cycles for heavily pretreated patients, elderly patients, or obese patients.
• Cumulative doses above 550 mg/m2 are associated with an increased risk of cardiomyopathy [see Warnings and Precautions (5.1)].

2.2 Dose Modifications

Cardiac Impairment

Discontinue doxorubicin in patients who develop signs or symptoms of cardiomyopathy.

Hepatic Impairment

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

Decrease the dose of doxorubicin hydrochloride in patients with elevated serum total bilirubin concentrations as follows:

[see Warnings and Precautions (5.5) and Use in Specific Population (8.7)]

2.3 Preparation and Administration

Preparation for Continuous Intravenous Infusion

Dilute doxorubicin hydrochloride solution in 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. Protect from light following preparation until completion of infusion.

Administration

Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard if the solution is discolored, cloudy, or contains particulate matter.

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

Administration by Intravenous Injection:

• Administer doxorubicin hydrochloride as an intravenous injection through a central intravenous line or a secure and free-flowing peripheral venous line containing 0.9% Sodium Chloride Injection, USP, 0.45% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP.
• Administer doxorubicin hydrochloride intravenously over 3 to 10 minutes. Decrease the rate of doxorubicin hydrochloride administration if erythematous streaking along the vein proximal to the site of infusion or facial flushing occur.

Administration by Continuous Intravenous Infusion:

• Infuse only through a central catheter. Decrease the rate of doxorubicin hydrochloride administration if erythematous streaking along the vein proximal to the site of infusion or facial flushing occur.
• Protect from light from preparation for infusion until completion of infusion.

Management of Suspected Extravasation

Discontinue doxorubicin hydrochloride for burning or stinging sensation or other evidence indicating peri­venous infiltration or extravasation. Manage confirmed or suspected extravasation as follows:

• Do not remove the needle until attempts are made to aspirate extravasated fluid.
• Do not flush the line.
• Avoid applying pressure to the site.
• Apply ice to the site intermittently for 15 min 4 times a day for 3 days.
• If the extravasation is in an extremity, elevate the extremity.
• In adults, consider administration of dexrazoxane [see Warnings and Precautions (5.3)].

Incompatibility with Other Drugs

Do not admix doxorubicin hydrochloride with other drugs. If doxorubicin hydrochloride is mixed with heparin or fluorouracil a precipitate may form. Avoid contact with alkaline solutions which can lead to hydrolysis of doxorubicin hydrochloride.

2.4 Procedures for Proper Handling and Disposal

Handle and dispose of doxorubicin hydrochloride 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.

5.1 Cardiomyopathy and Arrhythmias

Cardiomyopathy

Doxorubicin hydrochloride 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 hydrochloride. 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 hydrochloride, 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 hydrochloride 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 hydrochloride treatment.

Assess left ventricular cardiac function (e.g., MUGA or echocardiogram) prior to initiation of doxorubicin hydrochloride, 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 hydrochloride administration in patients who have received a cumulative doxorubicin hydrochloride dose of 300 mg/m2 and who will continue to receive doxorubicin hydrochloride.

Arrhythmias

Doxorubicin hydrochloride can result in arrhythmias, including life-threatening arrhythmias, during or within a few hours after doxorubicin hydrochloride 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 hydrochloride.

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)].

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 hydrochloride­containing 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 to 3 weeks) and doxorubicin hydrochloride (50 mg/m2 intravenous once per cycle every 2 to 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

Risk Summary

Doxorubicin hydrochloride can cause fetal harm when administered to a pregnant woman. Doxorubicin hydrochloride was teratogenic and embryotoxic in rats and rabbits at doses approximately 0.07 times (based on body surface area) the recommended human dose of 60 mg/m2. 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.

Animal Data

Doxorubicin hydrochloride was teratogenic and embryotoxic at doses of 0.8 mg/kg/day (about 0.07 times the recommended human dose based on body surface area) when administered during the period of organogenesis in rats. Teratogenicity and embryotoxicity were also seen using discrete periods of treatment. The most susceptible was the 6- to 9-day gestation period at doses of 1.25 mg/kg/day and greater. Characteristic malformations included esophageal and intestinal atresia, tracheo-esophageal fistula, hypoplasia of the urinary bladder, and cardiovascular anomalies. Doxorubicin hydrochloride was embryotoxic (increase in embryofetal deaths) and abortifacient at 0.4 mg/kg/day (about 0.07 times the recommended human dose based on body surface area) in rabbits when administered during the period of organogenesis.

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

Contraception

Females

Doxorubicin hydrochloride can cause fetal harm when administered during pregnancy. 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)].

Males

Doxorubicin hydrochloride may damage spermatozoa and testicular tissue, resulting in possible genetic fetal abnormalities. Males with female sexual partners of reproductive potential should use effective contraception during and for 6 months after treatment [see Nonclinical Toxicology (13.1)].

Infertility

Females

In females of reproductive potential, doxorubicin hydrochloride may cause infertility and result in amenorrhea. Premature menopause can occur. Recovery of menses and ovulation is related to age at treatment [see Nonclinical Toxicology (13.1)].

Males

Doxorubicin hydrochloride may result in oligospermia, azoospermia, and permanent loss of fertility.  Sperm counts have been reported to return to normal levels in some men. This may occur several years after the end of therapy.

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.

Metabolism

Enzymatic reduction at the 7 position and cleavage of the daunosamine sugar yields aglycones which are accompanied by free radical formation, the local production of which may contribute to the cardiotoxic activity of doxorubicin hydrochloride. Disposition of doxorubicinol in patients is formation rate limited, with the terminal half-life of doxorubicinol being similar to doxorubicin. The relative exposure of doxorubicinol, i.e., the ratio between the AUC of doxorubicinol and the AUC of doxorubicin is approximately 0.5.

Excretion

Plasma clearance is in the range 324 to 809 mL/min/m2 and is predominately by metabolism and biliary excretion. Approximately 40% of the dose appears in the bile in 5 days, while only 5 to 12% of the drug and its metabolites appear in the urine during the same time period. In urine, <3% of the dose was recovered as doxorubicinol over 7 days.

Systemic clearance of doxorubicin is significantly reduced in obese women with ideal body weight greater than 130%. There was a significant reduction in clearance without any change in volume of distribution in obese patients when compared with normal patients with less than 115% ideal body weight.

Pediatric patients

Following administration of doses ranging from 10 to 75 mg/m2 of doxorubicin hydrochloride to 60 children and adolescents ranging from 2 months to 20 years of age, doxorubicin clearance averaged 1443 ± 114 mL/min/m2. Further analysis demonstrated that clearance in 52 children greater than 2 years of age (1540 mL/min/m2) was increased compared with adults. However, clearance in infants younger than 2 years of age (813 mL/min/m2) was decreased compared with older children and approached the range of clearance values determined in adults [see Use in Specific Populations (8.4)].

Patient Gender

There is no recommended dose adjustment based on gender. A published clinical study involving 6 men and 21 women with no prior anthracycline therapy reported a significantly higher median doxorubicin clearance in men compared to women (1088 mL/min/m2 versus 433 mL/min/m2). However, the terminal half-life of doxorubicin was longer in men compared to women (54 versus 35 hours).

Patients with hepatic impairment

The clearance of doxorubicin and doxorubicinol was reduced in patients with elevation in serum bilirubin [see Dosage and Administration (2.2) and Warnings and Precautions (5.5)].

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.