ADRIAMYCIN- doxorubicin hydrochloride injection, powder, lyophilized, for solution 
Hikma Pharmaceuticals USA Inc.

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HIGHLIGHTS OF PRESCRIBING INFORMATION

HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use ADRIAMYCIN (DOXOrubicin HCl) FOR INJECTION safely and effectively.  See full prescribing information for ADRIAMYCIN (DOXOrubicin HCl) FOR INJECTION.
ADRIAMYCIN (DOXOrubicin HCl) for Injection, USP, for intravenous use
Initial U.S. Approval: 1974

WARNING: CARDIOMYOPATHY, SECONDARY MALIGNANCIES,

EXTRAVASATION AND TISSUE NECROSIS, and SEVERE MYELOSUPPRESSION

See full prescribing information for complete boxed warning.

  • Cardiomyopathy: Myocardial damage can occur with doxorubicin with incidences from 1% to 20% for cumulative doses from 300 mg/m2 to 500 mg/m2 when doxorubicin is administered every 3 weeks. The risk of cardiomyopathy is further increased with concomitant cardiotoxic therapy. Assess left ventricular ejection fraction (LVEF) before and regularly during and after treatment with doxorubicin. (5.1)
  • Secondary Malignancies: Secondary acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) occur at a higher incidence in patients treated with anthracyclines, including doxorubicin. (5.2)
  • Extravasation and Tissue Necrosis: Extravasation of doxorubicin can result in severe local tissue injury and necrosis requiring wide excision and skin grafting. Immediately terminate the drug, and apply ice to the affected area. (5.3)
  • Severe myelosuppression resulting in serious infection, septic shock, requirement for transfusions, hospitalization, and death may occur. (5.4)

INDICATIONS AND USAGE

Doxorubicin is an anthracycline topoisomerase II inhibitor indicated:

  • as a component of multiagent adjuvant chemotherapy for treatment of women with axillary lymph node involvement following resection of primary breast cancer (1.1) .
  • for the treatment of: acute lymphoblastic leukemia, acute myeloblastic leukemia, Hodgkin lymphoma, Non-Hodgkin lymphoma, metastatic breast cancer, metastatic Wilms’ tumor, metastatic neuroblastoma, metastatic soft tissue sarcoma, metastatic bone sarcomas, metastatic ovarian carcinoma, metastatic transitional cell bladder carcinoma, metastatic thyroid carcinoma, metastatic gastric carcinoma, metastatic bronchogenic carcinoma (1.2) .

DOSAGE AND ADMINISTRATION

  • Single agent: 60 to 75 mg/m2 given intravenously every 21 days (2.1) .
  • In combination therapy: 40 to 75 mg/m2 given intravenously every 21 to 28 days (2.1) .
  • Discontinue doxorubicin in patients who develop signs or symptoms of cardiomyopathy (2.2) .
  • Reduce dose in patients with hepatic impairment (2.2) .

DOSAGE FORMS AND STRENGTHS

  • Adriamycin (DOXOrubicin HCl) for Injection, USP: Vials contain 10 mg and 50 mg as a lyophilized powder (3) 

CONTRAINDICATIONS

  • •Severe myocardial insufficiency (4)
  • •Recent myocardial infarction (4)
  • •Severe persistent drug-induced myelosuppression (4)
  • •Severe hepatic impairment (4)
  • •Hypersensitivity to doxorubicin HCl (4)

WARNINGS AND PRECAUTIONS

  • Radiation-induced toxicity can be increased by the administration of doxorubicin. Radiation recall can occur in patients who receive doxorubicin after prior radiation therapy (5.7) .
  • Embryofetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of potential risk to the fetus (5.8) .

ADVERSE REACTIONS

The most common (>10%) adverse drug reactions are alopecia, nausea and vomiting (6.1).

To report SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceutical Corp. at 1-877-845-0689, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

  • Avoid concurrent use of doxorubicin with inhibitors and inducers of CYP3A4, CYP2D6, and/or P-gp (7.1) .
  • Do not administer doxorubicin in combination with trastuzumab due to increased risk of cardiac dysfunction(5.1 , 7.2) .

USE IN SPECIFIC POPULATIONS

  • Nursing Mothers: Discontinue drug or nursing taking into consideration importance of drug to mother (8.3).
  • Pediatric Use: Recommend long-term follow-up cardiac evaluations due to risk of delayed cardiotoxicity(8.4) .
  • Females and Males of Reproductive Potential: May impair fertility. Counsel female and male patients on pregnancy planning and prevention (8.6) .

See 17 for PATIENT COUNSELING INFORMATION and PATIENT COUNSELING INFORMATION.

Revised: 3/2018

FULL PRESCRIBING INFORMATION: CONTENTS*

BOXED WARNING

1 INDICATIONS AND USAGE

1.1 Adjuvant Breast Cancer

1.2 Other Cancers

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dose

2.2 Dose Modifications

2.3 Preparation and Administration

2.4 Procedures for Proper Handling and Disposal

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Cardiomyopathy and Arrhythmias

5.2 Secondary Malignancies

5.3 Extravasation and Tissue Necrosis

5.4 Severe Myelosuppression

5.5 Use in Patients with Hepatic Impairment

5.6 Tumor Lysis Syndrome

5.7 Radiation Sensitization and Radiation Recall

5.8 Embryofetal Toxicity

6 ADVERSE REACTIONS

6.1 Clinical Trial Experience in Breast Cancer

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 Effect of CYP3A4 Inhibitors, Inducers and P-gp

7.2 Trastuzumab

7.3 Paclitaxel

7.4 Dexrazoxane

7.5 6-Mercaptopurine

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Females and Males of Reproductive Potential

8.7 Hepatic Impairment

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

15 REFERENCES

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

*
Sections or subsections omitted from the full prescribing information are not listed.

FULL PRESCRIBING INFORMATION

BOXED WARNING

 

WARNING: CARDIOMYOPATHY, SECONDARY MALIGNANCIES,

EXTRAVASATION AND TISSUE NECROSIS, and SEVERE MYELOSUPPRESSION

See full prescribing information for complete boxed warning.

  • Cardiomyopathy: Myocardial damage can occur with doxorubicin with incidences from 1% to 20% for cumulative doses from 300 mg/mto 500 mg/m2 when doxorubicin is administered every 3 weeks. The risk of cardiomyopathy is further increased with concomitant cardiotoxic therapy. Assess left ventricular ejection fraction (LVEF) before and regularly during and after treatment with doxorubicin. (5.1)
  • Secondary Malignancies: Secondary acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) occur at a higher incidence in patients treated with anthracyclines, including doxorubicin. (5.2)
  • Extravasation and Tissue Necrosis: Extravasation of doxorubicin can result in severe local tissue injury and necrosis requiring wide excision and skin grafting. Immediately terminate the drug, and apply ice to the affected area. (5.3)
  • Severe myelosuppression resulting in serious infection, septic shock, requirement for transfusions, hospitalization, and death may occur. (5.4)

1 INDICATIONS AND USAGE

1.1 Adjuvant Breast Cancer

Adriamycin (DOXOrubicin HCl) for Injection, USP is indicated as a component of multi-agent adjuvant chemotherapy for treatment of women with axillary lymph node involvement following resection of primary breast cancer [see Clinical Studies (14.1)].

1.2 Other Cancers

Doxorubicin 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

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dose

Adjuvant Breast Cancer

The recommended dose of doxorubicin 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 when used as a single agent is 60 to 75 mg/m2 intravenously every 21 days.
  • The recommended dose of doxorubicin, 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 is contraindicated in patients with severe hepatic impairment (Child-Pugh Class C or serum bilirubin >5.0 mg/dL) [see Contraindications (4) ].

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

 

Serum bilirubin concentration

 

Doxorubicin Dose reduction

 

1.2 to 3 mg/dL

 

50 %

 

3.1 to 5 mg/dL

 

75 %

 

greater than 5 mg/dL

 

Do not initiate doxorubicin

Discontinue doxorubicin

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

2.3 Preparation and Administration

Preparation or Adriamycin (DOXOrubicin HCl) for Injection, USP;

Reconstitute doxorubicin hydrochloride for injection with 0.9% Sodium Chloride Injection to obtain a final concentration of 2 mg per mL as follows:

  • 5 mL 0.9% Sodium Chloride Injection to reconstitute 10 mg doxorubicin HCl vial
  • 25 mL 0.9% Sodium Chloride Injection to reconstitute 50 mg doxorubicin HCl vial

Gently shake vial until the contents have dissolved.

Protect reconstituted solution from light.

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 Adriamycin (DOXOrubicin HCl) for Injection, USP 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  as an intravenous injection  through a central intravenous line or a secure and free-flowing peripheral venous line containing 0.9% Sodium Chloride Injection, 0.45% Sodium Chloride Injection, or 5% Dextrose Injection. 
  • Administer doxorubicin intravenously over 3 to 10 minutes. Decrease the rate of doxorubicin 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 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 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 with other drugs. If doxorubicin is mixed with heparin or fluorouracil a precipitate may form. Avoid contact with alkaline solutions which can lead to hydrolysis of doxorubicin.

2.4 Procedures for Proper Handling and Disposal

Handle and dispose of doxorubicin 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.

3 DOSAGE FORMS AND STRENGTHS

Adriamycin (DOXOrubicin HCl) for Injection, USP: Vials contain 10 mg and 50 mg doxorubicin hydrochloride as a red-orange lyophilized powder.

4 CONTRAINDICATIONS

Doxorubicin is contraindicated in patients with:

5 WARNINGS AND PRECAUTIONS

5.1 Cardiomyopathy and Arrhythmias

Cardiomyopathy

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

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

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

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

Arrhythmias

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

5.2 Secondary Malignancies

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

5.3 Extravasation and Tissue Necrosis

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

5.4 Severe Myelosuppression

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

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

5.5 Use in Patients with Hepatic Impairment

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

5.6 Tumor Lysis Syndrome

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

5.7 Radiation Sensitization and Radiation Recall

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

5.8 Embryofetal Toxicity

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

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

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

6 ADVERSE REACTIONS

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

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 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.

 

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

 

Adverse reactions, % of patients

 

AC*

N=1492

 

Conventional CMF

N=739

 

Leukopenia

Grade 3 (1,000 to 1,999 /mm3)

Grade 4 (<1000 /mm3)

 

3.4

0.3

 

9.4

0.3

 

Thrombocytopenia

Grade 3 (25,000 to 49,999 /mm3)

Grade 4 (<25,000 /mm3)

 

0

0.1

 

0

3 0

 

Shock, sepsis

 

2

 

1

 

Systemic infection

 

2

 

1

 

Vomiting

Vomiting ≤12 hours

Vomiting >12 hours

Intractable

 

34

37

5

 

25

12

2

 

Alopecia

 

92

 

71

 

Cardiac dysfunction

Asymptomatic

Transient

Symptomatic

 

0.2

0.1

0.1

 

0.1

0

0

* 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

6.2 Postmarketing Experience

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

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 with inhibitors and inducers of CYP3A4, CYP2D6, or P-gp.

7.2 Trastuzumab

Concurrent use of trastuzumab and doxorubicin 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, increases the plasma-concentrations of doxorubicin and its metabolites. Administer doxorubicin prior to paclitaxel if used concomitantly.

7.4 Dexrazoxane

Do not administer dexrazoxane as a cardioprotectant at the initiation of doxorubicin containing chemotherapy regimens. In a randomized trial in women with metastatic breast cancer, initiation of dexrazoxane with doxorubicin 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 based chemotherapy alone.

7.5 6-Mercaptopurine

Doxorubicin 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 (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 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category D

Risk Summary

Doxorubicin can cause fetal harm when administered to a pregnant woman. Doxorubicin 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 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 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 , 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 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. Doxorubicin, 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 HCl-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 can cause fetal harm when administered during pregnancy. Advise female patients of reproductive potential to use highly effective contraception during treatment with doxorubicin and for 6 months after treatment. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking doxorubicin [see Use in Specific Populations (8.1)].

Males

Doxorubicin 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 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 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 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 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)].

10 OVERDOSAGE

Few cases of overdose have been described. A 58-year-old man with acute lymphoblastic leukemia received 10-fold overdose of doxorubicin (300 mg/m2) 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 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.

11 DESCRIPTION

Doxorubicin is a cytotoxic anthracycline antibiotic isolated from cultures of Streptomyces peucetius var.caesius. Doxorubicin consists of a naphthacenequinone nucleus linked through a glycosidic bond at ring atom 7 to an amino sugar, daunosamine. Chemically, doxorubicin hydrochloride is (8S,10S)-10-[(3-Amino-2,3,6-trideoxy-a-L-lyxo-hexopyranosyl)-oxy]-8-glycoloyl-7,8,9,10-tetrahydro-

6,8,11-trihydroxy-1-methoxy-5,12-naphthacenedione hydrochloride. The structural formula is as follows:

Structural Formula

Doxorubicin binds to nucleic acids, presumably by specific intercalation of the planar anthracycline nucleus with the DNA double helix. The anthracycline ring is lipophilic, but the saturated end of the ring system contains abundant hydroxyl groups adjacent to the amino sugar, producing a hydrophilic center. The molecule is amphoteric, containing acidic functions in the ring phenolic groups and a basic function in the sugar amino group. It binds to cell membranes as well as plasma proteins.

It is supplied in the hydrochloride form as a sterile red-orange lyophilized powder containing lactose and as a sterile parenteral, isotonic solution with sodium chloride for intravenous use only.

Adriamycin (DOXOrubicin HCl) for Injection, USP:

Each 10 mg lyophilized vial contains 10 mg of Doxorubicin Hydrochloride, USP and 50 mg of Lactose Monohydrate, NF.

Each 50 mg lyophilized vial contains 50 mg of Doxorubicin Hydrochloride, USP and 250 mg of Lactose Monohydrate, NF.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The cytotoxic effect of doxorubicin 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 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 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. 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 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 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Doxorubicin treatment results in an increased risk of secondary malignancies based on postmarketing reports [see Warnings and Precautions (5.2)]. Doxorubicin 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 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 (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 induces DNA damage in rabbit spermatozoa and dominant lethal mutations in mice.

14 CLINICAL STUDIES

The clinical efficacy of doxorubicin HCl-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 5-fluorouracil (CMF) to no chemotherapy (19 trials including 7523 patients) and doxorubicin HCl-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 HCl-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 HCl-containing regimens retained at least 75% of the historical CMF adjuvant effect on DFS with a hazard ratio (HR) of 0.91 (95% CI, 0.8 to 1.01 ) and on OS with a HR of 0.91 (95% CI, 0.8 to 1.03 ). Results of these analyses for both DFS and OS are provided in Table 2 and Figures 1 and 2.

Table 2. Summary of Randomized Trials Comparing Doxorubicin Containing Regimens Versus CMF in Meta-Analysis

 

Study (starting year)

 

Regimens

 

No. of Cycles

 

No. of Patients

 

Doxorubicin HCl-Containing Regimens vs. CMF HR** (95% CI)

 

DFS

 

OS

 

NSABP B-15 (1984)

 

AC

CMF

 

4

6

 

1562*

776

 

0.93 (0.82 to 1.06)

 

0.97 (0.83 to 1.12)

 

SECSG 2 (1976)

 

FAC

CMF

 

6

6

 

260

268

 

0.86 (0.66 to 1.13)

 

0.93 (0.69 to 1.26)

 

ONCOFRANCE (1978)

 

FACV

CMF

 

12

12

 

138

113

 

0.71 (0.49 to 1.03)

 

0.65 (0.44 to 0.96)

 

SE Sweden BCG A (1980)

 

AC

CMF

 

6

6

 

21

22

 

0.59 (0.22 to 1.61)

 

0.53 (0.21 to 1.37)

 

NSABC Israel Br0283 (1983)

 

AVbCMF†

CMF

 

4

6

6

 

55

50

 

0.91 (0.53 to 1.57)

 

0.88 (0.47 to 1.63)

 

Austrian BCSG 3 (1984)

 

CMFVA

CMF

 

6

8

 

121

124

 

1.07 (0.73 to 1.55)

 

0.93 (0.64 to 1.35)

 

Combined Studies

 

Doxorubicin HCl-Containing Regimens CMF

 

2157

1353

 

0.91 (0.82 to 1.01)

 

0.91 (0.81 to 1.03)

Abbreviations: DFS = disease free survival; OS = overall survival; AC = doxorubicin, cyclophosphamide; AVbCMF = doxorubicin, vinblastine, cyclophosphamide, methotrexate, 5-fluorouracil; CMF = cyclophosphamide, methotrexate, 5-fluorouracil; CMFVA = cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, doxorubicin; FAC = 5-fluorouracil, doxorubicin, cyclophosphamide; FACV = 5-fluorouracil, doxorubicin, cyclophosphamide, vincristine; HR = hazard ratio; CI = confidence interval

* 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.
** a hazard ratio of less than 1 indicates that the treatment with doxorubicin HCl-containing regimens is associated
with lower risk of disease recurrences or death compared to the treatment with CMF.

† Patients received alternating cycles of AVb and CMF.

Figure 1 and 2

15 REFERENCES

1. “Hazardous Drugs”. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html

16 HOW SUPPLIED/STORAGE AND HANDLING

Adriamycin (DOXOrubicin HCI) for Injection, USP is supplied as a sterile red-orange lyophilized powder in single dose flip-top vials in the following package strengths:

NDC 0143-9275-01: 10 mg vial; individually boxed.

NDC 0143-9277-01: 50 mg vial; individually boxed.

Store all vials at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Protect from light. Retain in carton until time of use. Discard unused portion.

Reconstituted Solution Stability

After adding the diluent, the vial should be shaken and the contents allowed to dissolve. The reconstituted solution is stable for 7 days at room temperature and under normal room light (100 foot-candles) and 15 days under refrigeration (2° to 8°C). It should be protected from exposure to sunlight. Discard any unused solution from the 10 mg and 50 mg single dose vials.

Handling and Disposal

Handle and dispose of Adriamycin (DOXOrubicin HCl) for Injection, USP consistent with recommendations for the handling and disposal of hazardous drugs.

17 PATIENT COUNSELING INFORMATION

See FDA-Approved Patient Labeling (Patient Information). Inform patients of the following:

Manufactured by

THYMOORGAN PHARMAZIE GmbH,

Schiffgraben 23, 38690 Goslar, Germany

Distributed by

West-Ward Pharmaceuticals 

Eatontown, NJ 07724 USA

Revised January 2018

127.207.029/01

PATIENT INFORMATION

Patient Information

DOXORUBICIN (dok-suh-roo-buh-sin) HYDROCHLORIDE for Injection, for intravenous use

What is the most important information I should know about Doxorubicin? 

Doxorubicin may cause serious side effects including:

What is Doxorubicin?

Doxorubicin is a prescription medicine used to treat certain types of cancers. Doxorubicin may be used alone or along with other anti-cancer medicines.

Who should not receive Doxorubicin?

Do not receive Doxorubicin if:

What should I tell my doctor before receiving Doxorubicin?

Before you receive Doxorubicin, tell your doctor if you:

Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Doxorubicin can interact with other medicines. Do not start any new medicine before you talk with the doctor that prescribed Doxorubicin.

Know the medicines you take. Keep a list to show your doctor and pharmacist each time you get a new medicine.

How will I receive Doxorubicin?

What are the possible side effects of Doxorubicin?

Doxorubicin may cause serious side effects, including:

Doxorubicin may cause lower sperm counts and sperm problems in men.

This could affect your ability to father a child and cause birth defects. Talk to your healthcare provider if this is a concern for you. Talk to your healthcare provider about family planning options that might be right for you.

Irreversible amenorrhea or early menopause. Your periods (menstrual cycle) may completely stop when you receive Doxorubicin. Your periods may or may not return following treatment. Talk to your healthcare provider about family planning options that might be right for you.

The most common side effects of Doxorubicin include:

Other side effects:

Tell your doctor or nurse if you have any side effect that bothers you or that does not go away.

These are not all of the possible side effects of Doxorubicin.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

General information about the safe and effective use of Doxorubicin.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet.

You can ask your pharmacist or doctor for information about Doxorubicin that is written for health professionals.

For more information, call 1-877-845-0689.

What are the ingredients of Doxorubicin?

Active ingredient: doxorubicin hydrochloride

Inactive ingredients for Doxorubicin Hydrochloride for Injection: Lactose Monohydrate

This Patient Information has been approved by the U.S. Food and Drug Administration.

Manufactured by

THYMOORGAN PHARMAZIE GmbH,

Schiffgraben 23, 38690 Goslar, Germany

Distributed by

West-Ward Pharmaceuticals

Eatontown, NJ 07724 USA

Revised January 2018 

127.207.029/01

10 MG PACKAGE/LABEL PRINCIPAL DISPLAY PANEL

Vial label for 10 mg/vial

Vial label for 10 mg/vial

NDC 0143-9275-01 Rx only
ADRIAMYCIN (DOXOrubicin HCl) for Injection, USP

10 mg/vial
FOR INTRAVENOUS USE ONLY

LYOPHILIZED

50 MG PACKAGE/LABEL PRINCIPAL DISPLAY PANEL

Adriamycin (Doxorubicin HCl) for Injection vial label for 50 mg/vial

Adriamycin (Doxorubicin HCl) for Injection vial label for 50 mg/vial

NDC 0143-9277-01 Rx only
ADRIAMYCIN (DOXOrubicin HCl) for Injection, USP

50 mg/vial
FOR INTRAVENOUS USE ONLY

LYOPHILIZED

SERIALIZATION IMAGE 10 MG CARTON

Representative Carton Serialization Image

Representative Carton Serialization Image


SERIALIZATION IMAGE 50 MG CARTON

Representative Carton Serialization Image

Representative Carton Serialization Image


ADRIAMYCIN 
doxorubicin hydrochloride injection, powder, lyophilized, for solution
Product Information
Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:0143-9275
Route of AdministrationINTRAVENOUS
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
DOXORUBICIN HYDROCHLORIDE (UNII: 82F2G7BL4E) (DOXORUBICIN - UNII:80168379AG) DOXORUBICIN HYDROCHLORIDE2 mg  in 1 mL
Inactive Ingredients
Ingredient NameStrength
LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)  
Packaging
#Item CodePackage DescriptionMarketing Start DateMarketing End Date
1NDC:0143-9275-011 in 1 BOX01/19/2018
15 mL in 1 VIAL; Type 0: Not a Combination Product
Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
ANDAANDA06292101/19/2018
ADRIAMYCIN 
doxorubicin hydrochloride injection, powder, lyophilized, for solution
Product Information
Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:0143-9277
Route of AdministrationINTRAVENOUS
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
DOXORUBICIN HYDROCHLORIDE (UNII: 82F2G7BL4E) (DOXORUBICIN - UNII:80168379AG) DOXORUBICIN HYDROCHLORIDE2 mg  in 1 mL
Inactive Ingredients
Ingredient NameStrength
LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)  
Packaging
#Item CodePackage DescriptionMarketing Start DateMarketing End Date
1NDC:0143-9277-011 in 1 BOX01/19/2018
125 mL in 1 VIAL; Type 0: Not a Combination Product
Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
ANDAANDA06292101/19/2018
Labeler - Hikma Pharmaceuticals USA Inc. (001230762)

Revised: 12/2019
Document Id: a88e80b5-b556-4dd0-8532-bed33bcd25b8
Set id: 090bc1b1-3dc2-408d-94e6-48d2a3d4426c
Version: 5
Effective Time: 20191230
 
Hikma Pharmaceuticals USA Inc.