Doxorubicine HCL Agila

Adjuvant Breast Cancer

Doxorubicine HCL Agila HCl 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.

Other Cancers

Doxorubicine HCL Agila HCl is indicated for the treatment of

• acute lymphoblastic leukemia
• acute myeloblastic leukemia
• Hodgkin lymphoma
• non-Hodgkin lymphoma (NHL)
• metastatic breast cancer
• metastatic Wilms' tumor
• metastatic neuroblastoma
• metastatic soft tissue sarcoma
• metastatic bone sarcoma
• metastatic ovarian carcinoma
• metastatic transitional cell bladder carcinoma
• metastatic thyroid carcinoma
• metastatic gastric carcinoma
• metastatic bronchogenic carcinoma

Adjuvant Breast Cancer

Doxorubicin HCl 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.

Other Cancers

Doxorubicin HCl is indicated for the treatment of

• acute lymphoblastic leukemia
• acute myeloblastic leukemia
• Hodgkin lymphoma
• non-Hodgkin lymphoma (NHL)
• metastatic breast cancer
• metastatic Wilms' tumor
• metastatic neuroblastoma
• metastatic soft tissue sarcoma
• metastatic bone sarcoma
• metastatic ovarian carcinoma
• metastatic transitional cell bladder carcinoma
• metastatic thyroid carcinoma
• metastatic gastric carcinoma
• metastatic bronchogenic carcinoma

Recommended Dose

Adjuvant Breast Cancer

The recommended dose of Doxorubicine HCL Agila HCl is 60 mg/m administered as an intravenous bolus on day 1 of each 21-day treatment cycle, in combination with cyclophosphamide, for a total of four cycles.

Metastatic Disease, Leukemia, Or Lymphoma

• The recommended dose of Doxorubicine HCL Agila HCl when used as a single agent is 60 to 75 mg/m intravenously every 21 days.
• The recommended dose of Doxorubicine HCL Agila HCl, 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 Doxorubicine HCL Agila 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/m are associated with an increased risk of cardiomyopathy.

Dose Modifications

Cardiac Impairment

Discontinue Doxorubicine HCL Agila in patients who develop signs or symptoms of cardiomyopathy.

Hepatic Impairment

Doxorubicine HCL Agila HCl is contraindicated in patients with severe hepatic impairment (Child-Pugh Class C or serum bilirubin >5.0 mg/dL).

Decrease the dose of Doxorubicine HCL Agila HCl in patients with elevated serum total bilirubin concentrations as follows:

Preparation And Administration

Preparation Of Doxorubicine HCL Agila HCl For injection

Reconstitute Doxorubicine HCL Agila hydrochloride for injection with 0.9% Sodium Chloride Injection, USP to obtain a final concentration of 2 mg per mL as follows:

• 5 mL 0.9% Sodium Chloride Injection, USP to reconstitute 10 mg Doxorubicine HCL Agila HCl vial
• 10 mL 0.9% Sodium Chloride Injection, USP to reconstitute 20 mg Doxorubicine HCL Agila HCl vial
• 25 mL 0.9% Sodium Chloride Injection, USP to reconstitute 50 mg Doxorubicine HCL Agila HCl vial
• 75 mL 0.9% Sodium Chloride Injection, USP to reconstitute 150 mg Doxorubicine HCL Agila HCl vial

Gently shake vial until the contents have dissolved.

Protect reconstituted solution from light.

Preparation For Continuous Intravenous Infusion

Dilute Doxorubicine HCL Agila HCl solution or reconstituted 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 Doxorubicine HCL Agila HCl Injection or Doxorubicine HCL Agila HCl for Injection following reconstitution 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 Doxorubicine HCL Agila HCl 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 Doxorubicine HCL Agila HCl intravenously over 3 to 10 minutes. Decrease the rate of Doxorubicine HCL Agila HCl 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 Doxorubicine HCL Agila HCl 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 Doxorubicine HCL Agila HCl for burning or stinging sensation or other evidence indicating peri-venous 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.

Incompatibility With Other Drugs

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

Procedures For Proper Handling And Disposal

Handle and dispose of Doxorubicine HCL Agila HCl 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.

Recommended Dose

Adjuvant Breast Cancer

The recommended dose of doxorubicin HCl is 60 mg/m administered as an intravenous bolus on day 1 of each 21-day treatment cycle, in combination with cyclophosphamide, for a total of four cycles.

Metastatic Disease, Leukemia, Or Lymphoma

• The recommended dose of doxorubicin HCl when used as a single agent is 60 to 75 mg/m intravenously every 21 days.
• The recommended dose of doxorubicin HCl, 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/m are associated with an increased risk of cardiomyopathy.

Dose Modifications

Cardiac Impairment

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

Hepatic Impairment

Doxorubicin HCl is contraindicated in patients with severe hepatic impairment (Child-Pugh Class C or serum bilirubin >5.0 mg/dL).

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

Preparation And Administration

Preparation Of Doxorubicin HCl For injection

Reconstitute Doxorubicine HCL Agila for injection with 0.9% Sodium Chloride Injection, USP to obtain a final concentration of 2 mg per mL as follows:

• 5 mL 0.9% Sodium Chloride Injection, USP to reconstitute 10 mg doxorubicin HCl vial
• 10 mL 0.9% Sodium Chloride Injection, USP to reconstitute 20 mg doxorubicin HCl vial
• 25 mL 0.9% Sodium Chloride Injection, USP to reconstitute 50 mg doxorubicin HCl vial
• 75 mL 0.9% Sodium Chloride Injection, USP to reconstitute 150 mg doxorubicin HCl vial

Gently shake vial until the contents have dissolved.

Protect reconstituted solution from light.

Preparation For Continuous Intravenous Infusion

Dilute doxorubicin HCl solution or reconstituted 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 HCl Injection or Doxorubicin HCl for Injection following reconstitution 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 HCl 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 HCl intravenously over 3 to 10 minutes. Decrease the rate of doxorubicin HCl 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 HCl 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 HCl for burning or stinging sensation or other evidence indicating peri-venous 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.

Incompatibility With Other Drugs

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

Procedures For Proper Handling And Disposal

Handle and dispose of doxorubicin HCl 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.

Doxorubicine HCL Agila HCl is contraindicated in patients with:

• Severe myocardial insufficiency
• Recent (occurring within the past 4–6 weeks) myocardial infarction
• Severe persistent drug-induced myelosuppression
• Severe hepatic impairment (defined as Child Pugh Class C or serum bilirubin level greater than 5 mg/dL)
• Severe hypersensitivity reaction to Doxorubicine HCL Agila HCl including anaphylaxis

Doxorubicin HCl is contraindicated in patients with:

• Severe myocardial insufficiency
• Recent (occurring within the past 4–6 weeks) myocardial infarction
• Severe persistent drug-induced myelosuppression
• Severe hepatic impairment (defined as Child Pugh Class C or serum bilirubin level greater than 5 mg/dL)
• Severe hypersensitivity reaction to doxorubicin HCl including anaphylaxis

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONS

Cardiomyopathy And Arrhythmias

Cardiomyopathy

Doxorubicine HCL Agila HCl 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 Doxorubicine HCL Agila HCl. 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 Doxorubicine HCL Agila HCl, 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 Doxorubicine HCL Agila HCl 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 Doxorubicine HCL Agila HCl treatment.

Assess left ventricular cardiac function (e.g., MUGA or echocardiogram) prior to initiation of Doxorubicine HCL Agila HCl, 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.

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

Arrhythmias

Doxorubicine HCL Agila HCl can result in arrhythmias, including life-threatening arrhythmias, during or within a few hours after Doxorubicine HCL Agila HCl 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 Doxorubicine HCL Agila HCl.

Secondary Malignancies

The risk of developing secondary acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) is increased following treatment with Doxorubicine HCL Agila HCl. 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.

Extravasation And Tissue Necrosis

Extravasation of Doxorubicine HCL Agila HCl 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 Doxorubicine HCL Agila 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. 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.

Severe Myelosuppression

Doxorubicine HCL Agila HCl 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 Doxorubicine HCL Agila HCl. When Doxorubicine HCL Agila HCl 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.

Use In Patients With Hepatic Impairment

The clearance of Doxorubicine HCL Agila is decreased in patients with elevated serum bilirubin with an increased risk of toxicity. Reduce the dose of Doxorubicine HCL Agila HCl in patients with serum bilirubin levels of 1.2–5.0 mg/dL. Doxorubicine HCL Agila is contraindicated in patients with severe hepatic impairment (defined as Child Pugh Class C or serum bilirubin level greater than 5 mg/dL). Obtain liver tests including SGOT, SGPT, alkaline phosphatase, and bilirubin prior to and during Doxorubicine HCL Agila HCl therapy.

Tumor Lysis Syndrome

Doxorubicine HCL Agila HCl 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.

Radiation Sensitization And Radiation Recall

Doxorubicine HCL Agila HCl 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 Doxorubicine HCL Agila HCl after prior radiation therapy.

Embryofetal Toxicity

Doxorubicine HCL Agila HCl can cause fetal harm when administered to a pregnant woman. Doxorubicine HCL Agila HCl 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.

Advise female patients of reproductive potential to use highly effective contraception during treatment with Doxorubicine HCL Agila HCl and for 6 months after treatment. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking Doxorubicine HCL Agila HCl.

Patient Counseling Information

See FDA-Approved Patient Labeling (PATIENT INFORMATION).

Inform patients of the following:

• Doxorubicine HCL Agila HCl can cause irreversible myocardial damage. Advise patients to contact a healthcare provider for symptoms of heart failure during or after treatment with Doxorubicine HCL Agila HCl.
• There is an increased risk of treatment-related leukemia from Doxorubicine HCL Agila HCl.
• Doxorubicine HCL Agila HCl can reduce the absolute neutrophil count resulting in an increased risk of infection. Advise patients to contact a healthcare provider for new onset fever or symptoms of infection.
• Doxorubicine HCL Agila HCl can cause fetal harm when administered during pregnancy. Advise females of reproductive potential to use effective contraception during treatment with Doxorubicine HCL Agila HCl and for 6 months after treatment, and to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with Doxorubicine HCL Agila HCl.
• Doxorubicine HCL Agila HCl may induce chromosomal damage in sperm, which may lead to loss of fertility and offspring with birth defects. Advise patients to use effective contraception during and for 6 months after treatment.
• Doxorubicine HCL Agila HCl can cause premature menopause in females and loss of fertility in males.
• Discontinue nursing while receiving Doxorubicine HCL Agila HCl.
• Doxorubicine HCL Agila HCl can cause nausea, vomiting, diarrhea, mouth/oral pain and sores. Advise patients to contact a healthcare provider should they develop any severe symptoms that prevent them from eating and drinking.
• Doxorubicine HCL Agila HCl causes alopecia.
• Doxorubicine HCL Agila HCl can cause their urine to appear red for 1 to 2 days after administration.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Doxorubicine HCL Agila HCl treatment results in an increased risk of secondary malignancies based on postmarketing reports. Doxorubicine HCL Agila HCl 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.

Doxorubicine HCL Agila HCl 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 Doxorubicine HCL Agila HCl (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. Doxorubicine HCL Agila HCl induces DNA damage in rabbit spermatozoa and dominant lethal mutations in mice.

Use In Specific Populations

Pregnancy

Pregnancy Category D

Risk Summary

Doxorubicine HCL Agila HCl can cause fetal harm when administered to a pregnant woman. Doxorubicine HCL Agila HCl 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/m. 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

Doxorubicine HCL Agila HCl 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 Includes pooled data from patients who received either AC alone for 4 cycles, or who were treated with AC for 4 cycles followed by 3 cycles of CMF 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. Doxorubicine HCL Agila HCl 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.

Nursing Mothers

Doxorubicine HCL Agila has been detected in the milk of at least one lactating patient. Because of the potential for serious adverse reactions in nursing infants from Doxorubicine HCL Agila HCl, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Based on postmarketing reports, pediatric patients treated with Doxorubicine HCL Agila HCl 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. Longterm periodic cardiovascular monitoring is recommended for all pediatric patients who have received Doxorubicine HCL Agila HCl. Doxorubicine HCL Agila HCl, 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. Doxorubicine HCL Agila clearance was increased in patients aged 2 years to 20 years as compared to adults, while Doxorubicine HCL Agila clearance was similar in children less than 2 years as compared to adults.

Geriatric Use

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

Females And Males Of Reproductive Potential

Contraception

Females

Doxorubicine HCL Agila HCl can cause fetal harm when administered during pregnancy. Advise female patients of reproductive potential to use highly effective contraception during treatment with Doxorubicine HCL Agila HCl and for 6 months after treatment. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking Doxorubicine HCL Agila HCl.

Males

Doxorubicine HCL Agila HCl 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.

Infertility

Females

In females of reproductive potential, Doxorubicine HCL Agila HCl may cause infertility and result in amenorrhea. Premature menopause can occur. Recovery of menses and ovulation is related to age at treatment.

Males

Doxorubicine HCL Agila HCl 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.

Hepatic Impairment

The clearance of Doxorubicine HCL Agila was reduced in patients with elevated serum bilirubin levels. Reduce the dose of Doxorubicine HCL Agila HCl in patients with serum bilirubin levels greater than 1.2 mg/dL.

Doxorubicine HCL Agila HCl is contraindicated in patients with severe hepatic impairment (defined as Child Pugh Class C or serum bilirubin levels greater than 5 mg/dL).

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONS

Cardiomyopathy And Arrhythmias

Cardiomyopathy

Doxorubicin HCl 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 HCl. 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 HCl, 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 HCl 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 HCl treatment.

Assess left ventricular cardiac function (e.g., MUGA or echocardiogram) prior to initiation of doxorubicin HCl, 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.

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

Arrhythmias

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

Secondary Malignancies

The risk of developing secondary acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) is increased following treatment with doxorubicin HCl. 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.

Extravasation And Tissue Necrosis

Extravasation of doxorubicin HCl 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. 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.

Severe Myelosuppression

Doxorubicin HCl 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 HCl. When doxorubicin HCl 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.

Use In Patients With Hepatic Impairment

The clearance of doxorubicin is decreased in patients with elevated serum bilirubin with an increased risk of toxicity. Reduce the dose of doxorubicin HCl in patients with serum bilirubin levels of 1.2–5.0 mg/dL. Doxorubicin is contraindicated in patients with severe hepatic impairment (defined as Child Pugh Class C or serum bilirubin level greater than 5 mg/dL). Obtain liver tests including SGOT, SGPT, alkaline phosphatase, and bilirubin prior to and during doxorubicin HCl therapy.

Tumor Lysis Syndrome

Doxorubicin HCl 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.

Radiation Sensitization And Radiation Recall

Doxorubicin HCl 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 HCl after prior radiation therapy.

Embryofetal Toxicity

Doxorubicin HCl can cause fetal harm when administered to a pregnant woman. Doxorubicin HCl 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.

Advise female patients of reproductive potential to use highly effective contraception during treatment with doxorubicin HCl 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 HCl.

Patient Counseling Information

See FDA-Approved Patient Labeling (PATIENT INFORMATION).

Inform patients of the following:

• Doxorubicin HCl can cause irreversible myocardial damage. Advise patients to contact a healthcare provider for symptoms of heart failure during or after treatment with doxorubicin HCl.
• There is an increased risk of treatment-related leukemia from doxorubicin HCl.
• Doxorubicin HCl can reduce the absolute neutrophil count resulting in an increased risk of infection. Advise patients to contact a healthcare provider for new onset fever or symptoms of infection.
• Doxorubicin HCl can cause fetal harm when administered during pregnancy. Advise females of reproductive potential to use effective contraception during treatment with doxorubicin HCl and for 6 months after treatment, and to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with doxorubicin HCl.
• Doxorubicin HCl may induce chromosomal damage in sperm, which may lead to loss of fertility and offspring with birth defects. Advise patients to use effective contraception during and for 6 months after treatment.
• Doxorubicin HCl can cause premature menopause in females and loss of fertility in males.
• Discontinue nursing while receiving doxorubicin HCl.
• Doxorubicin HCl can cause nausea, vomiting, diarrhea, mouth/oral pain and sores. Advise patients to contact a healthcare provider should they develop any severe symptoms that prevent them from eating and drinking.
• Doxorubicin HCl causes alopecia.
• Doxorubicin HCl can cause their urine to appear red for 1 to 2 days after administration.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Doxorubicin HCl treatment results in an increased risk of secondary malignancies based on postmarketing reports. Doxorubicin HCl 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 HCl 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 HCl (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 HCl induces DNA damage in rabbit spermatozoa and dominant lethal mutations in mice.

Use In Specific Populations

Pregnancy

Pregnancy Category D

Risk Summary

Doxorubicin HCl can cause fetal harm when administered to a pregnant woman. Doxorubicin HCl 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/m. 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 HCl 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 Includes pooled data from patients who received either AC alone for 4 cycles, or who were treated with AC for 4 cycles followed by 3 cycles of CMF 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 HCl 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.

Nursing Mothers

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

Pediatric Use

Based on postmarketing reports, pediatric patients treated with doxorubicin HCl 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. Longterm periodic cardiovascular monitoring is recommended for all pediatric patients who have received doxorubicin HCl. Doxorubicin HCl, 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.

Geriatric Use

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

Females And Males Of Reproductive Potential

Contraception

Females

Doxorubicin HCl can cause fetal harm when administered during pregnancy. Advise female patients of reproductive potential to use highly effective contraception during treatment with doxorubicin HCl 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 HCl.

Males

Doxorubicin HCl 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.

Infertility

Females

In females of reproductive potential, doxorubicin HCl may cause infertility and result in amenorrhea. Premature menopause can occur. Recovery of menses and ovulation is related to age at treatment.

Males

Doxorubicin HCl 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.

Hepatic Impairment

The clearance of doxorubicin was reduced in patients with elevated serum bilirubin levels. Reduce the dose of doxorubicin HCl in patients with serum bilirubin levels greater than 1.2 mg/dL.

Doxorubicin HCl is contraindicated in patients with severe hepatic impairment (defined as Child Pugh Class C or serum bilirubin levels greater than 5 mg/dL).

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

• Cardiomyopathy and Arrhythmias
• Secondary Malignancies
• Extravasation and Tissue Necrosis
• Severe Myelosuppression
• Tumor Lysis Syndrome
• Radiation Sensitization and Radiation Recall

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 Doxorubicine HCL Agila HCl at a dose of 60 mg/m and cyclophosphamide at a dose of 600 mg/m (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.

Table 1. Selected Adverse Reactions in Patients with Early Breast Cancer Involving Axillary Lymph Nodes

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Doxorubicine HCL Agila HCl. 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

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

• Cardiomyopathy and Arrhythmias
• Secondary Malignancies
• Extravasation and Tissue Necrosis
• Severe Myelosuppression
• Tumor Lysis Syndrome
• Radiation Sensitization and Radiation Recall

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 HCl at a dose of 60 mg/m and cyclophosphamide at a dose of 600 mg/m (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.

Table 1. Selected Adverse Reactions in Patients with Early Breast Cancer Involving Axillary Lymph Nodes

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of doxorubicin HCl. 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

Few cases of overdose have been described. A 58-year-old man with acute lymphoblastic leukemia received 10-fold overdose of Doxorubicine HCL Agila HCl (300 mg/m ) in one day. He was treated with charcoal filtration, hemopoietic growth factor (G-CSF), proton pump inhibitor and antimicrobial prophylaxis. The patient suffered sinus tachycardia, grade 4 neutropenia and thrombocytopenia for 11 days, severe mucositis and sepsis. The patient recovered completely 26 days after the overdose. A 17-year-old girl with osteogenic sarcoma received 150 mg of Doxorubicine HCL Agila HCl daily for 2 days (intended dose was 50 mg per day for 3 days). The patient developed severe mucositis on days 4–7 after the overdose and chills and pyrexia on day 7. The patient was treated with antibiotics and platelets and recovered 18 days after overdose.

Few cases of overdose have been described. A 58-year-old man with acute lymphoblastic leukemia received 10-fold overdose of doxorubicin HCl (300 mg/m ) in one day. He was treated with charcoal filtration, hemopoietic growth factor (G-CSF), proton pump inhibitor and antimicrobial prophylaxis. The patient suffered sinus tachycardia, grade 4 neutropenia and thrombocytopenia for 11 days, severe mucositis and sepsis. The patient recovered completely 26 days after the overdose. A 17-year-old girl with osteogenic sarcoma received 150 mg of doxorubicin HCl daily for 2 days (intended dose was 50 mg per day for 3 days). The patient developed severe mucositis on days 4–7 after the overdose and chills and pyrexia on day 7. The patient was treated with antibiotics and platelets and recovered 18 days after overdose.

Pharmacokinetic studies conducted in patients with various types of tumors have shown that Doxorubicine HCL Agila 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, Doxorubicine HCL Agila 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 Doxorubicine HCL Agila and its major metabolite, Doxorubicine HCL Agilaol, to plasma proteins is about 75% and is independent of plasma concentration of Doxorubicine HCL Agila up to 1.1 μg/mL.

Doxorubicine HCL Agila was measured in the milk of one lactating patient after therapy with 70 mg/m of Doxorubicine HCL Agila HCl 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. Doxorubicine HCL Agila was detectable in the milk up to 72 hours.

Doxorubicine HCL Agila 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 Doxorubicine HCL Agila HCl. Disposition of Doxorubicine HCL Agilaol in patients is formation rate limited, with the terminal half-life of Doxorubicine HCL Agilaol being similar to Doxorubicine HCL Agila. The relative exposure of Doxorubicine HCL Agilaol, i.e., the ratio between the AUC of Doxorubicine HCL Agilaol and the AUC of Doxorubicine HCL Agila 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 Doxorubicine HCL Agilaol over 7 days.

Systemic clearance of Doxorubicine HCL Agila 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/m of Doxorubicine HCL Agila HCl to 60 children and adolescents ranging from 2 months to 20 years of age, Doxorubicine HCL Agila clearance averaged 1443 ± 114 mL/min/m. Further analysis demonstrated that clearance in 52 children greater than 2 years of age (1540 mL/min/m ) was increased compared with adults. However, clearance in infants younger than 2 years of age (813 mL/min/m ) was decreased compared with older children and approached the range of clearance values determined in adults.

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 Doxorubicine HCL Agila clearance in men compared to women (1088 mL/min/m versus 433 mL/min/m ). However, the terminal half-life of Doxorubicine HCL Agila was longer in men compared to women (54 versus 35 hours).

Patients With Hepatic Impairment

The clearance of Doxorubicine HCL Agila and Doxorubicine HCL Agilaol was reduced in patients with elevation in serum bilirubin.

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 μg/mL.

Doxorubicin was measured in the milk of one lactating patient after therapy with 70 mg/m of doxorubicin HCl 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 HCl. 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/m of doxorubicin HCl to 60 children and adolescents ranging from 2 months to 20 years of age, doxorubicin clearance averaged 1443 ± 114 mL/min/m. Further analysis demonstrated that clearance in 52 children greater than 2 years of age (1540 mL/min/m ) was increased compared with adults. However, clearance in infants younger than 2 years of age (813 mL/min/m ) was decreased compared with older children and approached the range of clearance values determined in adults.

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/m versus 433 mL/min/m ). 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.