DOXORUBICIN HYDROCHLORIDE injection, solution
For Healthcare Providers >

1. Doxorubicin May Cause Serious Side Effects Including:
2. Tell Your Doctor If You Get Any Of These Symptoms Of Heart Failure During Or After Treatment With Doxorubicin:
3. What Is Doxorubicin?
4. Active Ingredient:
5. Inactive Ingredients For Doxorubicin Hydrochloride Injection:
6. Revised: 10/2017document Id:
7. Do Not Receive Doxorubicin If:
8. Before You Receive Doxorubicin, Tell Your Doctor If You:
9. How Will I Receive Doxorubicin?
10. Inform Patients Of The Following:
11. Patient Information
12. Tell Your Doctor If You Get Any Of These Symptoms Of Heart Problems:
13. What Is Doxorubicin?
14. Do Not Receive Doxorubicin If:
15. Before You Receive Doxorubicin, Tell Your Doctor If You:
16. What Should I Avoid While Taking Doxorubicin?
17. Doxorubicin Can Cause Serious Side Effects Including:
18. Revised: 2/2017document Id:

Doxorubicin May Cause Serious Side Effects Including: ⮝

• Heart failure. Doxorubicin may cause heart muscle damage that may lead to heart failure, which is a condition in which the heart does not pump well. Heart failure is irreversible in some cases and can lead to death. Heart failure can happen during your treatment with Doxorubicin or months to years after stopping treatment. Your risk of heart muscle damage increases with higher total amounts of doxorubicin hydrochloride that you receive in your lifetime. Your risk of heart failure is higher if you:
  • already have other heart problems
  • have had or are currently receiving radiation therapy to your chest
  • have had treatment with certain other anti-cancer medicines
  • take other medicines that can have severe side effects on your heart

Tell Your Doctor If You Get Any Of These Symptoms Of Heart Failure During Or After Treatment With Doxorubicin: ⮝

extreme tiredness or weakness	fast heartbeat
shortness of breath	swelling of your feet and ankles

Your doctor will do tests to check the strength of your heart muscle before, during, and after your treatment with Doxorubicin.

• Risk of new cancers.You may have an increased risk of developing certain blood cancers called acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) after treatment with doxorubicin. Talk with your doctor about your risk of developing new cancers if you take Doxorubicin.
  
  
• Skin damage near the vein where Doxorubicin is given (Injection site reaction).Doxorubicin can damage the skin if it leaks out of the vein. Symptoms of infusion reaction include blisters and skin sores at injection site which may require skin grafts.
  
  
• Decreased blood cell counts.Doxorubicin can cause a decrease in neutrophils (a type of white blood cells important in fighting bacterial infections) and platelets (important for clotting and to control bleeding). This may lead to a serious infection, the need for blood transfusions, treatment in a hospital and death. Your doctor will check your blood cell count during your treatment with Doxorubicin and after you have stopped your treatment. Call your doctor right away if you get a fever (temperature of 100.4 F or greater) or chills with shivering.

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.

Active Ingredient: ⮝

doxorubicin hydrochloride

Inactive Ingredients For Doxorubicin Hydrochloride Injection: ⮝

0.9% sodium chloride, USP, water for injection, USP q.s., and hydrochloric acid, USP.

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

Athenex

Mfd. for Athenex
Schaumburg, IL 60173 (USA)
Made in India
2017 Athenex.

September 2017

PACKAGE LABEL PRINCIPAL DISPLAY PANEL Vial Label

NDC 70860-208-05

Doxorubicin HCl Injection, USP

10 mg per 5 mL (2 mg per mL)

Rx only

For Intravenous Use Only

5 mL Single-Dose Vial

Discard unused portion

Caution: Cytotoxic Agent

PACKAGE LABEL PRINCIPAL DISPLAY PANEL Carton

NDC 70860-208-05

Doxorubicin HCl Injection, USP

10 mg per 5 mL (2 mg per mL)

Rx only

For Intravenous Use Only

5 mL Single-Dose Vial

Discard unused portion

Caution: Cytotoxic Agent

PACKAGE LABEL PRINCIPAL DISPLAY PANEL Vial Label

NDC 70860-208-25

Doxorubicin HCl Injection, USP

50 mg per 25 mL (2 mg per mL)

Rx only

For Intravenous Use Only

25 mL Single-Dose Vial

Discard unused portion

Caution: Cytotoxic Agent

PACKAGE LABEL PRINCIPAL DISPLAY PANEL Carton

NDC 70860-208-25

Doxorubicin HCl Injection, USP

50 mg per 25 mL (2 mg per mL)

Rx only

For Intravenous Use Only

25 mL Single-Dose Vial

Discard unused portion

Caution: Cytotoxic Agent

PACKAGE LABEL PRINCIPAL DISPLAY PANEL Vial Label

NDC 70860-208-51

Doxorubicin HCl Injection, USP

200 mg per 100 mL (2 mg per mL)

Rx only

For Intravenous Use Only

100 mL Multi-Dose Vial

Caution: Cytotoxic Agent

PACKAGE LABEL PRINCIPAL DISPLAY PANEL Carton

NDC 70860-208-51

Doxorubicin HCl Injection, USP

200 mg per 100 mL (2 mg per mL)

Rx only

For Intravenous Use Only

100 mL Multi-Dose Vial

Caution: Cytotoxic Agent

DOXORUBICIN HYDROCHLORIDE doxorubicin hydrochloride injection, solution

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:70860-208 Route of Administration INTRAVENOUS

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength doxorubicin hydrochloride(UNII: 82F2G7BL4E) (doxorubicin - UNII:80168379AG) doxorubicin hydrochloride 2 mg in 1 mL

Inactive Ingredients Ingredient Name Strength sodium chloride(UNII: 451W47IQ8X) hydrochloric acid(UNII: QTT17582CB) water(UNII: 059QF0KO0R)

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:70860-208-05 1 in 1 CARTON 10/20/2017 1 5 mL in 1 VIAL, SINGLE-DOSE; Type 0: Not a Combination Product 2 NDC:70860-208-25 1 in 1 CARTON 10/20/2017 2 25 mL in 1 VIAL, SINGLE-DOSE; Type 0: Not a Combination Product 3 NDC:70860-208-51 1 in 1 CARTON 10/20/2017 3 100 mL in 1 VIAL, MULTI-DOSE; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA209825 10/20/2017

Labeler -Athenex Pharmaceutical Division, LLC. (080318964)

Revised: 10/2017document Id: ⮝

93ce419e-e621-46a8-9e35-b818a569a18a34391-3Set id: 8fa04d6d-ac9f-437a-9891-fed0d90a789dVersion: 1Effective Time: 20171020Athenex Pharmaceutical Division, LLC.

Do Not Receive Doxorubicin If: ⮝

• you have had a recent heart attack or have severe heart problems
• your blood cell counts (platelets, red blood cells, and white blood cells) are very low because of prior chemotherapy
• you have a severe liver problem
• you have had a serious allergic reaction to doxorubicin hydrochloride

Before You Receive Doxorubicin, Tell Your Doctor If You: ⮝

• have heart problems including heart failure
• are currently receiving radiation therapy or plan to receive radiation to the chest
• have severe liver problems
• have had an allergic reaction to doxorubicin
• have any other medical conditions
• are pregnant or plan to become pregnant. Doxorubicin can harm your unborn baby. Women who are able to become pregnant and men who take Doxorubicin should use effective birth control (contraception) during treatment and for 6 months after treatment. Talk to your doctor about birth control methods. If you or your partner becomes pregnant, tell your doctor right away.
• are breastfeeding or plan to breast feed. Doxorubicin can pass into your breast milk and harm your baby. You and your doctor should decide if you will receive Doxorubicin or breastfeed. You should not do both.

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? ⮝

• Doxorubicin will be given to you into your vein.

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[seeWarnings and Precautions (5.1)].
• There is an increased risk of treatment-related leukemia from doxorubicin HCl[seeWarnings and Precautions (5.2)].
• 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[seeWarnings and Precautions (5.4)].
• 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[seeWarnings and Precautions (5.8)andUse in Specific Populations (8.6)].
• 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[seeWarnings and Precautions (5.8andUse in Specific Populations (8.6)].
• Doxorubicin HCl can cause premature menopause in females and loss of fertility in males[seeUse in Specific Populations (8.6)].
• Discontinue nursing while receiving doxorubicin HCl[seeUse in Specific Populations (8.3)].
• 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[seeAdverse Reactions (6)].
• Doxorubicin HCl causes alopecia[seeAdverse Reactions (6.1)].
• Doxorubicin HCl can cause their urine to appear red for 1 to 2 days after administration.

This product's label may have been updated. For current full prescribing information, please visit www.pfizer.com.

PREMIERPro Rx is a trademark of Premier, Inc., used under license.

Distributed by
Pfizer Labs
Division of Pfizer, Inc.
New York, NY 10017

LAB-0702-2.0

Patient Information ⮝

Doxorubicin
(dakse-RU-besen)
Hydrochloride Injection, USP

Read this Patient information before you start receiving doxorubicin and before each infusion. This information leaflet does not take the place of talking with your doctor about your medical condition or your treatment.

Tell Your Doctor If You Get Any Of These Symptoms Of Heart Problems: ⮝

shortness of breath

cough

swelling of your feet and ankles

fast heartbeat

Your doctor should do tests to check your heart before, during, and after your treatment with doxorubicin.

Secondary cancers.Some people who have received doxorubicin have developed acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS). Your chance of developing a secondary cancer is higher if you receive doxorubicin along with other anti-cancer medicines or with radiation therapy.

Decreased blood cell counts.Doxorubicin can cause a severe decrease in neutrophils (a type of white blood cells important in fighting in bacterial infections), red blood cells (blood cells that carry oxygen to the tissues), and platelets (important for clotting and to control bleeding).Your doctor will check your blood cell count during your treatment with doxorubicin and after you have stopped your treatment.

What Is Doxorubicin? ⮝

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

Do Not Receive Doxorubicin If: ⮝

your blood cell counts are too low: platelets (which help your blood to clot), red blood cells (which help to carry iron and oxygen throughout your body), and white blood cells (which help to fight infection)

you have a severe liver problem

you have had a recent heart attack or have severe heart problems

you have had previous treatment with doxorubicin or certain other anticancer medicines and received the maximum dose allowed

you are allergic to certain other anti-cancer medicines, doxorubicin hydrochloride, or any other ingredient in Doxorubicin Hydrochloride Injection, USP.

Before You Receive Doxorubicin, Tell Your Doctor If You: ⮝

have heart problems

have had radiation treatment or currently receiving radiation therapy

are over the age of 50

have liver problems

plan to receive any vaccines. Talk to your doctor about which vaccines are safe for you to receive during your treatment with doxorubicin.

Your doctor will prescribe doxorubicin in an amount that is right for you.

Doxorubicin will be given to you by intravenous (IV) infusion into your vein.

Your doctor will do regular blood tests to check for side effects of doxorubicin.

Before receiving doxorubicin you may receive other medicines to prevent or treat side effects.

Caregivers of children receiving doxorubicin should take precautions (such as wearing latex gloves) to prevent contact with the patient s urine and other body fluids for at least 5 days after each treatment.

What Should I Avoid While Taking Doxorubicin? ⮝

Avoid receiving live vaccines during treatment with doxorubicin. Talk to your doctor to find out which vaccines are safe for you while receiving doxorubicin.

Doxorubicin Can Cause Serious Side Effects Including: ⮝

Active ingredient: Doxorubicin hydrochloride

Inactive ingredient: sodium chloride 0.9%, water for injection, hydrochloric acid and/or sodium hydroxide.

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

www.fresenius-kabi.us

45771E
Revised: August 2016

PACKAGE LABEL - PRINCIPAL DISPLAY - Doxorubicin 5 mL Single Dose Vial Label

DOXOrubicin HydrochlorideInjection, USP

10 mg per 5 mL
(2 mg per mL)

For intravenous use only.
Preservative free.

5 mLSingle Dose Vial Rx only

PACKAGE LABEL - PRINCIPAL DISPLAY - Doxorubicin 5 mL Single Dose Vial Carton Panel

DOXOrubicin HydrochlorideInjection, USP
10 mg per 5 mL
(2 mg per mL)

For intravenous use only.

Preservative free.
Rx only
5 mL
Single Dose Vial

PACKAGE LABEL - PRINCIPAL DISPLAY - Doxorubicin 100 mL Multiple Dose Vial Label

DOXOrubicin HydrochlorideInjection, USP

200 mg per 100 mL
(2 mg per mL)

For intravenous use only.

Preservative free.

100 mL
Multiple Dose Vial Rx only

PACKAGE LABEL - PRINCIPAL DISPLAY - Doxorubicin 100 mL Multiple Dose Vial Carton Panel

DOXOrubicin HydrochlorideInjection, USP

200 mg per 100 mL
(2 mg per mL)

For intravenous use only.
Preservative free.

Rx only
100 mL
Multiple Dose Vial

DOXORUBICIN HYDROCHLORIDE doxorubicin hydrochloride injection, solution

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:63323-883 Route of Administration INTRAVENOUS

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength DOXORUBICIN HYDROCHLORIDE(UNII: 82F2G7BL4E) (DOXORUBICIN - UNII:80168379AG) DOXORUBICIN HYDROCHLORIDE 2 mg in 1 mL

Inactive Ingredients Ingredient Name Strength SODIUM CHLORIDE(UNII: 451W47IQ8X) 9 mg in 1 mL HYDROCHLORIC ACID(UNII: QTT17582CB) SODIUM HYDROXIDE(UNII: 55X04QC32I)

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:63323-883-05 1 in 1 CARTON 04/14/2000 1 5 mL in 1 VIAL, SINGLE-DOSE; Type 0: Not a Combination Product 2 NDC:63323-883-10 1 in 1 CARTON 04/14/2000 2 10 mL in 1 VIAL, SINGLE-DOSE; Type 0: Not a Combination Product 3 NDC:63323-883-30 1 in 1 CARTON 04/14/2000 3 25 mL in 1 VIAL, SINGLE-DOSE; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA063277 04/14/2000

DOXORUBICIN HYDROCHLORIDE doxorubicin hydrochloride injection, solution

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:63323-101 Route of Administration INTRAVENOUS

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength DOXORUBICIN HYDROCHLORIDE(UNII: 82F2G7BL4E) (DOXORUBICIN - UNII:80168379AG) DOXORUBICIN HYDROCHLORIDE 2 mg in 1 mL

Inactive Ingredients Ingredient Name Strength SODIUM CHLORIDE(UNII: 451W47IQ8X) 9 mg in 1 mL HYDROCHLORIC ACID(UNII: QTT17582CB) SODIUM HYDROXIDE(UNII: 55X04QC32I)

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:63323-101-61 1 in 1 CARTON 06/14/2000 1 100 mL in 1 VIAL, MULTI-DOSE; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA063277 06/14/2000

Labeler -Fresenius Kabi USA, LLC (608775388)

Establishment
Name	Address	ID/FEI	Business Operations
Fresenius Kabi USA, LLC		023648251	MANUFACTURE(63323-101, 63323-883)

Revised: 2/2017document Id: ⮝

f48b1ac2-923f-4825-9c44-02df9253cf9634391-3Set id: e0349f98-42fa-4003-b6d8-a1db1401b0efVersion: 3Effective Time: 20170227Fresenius Kabi USA, LLC

1. Highlights Of Prescribing Information
2. Warning: Cardiomyopathy, Secondary Malignancies, Extravasation And Tissue Necrosis, And Severe Myelosuppression
3. See Full Prescribing Information For Complete Boxed Warning.
4. Indications And Usage
5. Dosage And Administration
6. Dosage Forms And Strengths
7. Contraindications
8. Warnings And Precautions
9. Adverse Reactions
10. Drug Interactions
11. Use In Specific Populations
12. Warning: Cardiomyopathy, Secondary Malignancies, Extravasation And Tissue Necrosis, And Severe Myelosuppression
13. 1 Indications And Usage
14. 2 Dosage And Administration
15. 3 Dosage Forms And Strengths
16. 4 Contraindications
17. 5 Warnings And Precautions
18. 6 Adverse Reactions
19. 7 Drug Interactions
20. 8 Use In Specific Populations
21. 10 Overdosage
22. 11 Description
23. 12 Clinical Pharmacology
24. 13 Nonclinical Toxicology
25. 14 Clinical Studies
26. 15 References
27. 16 How Supplied/storage And Handling
28. Warning: Cardiomyopathy, Secondary Malignancies, Extravasation And Tissue Necrosis, And Severe Myelosuppressionsee Full Prescribing Information For Complete Boxed Warning.
29. 1 Indications And Usage
30. 2 Dosage And Administration
31. 3 Dosage Forms And Strengths
32. 4 Contraindications
33. 5 Warnings And Precautions
34. 6 Adverse Reactions
35. 7 Drug Interactions
36. 8 Use In Specific Populations
37. 10 Overdosage
38. 11 Description
39. 12 Clinical Pharmacology
40. 13 Nonclinical Toxicology
41. 14 Clinical Studies
42. 15 References
43. 16 How Supplied
44. Package Label.principal Display Panel
45. Warning: Cardiomyopathy, Secondary Malignancies, Extravasation And Tissue Necrosis, And Severe Myelosuppressionsee Full Prescribing Information For Complete Boxed Warning.
46. 1 Indications & Usage
47. 2 Dosage & Administration
48. 3 Dosage Forms & Strengths
49. 16 How Supplied/storage And Handling
50. Warning
51. Description:
52. Clinical Pharmacology:
53. Clinical Studies:
54. Indications And Usage:
55. Contraindications:
56. Warnings:
57. Precautions:
58. Adverse Reactions:
59. Overdosage:
60. Dosage And Administration:
61. How Supplied:
62. References:
63. Principal Display Panel - 10 Mg/5 Ml Vial Label
64. Principal Display Panel - 10 Mg/5 Ml Vial Carton
65. Principal Display Panel - 20 Mg/10 Ml Vial Label
66. Principal Display Panel - 20 Mg/10 Ml Vial Carton
67. Principal Display Panel - 50 Mg/25 Ml Vial Label
68. Principal Display Panel - 50 Mg/25 Ml Vial Carton
69. Principal Display Panel - 200 Mg/100 Ml Vial Label
70. Principal Display Panel - 200 Mg/100 Ml Vial Carton

Highlights Of Prescribing Information ⮝

These highlights do not include all the information needed to use DOXORUBICIN HYDROCHLORIDE safely and effectively. See full prescribing information for DOXORUBICIN HYDROCHLORIDE.

DOXORUBICIN HYDROCHLORIDE injection, for intravenous use
Initial U.S. Approval: 1974

Warning: Cardiomyopathy, Secondary Malignancies, Extravasation And Tissue Necrosis, And Severe Myelosuppression ⮝

• Cardiomyopathy: Myocardial damage, including acute left ventricular failure can occur with doxorubicin HCl. The risk of cardiomyopathy is proportional to the cumulative exposure with incidence rates from 1% 20% for cumulative doses ranging from 300 mg/m2 to 500 mg/m2 when doxorubicin HCl is administered every 3 weeks. The risk of cardiomyopathy is further increased with concomitant cardiotoxic therapy. Assess LVEF before and regularly during and after treatment with doxorubicin HCl [see Warnings and Precautions (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 HCl [see Warnings and Precautions (5.2)].
• Extravasation and Tissue Necrosis: Extravasation of doxorubicin HCl can result in severe local tissue injury and necrosis requiring wide excision of the affected area and skin grafting. Immediately terminate the drug and apply ice to the affected area [see Warnings and Precautions (5.3)].
• Severe myelosuppression resulting in serious infection, septic shock, requirement for transfusions, hospitalization, and death may occur [see Warnings and Precautions (5.4)].

See Full Prescribing Information For Complete Boxed Warning. ⮝

• Cardiomyopathy: Myocardial damage can occur with doxorubicin HCl with incidences from 1% 20% for cumulative doses from 300 mg/m2 to 500 mg/m2 when doxorubicin HCl 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 HCl. (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 HCl. (5.2)
• Extravasation and Tissue Necrosis: Extravasation of doxorubicin HCl 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 hydrochloride (HCl) 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 HCl in patients who develop signs or symptoms of cardiomyopathy (2.2).
• Reduce dose in patients with hepatic impairment (2.2).

Dosage Forms And Strengths ⮝

• Doxorubicin HCl injection: Vials contain 10 mg/5 mL, 20 mg/10 mL, 50 mg/25 mL, and 200 mg/100 mL as a solution (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 HCl. Radiation recall can occur in patients who receive doxorubicin HCl 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 Pfizer, Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Drug Interactions ⮝

• Avoid concomitant use of doxorubicin HCl with inhibitors and inducers of CYP3A4, CYP2D6, and/or P-gp (7.1).
• Do not administer doxorubicin HCl 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 FDA-approved patient labeling.

Revised: 10/2019

Warning: Cardiomyopathy, Secondary Malignancies, Extravasation And Tissue Necrosis, And Severe Myelosuppression  ⮝

• Cardiomyopathy: Myocardial damage, including acute left ventricular failure can occur with doxorubicin HCl. The risk of cardiomyopathy is proportional to the cumulative exposure with incidence rates from 1% to 20% for cumulative doses ranging from 300 mg/m2 to 500 mg/m2 when doxorubicin HCl is administered every 3 weeks. The risk of cardiomyopathy is further increased with concomitant cardiotoxic therapy. Assess LVEF before and regularly during and after treatment with doxorubicin HCl [see Warnings and Precautions (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 HCl [see Warnings and Precautions (5.2)].
• Extravasation and Tissue Necrosis: Extravasation of doxorubicin HCl can result in severe local tissue injury and necrosis requiring wide excision of the affected area and skin grafting. Immediately terminate the drug and apply ice to the affected area [see Warnings and Precautions (5.3)].
• Severe myelosuppression resulting in serious infection, septic shock, requirement for transfusions, hospitalization, and death may occur [see Warnings and Precautions (5.4)].

1 Indications And Usage  ⮝

1.1 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 [see Clinical Studies (14.1)].

1.2 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

2 Dosage And Administration  ⮝

2.1 Recommended Dose

Adjuvant Breast Cancer

The recommended dose of doxorubicin HCl 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 HCl when used as a single agent is 60 to 75 mg/m2 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/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 HCl 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 HCl in patients with elevated serum total bilirubin concentrations as follows:

[see Warnings and Precautions (5.5) and Use in Specific Population (8.7)]
Serum bilirubin concentration	Doxorubicin HCl Dose reduction
1.2 to 3.0 mg/dL	50%
3.1 to 5.0 mg/dL	75%
greater than 5.0 mg/dL	Do not initiate doxorubicin HCl Discontinue doxorubicin HCl

2.3 Preparation and Administration

Preparation for Continuous Intravenous Infusion

Dilute doxorubicin HCl 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 under refrigerated conditions can result in the formation of a gelled product. Place gelled product at room temperature [15 to 30 C (59 to 86 F)] 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 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 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.

2.4 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.

3 Dosage Forms And Strengths  ⮝

Doxorubicin Hydrochloride Injection: Vials contain 10 mg per 5 mL, 50 mg per 25 mL, and 200 mg per 100 mL doxorubicin hydrochloride as a clear red solution.

4 Contraindications  ⮝

Doxorubicin HCl is contraindicated in patients with:

• Severe myocardial insufficiency [see Warnings and Precautions (5.1)]
• Recent (occurring within the past 4 to 6 weeks) myocardial infarction [see Warnings and Precautions (5.1)]
• Severe persistent drug-induced myelosuppression [see Warnings and Precautions (5.4)]
• Severe hepatic impairment (defined as Child Pugh Class C or serum bilirubin level greater than 5 mg/dL) [see Warnings and Precautions (5.5)]
• Severe hypersensitivity reaction to doxorubicin HCl including anaphylaxis [see Adverse Reactions (6.2)]

5 Warnings And Precautions  ⮝

5.1 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 [see Use in Specific Populations (8.4)].

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.

5.2 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.

5.3 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 [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 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.

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 HCl 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 HCl therapy.

5.6 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.

5.7 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.

5.8 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 [see Use in Specific Populations (8.1)].

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 [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.

• Cardiomyopathy and Arrhythmias [see Warnings and Precautions (5.1)]
• Secondary Malignancies [see Warnings and Precautions (5.2)]
• Extravasation and Tissue Necrosis [see Warnings and Precautions (5.3)]
• Severe Myelosuppression [see Warnings and Precautions (5.4)]
• Tumor Lysis Syndrome [see Warnings and Precautions (5.6)]
• Radiation Sensitization and Radiation Recall [see Warnings and Precautions (5.7)]

6.1 Clinical Trial Experience in Breast Cancer

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The safety data below were collected from 1492 women who received doxorubicin HCl 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

* 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
	AC*	Conventional CMF
	N=1492	N=739
Adverse reactions, % of patients
Leukopenia Grade 3 (1,000 to 1,999/mm3) Grade 4 (<1,000/mm3)	3.4 0.3	9.4 0.3
Thrombocytopenia Grade 3 (25,000 to 49,999/mm3)	0 0.1	0.3 0
Grade 4 (<25,000/mm3)
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

6.2 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

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

7.2 Trastuzumab

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

7.4 Dexrazoxane

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

7.5 6-Mercaptopurine

Doxorubicin HCl 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 HCl (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 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/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 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 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.

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 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.

8.4 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. Long-term 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 [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 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 [see Use in Specific Populations (8.1)].

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 [see Nonclinical Toxicology (13.1)].

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 [see Nonclinical Toxicology (13.1)].

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.

8.7 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 [see Dosage and Administration (2.2) and Warnings and Precautions (5.5)].

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) [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 HCl (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 HCl daily for 2 days (intended dose was 50 mg per day for 3 days). The patient developed severe mucositis on days 4 to 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 Hydrochloride is a cytotoxic, anthracycline, topoisomerase II inhibitor isolated from cultures of Streptomyces peucetius var. caesius. Chemically, doxorubicin hydrochloride is: 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy- -L-lyxo-hexopyranosyl)oxy]-7,8,9,10-tetrahydro 6,8,11-trihydroxy-8-(hydroxylacetyl)-1-methoxy-, hydrochloride (8S-cis)-. The chemical structure of doxorubicin HCl is:

Doxorubicin Hydrochloride Injection, USP is a clear, red, sterile, isotonic aqueous solution provided in vials containing 10 mg per 5 mL, 50 mg per 25 mL, and 200 mg per 100 mL of doxorubicin hydrochloride, USP. The drug product has demonstrated inherent antimicrobial activity suitable for a multiple dose presentation. Each milliliter of solution contains 2 mg of doxorubicin HCl. Inactive ingredients include sodium chloride 0.9%, USP, and water for injection, USP, quantity sufficient. The pH of the solution is adjusted to 2.5 to 4.5 with hydrochloric acid, USP.

12 Clinical Pharmacology  ⮝

12.1 Mechanism of Action

The cytotoxic effect of doxorubicin HCl 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 HCl 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 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/m2 of doxorubicin HCl 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 HCl treatment results in an increased risk of secondary malignancies based on postmarketing reports [see Warnings and Precautions (5.2)]. 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.

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, 0.82 1.01) and on OS with a HR of 0.91 (95% CI, 0.81 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 HCl-Containing Regimens Versus CMF in Meta-Analysis

Abbreviations: DFS = disease free survival; OS = overall survival; AC = doxorubicin HCl, cyclophosphamide; AVbCMF = doxorubicin HCl, vinblastine, cyclophosphamide, methotrexate, 5-fluorouracil; CMF = cyclophosphamide, methotrexate, 5-fluorouracil; CMFVA = cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, doxorubicin HCl; FAC = 5-fluorouracil, doxorubicin HCl, cyclophosphamide; FACV = 5-fluorouracil, doxorubicin HCl, 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.
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 1.06)	0.97 (0.83 1.12)
SECSG 2 (1976)	FAC CMF	6 6	260 268	0.86 (0.66 1.13)	0.93 (0.69 1.26)
ONCOFRANCE (1978)	FACV CMF	12 12	138 113	0.71 (0.49 1.03)	0.65 (0.44 0.96)
SE Sweden BCG A (1980)	AC CMF	6 6	21 22	0.59 (0.22 1.61)	0.53 (0.21 1.37)
NSABC Israel Br0283 (1983)	AVbCMF CMF	4 6 6	55 50	0.91 (0.53 1.57)	0.88 (0.47 1.63)
Austrian BCSG 3 (1984)	CMFVA CMF	6 8	121 124	1.07 (0.73 1.55)	0.93 (0.64 1.35)
Combined Studies	Doxorubicin HCl-Containing Regimens CMF		2157 1353	0.91 (0.82 1.01)	0.91 (0.81 1.03)

Figure 1. Meta-analysis of Disease-Free Survival

Figure 2. Meta-analysis of Overall Survival

15 References  ⮝

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

16 How Supplied/storage And Handling  ⮝

Doxorubicin Hydrochloride Injection, USP is supplied as follows:

NDC	Doxorubicin Hydrochloride Injection, USP (2 mg per mL)	Package Factor
70860-208-05	10 mg per 5 mL Single-Dose Vial	1 vial per carton
70860-208-25	50 mg per 25 mL Single-Dose Vial	1 vial per carton

Protect from light. Retain in carton until time of use. Discard unused portion.

NDC	Doxorubicin Hydrochloride Injection, USP (2 mg per mL)	Package Factor
70860-208-51	200 mg per 100 mL Multi-Dose Vial	1 vial per carton

Protect from light. Retain in carton until contents are used.

Doxorubicin Hydrochloride Injection, USP is a sterile parenteral, as a clear red isotonic solution, available in clear flip-top glass vials.

Storage Conditions

Store refrigerated between 2 and 8 C (36 and 46 F).

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

Handling and Disposal

Handle and dispose of Doxorubicin Hydrochloride Injection, USP consistent with recommendations for the handling and disposal of hazardous drugs.1

Sterile, Nonpyrogenic, Preservative-free.

The container closure is not made with natural rubber latex.

Warning: Cardiomyopathy, Secondary Malignancies, Extravasation And Tissue Necrosis, And Severe Myelosuppressionsee Full Prescribing Information For Complete Boxed Warning.  ⮝

• Cardiomyopathy: Myocardial damage can occur with doxorubicin hydrochloride with incidences from 1% to 20% for cumulative doses from 300 mg/m2 to 500 mg/m2 when doxorubicin hydrochloride 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 hydrochloride. (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 hydrochloride. (5.2)
• Extravasation and Tissue Necrosis: Extravasation of doxorubicin hydrochloride 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

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 [see Clinical Studies (14)].

1.2 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

2 Dosage And Administration ⮝

2.1 Recommended Dose

Adjuvant Breast Cancer

The recommended dose of doxorubicin HCl 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 HCl when used as a single agent is 60 to 75 mg/m2 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/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 HCl 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 HCl in patients with elevated serum total bilirubin concentrations as follows:

Serum bilirubin concentration	Doxorubicin HCl Dose reduction
1.2 3.0 mg/dL	50 %
3.1 5.0 mg/dL	75 %
greater than 5.0 mg/dL	Do not initiate doxorubicin HCl Discontinue doxorubicin HCl

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

2.3 Preparation and Administration

Preparation for Continuous Intravenous Infusion

Dilute doxorubicin HCl 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 under refrigerated conditions can result in the formation of a gelled product. Place gelled product at room temperature [15 to 30 C (59 to 86 F)] 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 [see Warnings and Precautions (5.3)].

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.

2.4 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.

3 Dosage Forms And Strengths ⮝

Doxorubicin Hydrochloride Injection: Vials contain 10 mg/5 mL, 20 mg/10 mL, 50 mg/25 mL, and 200 mg/100 mL doxorubicin hydrochloride as a clear red solution.

4 Contraindications ⮝

Doxorubicin HCl is contraindicated in patients with:

• Severe myocardial insufficiency [see Warnings and Precautions (5.1)]
• Recent (occurring within the past 4 6 weeks) myocardial infarction [see Warnings and Precautions (5.1)]
• Severe persistent drug-induced myelosuppression [see Warnings and Precautions (5.4)]
• Severe hepatic impairment (defined as Child Pugh Class C or serum bilirubin level greater than 5 mg/dL) [see Warnings and Precautions (5.5)]
• Severe hypersensitivity reaction to doxorubicin HCl including anaphylaxis [see Adverse Reactions (6.2)]

5 Warnings And Precautions ⮝

5.1 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 [see Use in Specific Populations (8.4)].

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.

5.2 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.

5.3 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 [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 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.

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 HCl in patients with serum bilirubin levels of 1.2 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 HCl therapy.

5.6 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.

5.7 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.

5.8 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 [see Use in Specific Populations (8.1)].

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 [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.

• Cardiomyopathy and Arrhythmias [see Warnings and Precautions (5.1)]
• Secondary Malignancies [see Warnings and Precautions (5.2)]
• Extravasation and Tissue Necrosis [see Warnings and Precautions (5.3)]
• Severe Myelosuppression [see Warnings and Precautions (5.4)]
• Tumor Lysis Syndrome [see Warnings and Precautions (5.6)]
• Radiation Sensitization and Radiation Recall [see Warnings and Precautions (5.7)]

6.1 Clinical Trial Experience in Breast Cancer

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The safety data below were collected from 1492 women who received doxorubicin HCl 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

	AC*	Conventional CMF
	N=1492	N=739
* 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
Adverse reactions, % of patients
Leukopenia
Grade 3 (1,000 1,999 /mm3)	3.4	9.4
Grade 4 (<1000 /mm3)	0.3	0.3
Thrombocytopenia
Grade 3 (25,000 49,999 /mm3)	0	0.3
Grade 4 (<25,000 /mm3)	0.1	0
Shock, sepsis	2	1
Systemic infection	2	1
Vomiting
Vomiting 12 hours	34	25
Vomiting >12 hours	37	12
Intractable	5	2
Alopecia	92	71
Cardiac dysfunction
Asymptomatic	0.2	0.1
Transient	0.1	0
Symptomatic	0.1	0

6.2 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

7 Drug Interactions ⮝

7.1 Effect of Other Drugs on Doxorubicin Hydrochloride Injection/for Injection

Inhibitors of CYP3A4, CYP2D6, and P-gp

Concomitant use of doxorubicin hydrochloride with inhibitors of CYP3A4, CYP2D6, or P-glycoprotein (P-gp), increased concentrations of doxorubicin, which may increase the incidence and severity of adverse reactions of doxorubicin hydrochloride. Avoid concomitant use of Doxorubicin Hydrochloride Injection/for Injection with inhibitors of CYP3A4, CYP2D6, or P-gp.

Inducers of CYP3A4, CYP2D6, or P-gp

Concomitant use of doxorubicin hydrochloride with inducers of CYP3A4, CYP2D6, or P-gp may decrease the concentration of doxorubicin. Avoid concomitant use of Doxorubicin Hydrochloride Injection/for Injection with inducers of CYP3A4, CYP2D6, or P-gp.

Paclitaxel

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

7.2 Concomitant Use of Trastuzumab

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

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

7.3 Concomitant Use of Dexrazoxane

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

7.4 Concomitant Use of 6-Mercaptopurine

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

8 Use In Specific Populations ⮝

8.1 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/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 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 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.

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 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.

8.4 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. Long-term 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 [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 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 [see Use in Specific Populations (8.1)].

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 [see Nonclinical Toxicology (13.1)].

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 [see Nonclinical Toxicology (13.1)].

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.

8.7 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 [See Dosage and Administration (2.2) and Warnings and Precautions (5.5)].

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) [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 HCl (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 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.

11 Description ⮝

Doxorubicin Hydrochloride is a cytotoxic, anthracycline, topoisomerase II inhibitor isolated from cultures of Streptomyces peucetius var. caesius. Chemically, doxorubicin hydrochloride is: 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy- -L-lyxo-hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxylacetyl)-1-methoxy-, hydrochloride (8S-cis)-. The chemical structure of doxorubicin HCl is:

Doxorubicin Hydrochloride Injection, USP is a clear, red, sterile, isotonic aqueous solution provided in vials containing 10 mg/5 mL, 20 mg/10 mL, 50 mg/25 mL, or 200 mg/100 mL of doxorubicin HCl. The drug product has demonstrated inherent antimicrobial activity suitable for a multiple dose presentation. Each milliliter of solution contains 2 mg of doxorubicin HCl. Inactive ingredients include sodium chloride 0.9%, USP, and water for injection, USP, quantity sufficient. The pH of the solution is adjusted to 3.0 with hydrochloric acid, USP.

12 Clinical Pharmacology ⮝

12.1 Mechanism of Action

The cytotoxic effect of doxorubicin HCl 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 HCl 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 g/mL.

Doxorubicin was measured in the milk of one lactating patient after therapy with 70 mg/m2 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

Doxorubicin is a substrate of CYP3A4, CYP2D6, and P-gp.

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/m2 of doxorubicin HCl 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 HCl treatment results in an increased risk of secondary malignancies based on postmarketing reports [see Warnings and Precautions (5.2)]. 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.

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, 0.82 1.01) and on OS with a HR of 0.91 (95% CI, 0.81 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 HCl-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
Abbreviations: DFS = disease free survival; OS = overall survival; AC = doxorubicin HCl, cyclophosphamide; AVbCMF = doxorubicin HCl, vinblastine, cyclophosphamide, methotrexate, 5-fluorouracil; CMF = cyclophosphamide, methotrexate, 5-fluorouracil; CMFVA = cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, doxorubicin HCl; FAC = 5-fluorouracil, doxorubicin HCl, cyclophosphamide; FACV = 5-fluorouracil, doxorubicin HCl, cyclophosphamide, vincristine; HR = hazard ratio; CI = confidence interval
* 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. 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. Patients received alternating cycles of AVb and CMF.
NSABP B-15 (1984)	AC	4	1562
				0.93 (0.82 1.06)	0.97 (0.83 1.12)
	CMF	6	776
SECSG 2 (1976)	FAC	6	260
				0.86 (0.66 1.13)	0.93 (0.69 1.26)
	CMF	6	268
ONCOFRANCE (1978)	FACV	12	138
				0.71 (0.49 1.03)	0.65 (0.44 0.96)
	CMF	12	113
SE Sweden BCG A (1980)	AC	6	21
				0.59 (0.22 1.61)	0.53 (0.21 1.37)
	CMF	6	22
NSABC Israel Br0283 (1983)	AVbCMF	4	55
		6		0.91 (0.53 1.57)	0.88 (0.47 1.63)
	CMF	6	50
Austrian BCSG 3 (1984)	CMFVA	6	121
				1.07 (0.73 1.55)	0.93 (0.64 1.35)
	CMF	8	124
Combined Studies	Doxorubicin HCl-Containing Regimens		2157
				0.91 (0.82 1.01)	0.91 (0.81 1.03)
	CMF		1353

Figure 1. Meta-analysis of Disease-Free Survival

Figure 2. Meta-analysis of Overall Survival

15 References ⮝

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

16 How Supplied ⮝

DOXOrubicin hydrochloride injection, USP is supplied in single-dose, flip-top vials, as a clear, red solution containing doxorubicin hydrochloride, USP 2 mg/mL in the following package strengths:

NDC 45963-733-55: 10 mg in 5 mL Single Dose Vial

NDC 45963-733-57: 20 mg in 10 mL; Single Dose Vial

NDC 45963-733-68: 50 mg in 25 mL; Single Dose Vial

NDC 45963-733-60: 200 mg in 100 mL; Multiple Dose Vial

For the single dose vials: Store under refrigeration between 2 to 8 C (36 to 46 F).

Protect from light. Retain in carton until time of use. Discard unused portion.

For the multiple dose vial: Store under refrigeration between 2 to 8 C (36 to 46 F).

Protect from light. Retain in carton until contents are used.

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

Handling and Disposal

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

Sterile, Nonpyrogenic, Preservative-free.

The vial stopper is not made with natural rubber latex.

Package Label.principal Display Panel ⮝

PRINCIPAL DISPLAY PANEL - 10 mg/5 mL Vial Label
NDC 68083-248-01
Rx only

Single-Dose

Discard unused portion

DOXOrubicin

Hydrochloride Injection, USP

10 mg/5 mL

(2 mg/mL)

For Intravenous Use Only

Caution: Cytotoxic Agent

PRINCIPAL DISPLAY PANEL - 10 mg/5 mL Carton label
NDC 68083-248-01

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Single-Dose

Discard unused portion

DOXOrubicin

Hydrochloride Injection, USP

10 mg/5 mL

(2 mg/mL)

For Intravenous Use Only
Caution: Cytotoxic Agent

PRINCIPAL DISPLAY PANEL - 50 mg/25 mL Vial Label
NDC 68083-249-01
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DOXOrubicin

Hydrochloride Injection, USP

50 mg/25 mL

(2 mg/mL)

For Intravenous Use Only

Caution: Cytotoxic Agent

PRINCIPAL DISPLAY PANEL - 50 mg/25 mL Carton label

NDC 68083-249-01

Rx only

Single-Dose

Discard unused portion

DOXOrubicin

Hydrochloride Injection, USP

50 mg/25 mL

(2 mg/mL)

For Intravenous Use Only
Caution: Cytotoxic Agent

PRINCIPAL DISPLAY PANEL - 200 mg/100 mL Vial Label

NDC 68083-250-01

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Discard unused portion

DOXOrubicin

Hydrochloride Injection, USP

200 mg/100 mL

(2 mg/mL)

For Intravenous Use Only

Caution: Cytotoxic Agent

PRINCIPAL DISPLAY PANEL - 200 mg/100 mL Carton label

NDC 68083-250-01

Rx only

Multiple Dose vial

Discard unused portion

DOXOrubicin

Hydrochloride Injection, USP

200 mg/100 mL

(2 mg/mL)

For Intravenous Use Only

Caution: Cytotoxic Agent

DOXORUBICIN HYDROCHLORIDE doxorubicin hydrochloride injection, solution

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:68083-248 Route of Administration INTRAVENOUS

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength DOXORUBICIN HYDROCHLORIDE (UNII: 82F2G7BL4E) (DOXORUBICIN - UNII:80168379AG) DOXORUBICIN HYDROCHLORIDE 2 mg in 1 mL

Inactive Ingredients Ingredient Name Strength SODIUM CHLORIDE (UNII: 451W47IQ8X) HYDROCHLORIC ACID (UNII: QTT17582CB) WATER (UNII: 059QF0KO0R)

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:68083-248-01 1 in 1 CARTON 08/22/2017 1 5 mL in 1 VIAL, SINGLE-DOSE; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA209825 08/22/2017

DOXORUBICIN HYDROCHLORIDE doxorubicin hydrochloride injection, solution

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:68083-249 Route of Administration INTRAVENOUS

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength DOXORUBICIN HYDROCHLORIDE (UNII: 82F2G7BL4E) (DOXORUBICIN - UNII:80168379AG) DOXORUBICIN HYDROCHLORIDE 2 mg in 1 mL

Inactive Ingredients Ingredient Name Strength SODIUM CHLORIDE (UNII: 451W47IQ8X) HYDROCHLORIC ACID (UNII: QTT17582CB) WATER (UNII: 059QF0KO0R)

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:68083-249-01 1 in 1 CARTON 08/22/2017 1 25 mL in 1 VIAL, SINGLE-DOSE; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA209825 08/22/2017

DOXORUBICIN HYDROCHLORIDE doxorubicin hydrochloride injection, solution

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:68083-250 Route of Administration INTRAVENOUS

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength DOXORUBICIN HYDROCHLORIDE (UNII: 82F2G7BL4E) (DOXORUBICIN - UNII:80168379AG) DOXORUBICIN HYDROCHLORIDE 2 mg in 1 mL

Inactive Ingredients Ingredient Name Strength SODIUM CHLORIDE (UNII: 451W47IQ8X) HYDROCHLORIC ACID (UNII: QTT17582CB) WATER (UNII: 059QF0KO0R)

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:68083-250-01 1 in 1 CARTON 08/22/2017 1 100 mL in 1 VIAL, MULTI-DOSE; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA209825 08/22/2017

Labeler - Gland Pharma Limited (918601238)

Establishment
Name	Address	ID/FEI	Business Operations
Gland Pharma Limited		650540227	ANALYSIS(68083-248, 68083-249, 68083-250) , MANUFACTURE(68083-248, 68083-249, 68083-250) , PACK(68083-248, 68083-249, 68083-250)

Revised: 10/2019 Document Id: 3ab4dfb1-cf1d-4d7c-9b06-89b35dbe8b81 34391-3 Set id: 74b14803-afc8-4a2e-ba92-43f1a72025eb Version: 7 Effective Time: 20191014 Gland Pharma Limited

Warning: Cardiomyopathy, Secondary Malignancies, Extravasation And Tissue Necrosis, And Severe Myelosuppressionsee Full Prescribing Information For Complete Boxed Warning. ⮝

• Cardiomyopathy: Myocardial damage can occur with doxorubicin HCl with incidences from 1% to 20% for cumulative doses from 300 mg/m2 to 500 mg/m2 when doxorubicin HCl 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 HCl. (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 HCl. (5.2)
• Extravasation and Tissue Necrosis: Extravasation of doxorubicin HCl 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 & Usage ⮝

1.1 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 [see Clinical Studies (14.1)].

1.2 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

2 Dosage & Administration ⮝

2.1 Recommended Dose

Adjuvant Breast Cancer
The recommended dose of doxorubicin HCl 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 HCl when used as a single agent is 60 to 75 mg/m2 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/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 HCl 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 HCl in patients with elevated serum total bilirubin concentrations as follows:

Serum bilirubin concentration	Doxorubicin HCl Dose reduction
1.2 to 3.0 mg/dL	50 %
3.1 to 5.0 mg/dL	75 %
greater than 5.0 mg/dL	Do not initiate doxorubicin HCl Discontinue doxorubicin HCl

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

2.3 Preparation and Administration

Preparation for Continuous Intravenous Infusion
Dilute doxorubicin 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 under refrigerated conditions can result in the formation of a gelled product. Place gelled product at room temperature [15 to 30 C (59 to 86 F)] 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 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 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.

2.4 Procedures for Proper Handling and Disposal

Handle and dispose of doxorubicin HCl consistent with recommendations for the handling and disposal of hazardous drugs.
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 & Strengths ⮝

Doxorubicin Hydrochloride Injection: Vials contain 10 mg/5 mL, 50 mg/25 mL, and 200 mg/100 mL doxorubicin hydrochloride as a clear red solution.

16 How Supplied/storage And Handling ⮝

Doxorubicin Hydrochloride Injection, USP is a sterile parenteral, isotonic solution, available in polypropylene (CYTOSAFE) vials in single vial packs as:

SINGLE-DOSE VIALS:
10 mg/5 mL (2 mg/mL) NDC 0069-4004-05
20 mg/10 mL (2 mg/mL) NDC 0069-4015-10
50 mg/25 mL (2 mg/mL) NDC 0069-4026-25

Retain in carton until time of use. Discard unused portion.

MULTIPLE-DOSE VIALS:
200 mg/100 mL (2 mg/mL) NDC 0069-4037-01

Retain in carton until contents are used.

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

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

Handling and Disposal

Handle and dispose of Doxorubicin Hydrochloride Injection consistent with recommendations for the handling and disposal of hazardous drugs.1

Warning ⮝

1. Severe local tissue necrosis will occur if there is extravasation during administration (see DOSAGE AND ADMINISTRATION). Doxorubicin must not be given by the intramuscular or subcutaneous route.
2. Myocardial toxicity manifested in its most severe form by potentially fatal congestive heart failure (CHF) may occur either during therapy or months to years after termination of therapy. The probability of developing impaired myocardial function based on a combined index of signs, symptoms and decline in left ventricular ejection fraction (LVEF) 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 450 mg/m2 and 6 to 20% at 500 mg/m2. The risk of developing CHF increases rapidly with increasing total cumulative doses of doxorubicin in excess of 400 mg/m2. Risk factors (active or dormant cardiovascular disease, prior or concomitant radiotherapy to the mediastinal/pericardial area, previous therapy with other anthracyclines or anthracenediones, concomitant use of other cardiotoxic drugs) may increase the risk of cardiac toxicity. Cardiac toxicity with doxorubicin may occur at lower cumulative doses whether or not cardiac risk factors are present. Pediatric patients are at increased risk for developing delayed cardiotoxicity.
3. Secondary acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) has been reported in patients treated with anthracyclines, including doxorubicin (see ADVERSE REACTIONS). The occurrence of refractory secondary AML or MDS is more common when anthracyclines are given in combination with DNA-damaging anti-neoplastic agents or radiotherapy, when patients have been heavily pretreated with cytotoxic drugs, or when doses of anthracyclines have been escalated. The rate of developing secondary AML or MDS has been estimated in an analysis of 8,563 patients with early breast cancer treated in 6 studies conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP), including NSABP B-15. Patients in these studies received standard doses of doxorubicin and standard or escalated doses of cyclophosphamide (AC) adjuvant chemotherapy and were followed for 61,810 patient years. Among 4,483 such patients who received conventional doses of AC, 11 cases of AML or MDS were identified, for an incidence of 0.32 cases per 1,000 patient years (95% Cl, 0.16 to 0.57) and a cumulative incidence at 5 years of 0.21% (95% Cl, 0.11 to 0.41%). In another analysis of 1,474 patients with breast cancer who received adjuvant treatment with doxorubicin-containing regimens in clinical trials conducted at University of Texas M.D. Anderson Cancer Center, the incidence was estimated at 1.5% at 10 years. In both experiences, patients who received regimens with higher cyclophosphamide dosages, who received radiotherapy, or who were aged 50 or older had an increased risk of secondary AML or MDS. Pediatric patients are also at risk of developing secondary AML.
4. Dosage should be reduced in patients with impaired hepatic function.
5. Severe myelosuppression may occur.
6. Doxorubicin should be administered only under the supervision of a physician who is experienced in the use of cancer chemotherapeutic agents.

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: 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy- -L-lyxo-hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxylacetyl)-1-methoxy-, hydrochloride (8S-cis)-. (8S, 10S)-10-[(3-Amino-2,3,6-trideoxy- -L-lyxo-hexopyranosyl)-oxy]-8-glycoloyl-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12-naphthacenedione hydrochloride [25316-40-9].

The structural formula is as follows:

C27H29NO11 HCl M.W.579.99

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.

Doxorubicin Hydrochloride Injection, USP is a sterile, isotonic, preservative-free solution for intravenous use. It is available in 5 mL (10 mg), 10 mL (20 mg) and 25 mL (50 mg) single dose vials and 100 mL (200 mg) multiple dose vials.

Each mL contains: Doxorubicin hydrochloride 2 mg; sodium chloride 9 mg for Isotonicity: Water for Injection q.s. Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment (2.5 to 4.5).

Clinical Pharmacology: ⮝

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.

Doxorubicin cellular membrane binding may affect a variety of cellular functions. Enzymatic electron reduction of doxorubicin by a variety of oxidases, reductases and dehydrogenases generates highly reactive species including the hydroxyl free radical OH . Free radical formation has been implicated in doxorubicin cardiotoxicity by means of Cu (II) and Fe (III) reduction at the cellular level.

Cells treated with doxorubicin have been shown to manifest the characteristic morphologic changes associated with apoptosis or programmed cell death. Doxorubicin-induced apoptosis may be an integral component of the cellular mechanism of action relating to therapeutic effects, toxicities, or both.

Animal studies have shown activity in a spectrum of experimental tumors, immunosuppression, carcinogenic properties in rodents, induction of a variety of toxic effects, including delayed and progressive cardiac toxicity, myelosuppression in all species and atrophy to testes in rats and dogs.

Pharmacokinetics

Pharmacokinetic studies, determined in patients with various types of tumors undergoing either single or multi-agent therapy have shown that doxorubicin follows a multiphasic disposition after intravenous injection. In four patients, doxorubicin has demonstrated dose-independent pharmacokinetics in the dose range of 30 to 70 mg/m2.

Distribution

The initial distribution half-life of approximately 5 minutes suggests rapid tissue uptake of doxorubicin, while its slow elimination from tissues is reflected by a terminal half-life of 20 to 48 hours. Steady-state distribution volume ranges from 809 to 1,214 L/m2 and is indicative of extensive drug uptake into tissues. Binding of doxorubicin and its major metabolite, doxorubicinol, to plasma proteins is about 74 to 76% and is independent of plasma concentration of doxorubicin up to 1.1 mcg/mL.

Doxorubicin was excreted in the milk of one lactating patient, with peak milk concentration at 24 hours after treatment being approximately 4.4-fold greater than the corresponding plasma concentration. Doxorubicin was detectable in the milk up to 72 hours after therapy with 70 mg/m2 of doxorubicin given as a 15-minute intravenous infusion and 100 mg/m2 of cisplatin as a 26-hour intravenous infusion. The peak concentration of doxorubicinol in milk at 24 hours was 0.11 mcg/mL and AUC up to 24 hours was 9 mcg h/mL while the AUC for doxorubicin was 5.4 mcg h/mL.

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 (DOX-OL) in patients is formation rate limited, with the terminal half-life of DOX-OL being similar to doxorubicin. The relative exposure of DOX-OL, i.e., the ratio between the AUC of DOX-OL and the AUC of doxorubicin, compared to doxorubicin ranges between 0.4 and 0.6.

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 DOX-OL 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.

Pharmacokinetics in Special Populations

Pediatric

Following administration of 10 to 75 mg/m2 doses of doxorubicin to 60 children and adolescents ranging from 2 months to 20 years of age, doxorubicin clearance averaged 1,443 114 mL/min/m2. Further analysis demonstrated that clearance in 52 children greater than 2 years of age (1,540 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.

Geriatric

While the pharmacokinetics of elderly subjects ( 65 years of age) have been evaluated, no dosage adjustment is recommended based on age (see PRECAUTIONS, Geriatric Use).

Gender

A published clinical study involving 6 men and 21 women with no prior anthracycline therapy reported a significantly higher median doxorubicin clearance in the men compared to the women (1,088 mL/min/m2 versus 433 mL/min/m2). However, the terminal half-life of doxorubicin was longer in men compared to the women (54 versus 35 hours).

Race

The influence of race on the pharmacokinetics of doxorubicin has not been evaluated.

Hepatic Impairment

The clearance of doxorubicin and doxorubicinol was reduced in patients with impaired hepatic function (see DOSAGE AND ADMINISTRATION).

Renal Impairment

The influence of renal function on the pharmacokinetics of doxorubicin has not been evaluated.

Clinical Studies: ⮝

The effectiveness of doxorubicin-containing regimens in the adjuvant therapy of early breast cancer has primarily been established based on data collected in a meta-analysis published in 1998 by the Early Breast Cancer Trialists Collaborative Group (EBCTCG). The EBCTCG obtains primary data on all relevant studies, both published and unpublished, for early stage breast cancer and regularly updates these analyses. The principal endpoints for the adjuvant chemotherapy trials were disease-free survival (DFS) and overall survival (OS). The meta-analyses allowed comparisons of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) to no chemotherapy (19 trials including 7,523 patients) and comparisons of doxorubicin-containing regimens with CMF as an active control (6 trials including 3,510 patients). The pooled estimates of DFS and OS from these trials were used to calculate the effect of CMF relative to no therapy. The hazard ratio for DFS for CMF compared to no chemotherapy was 0.76 (95% Cl, 0.71 to 0.82) and for OS was 0.86 (95% Cl, 0.8 to 0.93). Based on a conservative estimate of CMF effect (lower 2-sided 95% confidence limit of hazard ratio) and 75% retention of CMF effect on DFS, it was determined that the doxorubicin-containing regimens would be considered as non-inferior to CMF if the upper 2-sided 95% confidence limit of the hazard ratio was less than 1.06, i.e., not more than 6% worse than CMF. A similar calculation for OS would require a non-inferiority margin of 1.02.

Six randomized trials in the EBCTCG meta-analysis compared doxorubicin-containing regimens to CMF. A total of 3,510 women with early breast cancer involving axillary lymph nodes were evaluated; approximately 70% were premenopausal and 30% were postmenopausal. At the time of the meta-analysis, 1,745 first recurrences and 1,348 deaths had occurred. Analyses demonstrated that doxorubicin-containing regimens retained at least 75% of the historical CMF adjuvant effect on DFS and are effective. The hazard ratio for DFS (dox:CMF) was 0.91 (95% Cl, 0.82 to 1.01) and for OS was 0.91 (95% Cl, 0.81 to 1.03). Results of these analyses for both DFS and OS are provided in Table 1 and Figures 1 and 2.

Table 1. Summary of Randomized Trials Comparing Doxorubicin-Containing Regimens Versus CMF in EBCTCG Meta-Analysis

Study (starting year)	Regimens	No. of Cycles	No. of Patients	Doxorubicin-Containing Regimens vs CMF HR (95% CI)
				DFS	OS
NSABP B-15 (1984)	AC	4	1,562*	0.93 (0.82 to 1.06)	0.97 (0.83 to 1.12)
	CMF	6	776
SECSG 2 (1976)	FAC	6	260	0.86 (0.66 to 1.13)	0.93 (0.69 to 1.26)
	CMF	6	268
ONCOFRANCE (1978)	FACV	12	138	0.71 (0.49 to 1.03)	0.65 (0.44 to 0.96)
	CMF	12	113
SE Sweden BCG A (1980)	AC	6	21	0.59 (0.22 to 1.61)	0.53 (0.21 to 1.37)
	CMF	6	22
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	6	121	1.07 (0.73 to 1.55)	0.93 (0.64 to 1.35)
	CMF	8	124
Combined Studies	Doxorubicin-Containing Regimens		2,157	0.91 (0.82 to 1.01)	0.91 (0.81 to 1.03)
	CMF		1,353

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.

Patients received alternating cycles of AVb and CMF.

With respect to DFS, 2 of 6 studies (NSABP B-15 and ONCOFRANCE) met the non-inferiority standard individually and with respect to OS, 1 study met the non-inferiority margin individually (ONCOFRANCE). The largest of the 6 studies in the EBCTCG meta-analysis, a randomized, open-label, multicenter trial (NSABP B-15) was conducted in approximately 2,300 women (80% premenopausal; 20% postmenopausal) with early breast cancer involving axillary lymph nodes. In this trial, 6 cycles of conventional CMF was compared to 4 cycles of doxorubicin and cyclophosphamide (AC) and 4 cycles of AC followed by 3 cycles of CMF. No statistically significant differences in terms of DFS or OS were observed (see Table 1).

Indications And Usage: ⮝

Doxorubicin Hydrochloride Injection, USP has been used successfully to produce regression in disseminated neoplastic conditions such as acute lymphoblastic leukemia, acute myeloblastic leukemia, Wilms' tumor, neuroblastoma, soft tissue and bone sarcomas, breast carcinoma, ovarian carcinoma, transitional cell bladder carcinoma, thyroid carcinoma, gastric carcinoma, Hodgkin's disease, malignant lymphoma and bronchogenic carcinoma in which the small cell histologic type is the most responsive compared to other cell types.

Doxorubicin is also indicated for use as a component of adjuvant therapy in women with evidence of axillary lymph node involvement following resection of primary breast cancer.

Contraindications: ⮝

Patients should not be treated with doxorubicin if they have any of the following conditions: baseline neutrophil count <1,500 cells/mm3; severe hepatic impairment; recent myocardial infarction; severe myocardial insufficiency; severe arrhythmias; previous treatment with complete cumulative doses of doxorubicin, daunorubicin, idarubicin, and/or other anthracyclines and anthracenediones; or hypersensitivity to doxorubicin, any of its excipients, or other anthracyclines or anthracenediones (see WARNINGS and DOSAGE AND ADMINISTRATION).

Warnings: ⮝

General

Doxorubicin should be administered only under the supervision of qualified physicians experienced in the use of cytotoxic therapy. Patients should recover from acute toxicities of prior cytotoxic treatment (such as stomatitis, neutropenia, thrombocytopenia, and generalized infections) before beginning treatment with doxorubicin. Also, initial treatment with doxorubicin should be preceded by a careful baseline assessment of blood counts; serum levels of total bilirubin, AST, and creatinine; and cardiac function as measured by left ventricular ejection function (LVEF). Patients should be carefully monitored during treatment for possible clinical complications due to myelosuppression. Supportive care may be necessary for the treatment of severe neutropenia and severe infectious complications. Monitoring for potential cardiotoxicity is also important, especially with greater cumulative exposure to doxorubicin. Doxorubicin may potentiate the toxicity of other anticancer therapies (see PRECAUTIONS, Drug Interactions).

Cardiac Function

Cardiotoxicity is a known risk of anthracycline treatment. Anthracycline-induced cardiotoxicity may be manifested by early (or acute) or late (delayed) events. Early cardiotoxicity of doxorubicin consists mainly of sinus tachycardia and/or electrocardiogram (ECG) abnormalities such as non-specific ST-T wave changes. Tachyarrhythmias, including premature ventricular contractions and ventricular tachycardia, bradycardia, as well as atrioventricular and bundle-branch block have also been reported. These effects do not usually predict subsequent development of delayed cardiotoxicity, are rarely of clinical importance, and are generally not considered an indication for the suspension of doxorubicin treatment.

Delayed cardiotoxicity usually develops late in the course of therapy with doxorubicin or within 2 to 3 months after treatment termination, but later events, several months to years after completion of treatment, have also been reported. Delayed cardiomyopathy is manifested by a reduction in LVEF and/or signs and symptoms of congestive heart failure (CHF) such as tachycardia, dyspnea, pulmonary edema, dependent edema, cardiomegaly and hepatomegaly, oliguria, ascites, pleural effusion, and gallop rhythm. Subacute effects such as pericarditis/myocarditis have also been reported. Life-threatening CHF is the most severe form of anthracycline-induced cardiomyopathy and represents the cumulative dose-limiting toxicity of the drug.

The probability of developing impaired myocardial function, based on a combined index of signs, symptoms and decline in left ventricular ejection fraction (LVEF) 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 given in a schedule of a bolus injection once every 3 weeks. In a retrospective review, the probability of developing congestive heart failure was reported to be 5/168 (3%) at a cumulative dose of 430 mg/m2 of doxorubicin, 8/110 (7%) at 575 mg/m2, and 3/14 (21%) at 728 mg/m2. In a prospective study of doxorubicin in combination with cyclophosphamide, fluorouracil and/or vincristine in patients with breast cancer or small cell lung cancer, the probability of CHF at various cumulative doses of doxorubicin was 1.5% at 300 mg/m2, 4.9% at 400 mg/m2, 7.7% at 450 mg/m2 and 20.5% at 500 mg/m2. The risk of developing CHF increases rapidly with increasing total cumulative doses of doxorubicin in excess of 400 mg/m2.

Cardiotoxicity may occur at lower doses in patients with prior mediastinal/pericardial irradiation, concomitant use of other cardiotoxic drugs, doxorubicin exposure at an early age, and advanced age. Data also suggest that pre-existing heart disease is a co-factor for increased risk of doxorubicin cardiotoxicity. In such cases, cardiac toxicity may occur at doses lower than the recommended cumulative dose of doxorubicin. Studies have suggested that concomitant administration of doxorubicin and calcium channel entry blockers or cardiotoxic drugs, especially those with long half-lives, e.g. trastuzumab, may increase the risk of doxorubicin cardiotoxicity (see PRECAUTIONS, General, DOSAGE AND ADMINISTRATION). The total dose of doxorubicin administered to the individual patient should also take into account previous or concomitant therapy with related compounds such as daunorubicin, idarubicin and mitoxantrone. Although not formally tested, it is probable that the toxicity of doxorubicin and other anthracyclines or anthracenediones is additive. Cardiomyopathy and/or congestive heart failure may be encountered several months or years after discontinuation of doxorubicin therapy.

The risk of acute manifestations of doxorubicin cardiotoxicity in pediatric patients may be as much or lower than in adults. Pediatric patients appear to be at particular risk for developing delayed cardiac toxicity in that doxorubicin-induced cardiomyopathy impairs myocardial growth as pediatric patients mature, subsequently leading to possible development of congestive heart failure during early adulthood. As many as 40% of pediatric patients may have subclinical cardiac dysfunction and 5 to 10% of pediatric patients may develop congestive heart failure on long term follow-up. This late cardiac toxicity may be related to the dose of doxorubicin. The longer the length of follow-up, the greater the increase in the detection rate. Treatment of doxorubicin-induced congestive heart failure includes the use of digitalis, diuretics, after load reducers such as angiotensin I converting enzyme (ACE) inhibitors, low salt diet, and bed rest. Such intervention may relieve symptoms and improve the functional status of the patient.

Monitoring Cardiac Function

The risk of serious cardiac impairment may be decreased through regular monitoring of LVEF during the course of treatment with prompt discontinuation of doxorubicin at the first sign of impaired function. The preferred method for assessment of cardiac function is evaluation of LVEF measured by multi-gated radionuclide angiography (MUGA) or echocardiography (ECHO). An ECG may also be done. A baseline cardiac evaluation with a MUGA scan or an ECHO is recommended, especially in patients with risk factors for increased cardiac toxicity. Repeated MUGA or ECHO determinations of LVEF should be performed, particularly with higher, cumulative anthracycline doses. The technique used for assessment should be consistent through follow-up. In patients with risk factors, particularly prior anthracycline or anthracenedione use, the monitoring of cardiac function must be particularly strict and the risk-benefit of continuing treatment with doxorubicin in patients with impaired cardiac function must be carefully evaluated.

Endomyocardial biopsy is recognized as the most sensitive diagnostic tool to detect anthracycline-induced cardiomyopathy; however, this invasive examination is not practically performed on a routine basis. ECG changes such as dysrhythmias, a reduction of the QRS voltage, or a prolongation beyond normal limits of the systolic time interval may be indicative of anthracycline-induced cardiomyopathy, but ECG is not a sensitive or specific method for following anthracycline-related cardiotoxicity.

Pediatric patients are at increased risk for developing delayed cardiotoxicity following doxorubicin administration and therefore a follow-up cardiac evaluation is recommended periodically to monitor for this delayed cardiotoxicity.

In adults, a 10% decline in LVEF to below the lower limit of normal or an absolute LVEF of 45%, or a 20% decline in LVEF at any level is indicative of deterioration in cardiac function. In pediatric patients, deterioration in cardiac function during or after the completion of therapy with doxorubicin is indicated by a drop in fractional shortening (FS) by an absolute value of 10 percentile units or below 29%, and a decline in LVEF of 10 percentile units or an LVEF below 55%. In general, if test results indicate deterioration in cardiac function associated with doxorubicin, the benefit of continued therapy should be carefully evaluated against the risk of producing irreversible cardiac damage. Acute life-threatening arrhythmias have been reported to occur during or within a few hours after doxorubicin administration.

Hematologic Toxicity

As with other cytotoxic agents, doxorubicin may produce myelosuppression. Myelosuppression requires careful monitoring. Total and differential WBC, red blood cell (RBC), and platelet counts should be assessed before and during each cycle of therapy with doxorubicin. A dose-dependent, reversible leukopenia and/or granulocytopenia (neutropenia) are the predominant manifestations of doxorubicin hematologic toxicity and is the most common acute dose-limiting toxicities of this drug. With the recommended dose schedule, leukopenia is usually transient, reaching its nadir 10 to 14 days after treatment with recovery usually occurring by the 21st day. Thrombocytopenia and anemia may also occur. Clinical consequences of severe myelosuppression include fever, infections, sepsis/septicemia, septic shock, hemorrhage, tissue hypoxia, or death.

Secondary Leukemia

The occurrence of secondary AML or MDS has been reported most commonly in patients treated with chemotherapy regimens containing anthracyclines (including doxorubicin) and DNA-damaging antineoplastic agents, in combination with radiotherapy, when patients have been heavily pretreated with cytotoxic drugs, or when doses of anthracyclines have been escalated. Such cases generally have a 1 to 3 year latency period. The rate of developing secondary AML or MDS has been estimated in an analysis of 8,563 patients with early breast cancer treated in 6 studies conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP), including NSABP B-15. Patients in these studies received standard doses of doxorubicin and standard or escalated doses of cyclophosphamide (AC) adjuvant chemotherapy and were followed for 61,810 patient years. Among 4,483 such patients who received conventional doses of AC, 11 cases of AML or MDS were identified, for an incidence of 0.32 cases per 1,000 patient years (95% Cl, 0.16 to 0.57) and a cumulative incidence at 5 years of 0.21% (95% Cl, 0.11 to 0.41%). In another analysis of 1,474 patients with breast cancer who received adjuvant treatment with doxorubicin-containing regimens in clinical trials conducted at University of Texas M.D. Anderson Cancer Center, the incidence was estimated at 1.5% at 10 years. In both experiences, patients who received regimens with higher cyclophosphamide dosages, who received radiotherapy, or who were aged 50 or older had an increased risk of secondary AML or MDS.

Pediatric patients are also at risk of developing secondary AML.

Effects at Site of Injection

Phlebosclerosis may result from an injection into a small vessel or from repeated injections into the same vein. Following the recommended administration procedures may minimize the risk of phlebitis/thrombophlebitis at the injection site (see DOSAGE AND ADMINISTRATION, Instruction for Use/Handling).

Extravasation

On intravenous administration of doxorubicin, extravasation may occur with or without an accompanying stinging or burning sensation, even if blood returns well on aspiration of the infusion needle. If any signs or symptoms of extravasation have occurred, the injection or infusion should be immediately terminated and restarted in another vein (see DOSAGE AND ADMINISTRATION).

Hepatic Impairment

Since metabolism and excretion of doxorubicin occurs predominantly by the hepatobiliary route, toxicity of recommended doses of doxorubicin can be enhanced by hepatic impairment; therefore, prior to individual dosing, evaluation of hepatic function is recommended using conventional laboratory tests such as SGOT, SGPT, alkaline phosphatase, and bilirubin (see DOSAGE AND ADMINISTRATION).

Immunosuppressant Effects/Increased Susceptibility to Infections

Administration of live or live attenuated vaccines in patients immunocompromised by chemotherapeutic agents including doxorubicin, may result in serious or fatal infections. Vaccination with a live vaccine should be avoided in patients receiving doxorubicin. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.

Pregnancy Category D

Doxorubicin can cause fetal harm when administered to a pregnant woman. Doxorubicin was teratogenic and embryotoxic at doses of 0.8 mg/kg/day (about 1/13 the recommended human dose on a body surface area basis) 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, tracheoesophageal 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 1/14 the recommended human dose on a body surface area basis) in rabbits when administered during the period of organogenesis.

There are no adequate and well-controlled studies in pregnant women. If doxorubicin is to be used during pregnancy, or if the patient becomes pregnant during therapy, the patient should be apprised of the potential hazard to the fetus. Women of childbearing age should be advised to avoid becoming pregnant.

Precautions: ⮝

General

Doxorubicin is not an anti-microbial agent. Doxorubicin is emetigenic. Antiemetics may reduce nausea and vomiting; prophylactic use of antiemetics should be considered before administration of doxorubicin, particularly when given in conjunction with other emetigenic drugs. Doxorubicin should not be administered in combination with other cardiotoxic agents unless the patient's cardiac function is closely monitored. Patients receiving doxorubicin after stopping treatment with other cardiotoxic agents, especially those with long half-lives such as trastuzumab, may also be at an increased risk of developing cardiotoxicity. Physicians should avoid doxorubicin-based therapy for up to 24 weeks after stopping trastuzumab when possible. If doxorubicin used before this time, careful monitoring of cardiac function is recommended (see WARNINGS, DOSAGE AND ADMINISTRATION).

Information for Patients

Patients should be informed of the expected adverse effects of doxorubicin, including gastrointestinal symptoms (nausea, vomiting, diarrhea, and stomatitis) and potential neutropenic complications. Patients should consult their physician if vomiting, dehydration, fever, evidence of infection, symptoms of CHF, or injection-site pain occurs following therapy with doxorubicin. Patients should be informed that they will almost certainly develop alopecia. Patients should be advised that their urine may appear red for 1 to 2 days after administration of doxorubicin and that they should not be alarmed. Patients should understand that there is a risk of irreversible myocardial damage associated with treatment with doxorubicin, as well as a risk of treatment-related leukemia. Because doxorubicin may induce chromosomal damage in sperm, men undergoing treatment with doxorubicin should use effective contraceptive methods. Women treated with doxorubicin may develop irreversible amenorrhea, or premature menopause.

Drug Interactions

Doxorubicin is extensively metabolized by the liver. Changes in hepatic function induced by concomitant therapies may affect doxorubicin metabolism, pharmacokinetics, therapeutic efficacy, and/or toxicity. Toxicities associated with doxorubicin, especially hematologic and gastrointestinal events, may be increased when doxorubicin is used in combination with other cytotoxic drugs.

Paclitaxel

There have been a number of reports in the literature that describe an increase in cardiotoxicity when doxorubicin is co-administered with paclitaxel. Two published studies report that initial administration of paclitaxel infused over 24 hours followed by doxorubicin administered over 48 hours resulted in a significant decrease in doxorubicin clearance with more profound neutropenic and stomatitis episodes than the reverse sequence of administration.

Progesterone

In a published study, progesterone was given intravenously to patients with advanced malignancies (ECOG PS< 2) at high doses (up to 10 g over 24 hours) concomitantly with a fixed doxorubicin dose (60 mg/m2) via bolus injection. Enhanced doxorubicin-induced neutropenia and thrombocytopenia were observed.

Verapamil

A study of the effects of verapamil on the acute toxicity of doxorubicin in mice revealed higher initial peak concentrations of doxorubicin in the heart with a higher incidence and severity of degenerative changes in cardiac tissue resulting in a shorter survival.

Cyclosporine

The addition of cyclosporine to doxorubicin may result in increases in AUC for both doxorubicin and doxorubicinol possibly due to a decrease in clearance of parent drug and a decrease in metabolism of doxorubicinol. Literature reports suggest that adding cyclosporine to doxorubicin results in more profound and prolonged hematologic toxicity than doxorubicin alone. Coma and/or seizures have also been described.

Dexrazoxane

In a clinical study of women with metastatic breast cancer, the concurrent use of the cardioprotectant, dexrazoxane, with the initiation of a regimen of fluorouracil, doxorubicin, and cyclophosphamide (FAC) was associated with a lower tumor response rate. Later initiation of dexrazoxane (after administration of a cumulative doxorubicin dose of 300 mg/m2 of doxorubicin had been given as a component of FAC) was not associated with a reduction in chemotherapy activity. Dexrazoxane is only indicated for use in women with metastatic breast cancer who have received a cumulative doxorubicin dose of 300 mg/m2 and are continuing with doxorubicin therapy.

Cytarabine

Necrotizing colitis manifested by typhlitis (cecal inflammation), bloody stools and severe and sometimes fatal infections have been associated with a combination of doxorubicin given by intravenous push daily for 3 days and cytarabine given by continuous infusion daily for 7 or more days.

Sorafenib

In clinical studies, both an increase of 21% and 47% and no change in the AUC of doxorubicin were observed with concomitant treatment with sorafenib 400 mg twice daily. The clinical significance of these findings is unknown.
Cyclophosphamide

The addition of cyclophosphamide to doxorubicin treatment does not affect exposure to doxorubicin, but may result in an increase in exposure to doxorubicinol, a metabolite. Doxorubicinol only has 5% of the cytotoxic activity of doxorubicin. Concurrent treatment with doxorubicin has been reported to exacerbate cyclophosphamide-induced hemorrhagic cystitis. Acute myeloid leukemia has been reported as a second malignancy after treatment with doxorubicin and cyclophosphamide.

Literature reports have also described the following drug interactions

Phenobarbital increases the elimination of doxorubicin; phenytoin levels may be decreased by doxorubicin; streptozocin (Zanosar ) may inhibit hepatic metabolism of doxorubicin; saquinavir in combination with cyclophosphamide, doxorubicin, and etoposide increased mucosal toxicity in patients with HIV-associated non-Hodgkin's lymphoma; and administration of live vaccines to immunosuppressed patients including those undergoing cytotoxic chemotherapy may be hazardous (see WARNINGS).

Laboratory Tests

Initial treatment with doxorubicin requires observation of the patient and periodic monitoring of complete blood counts, hepatic function tests, and left ventricular ejection fraction (see WARNINGS). Abnormalities of hepatic function tests may occur. Like other cytotoxic drugs, doxorubicin may induce "tumor-lysis syndrome" and hyperuricemia in patients with rapidly growing tumors. Blood uric acid levels, potassium, calcium, phosphate, and creatinine should be evaluated after initial treatment. Hydration, urine alkalinization, and prophylaxis with allopurinol to prevent hyperuricemia may minimize potential complications of tumor-lysis syndrome.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been conducted with doxorubicin. Secondary acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) have been reported in patients treated with doxorubicin-containing combination chemotherapy regimens (see WARNINGS). Pediatric patients treated with doxorubicin or other topoisomerase II inhibitors are at risk for developing acute myelogenous leukemia and other neoplasms. 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 (about 1/200 and 1/50 the recommended human dose on a body surface area basis) when administered from 14 days before mating through late gestation period. A single IV dose of doxorubicin at 0.1 mg/kg (about 1/100 the recommended human dose on a body surface area basis) was toxic to male reproductive organs producing testicular atrophy and oligospermia in rats. Doxorubicin is mutagenic as it induced DNA damage in rabbit spermatozoa and dominant lethal mutations in mice. Therefore, doxorubicin may potentially induce chromosomal damage in human spermatozoa. Oligospermia or azoospermia were evidenced in men treated with doxorubicin, mainly in combination therapies. Men undergoing doxorubicin treatment should use effective contraceptive methods.

Doxorubicin was toxic to male reproductive organs in animal studies, producing testicular atrophy, diffuse degeneration of the seminiferous tubules, and hypospermia. Doxorubicin is mutagenic as it induces DNA damage in rabbit spermatozoa and dominant lethal mutations in mice. Therefore, doxorubicin can potentially induce chromosomal damage in human spermatozoa. Oligospermia or azoospermia were evidenced in men treated with doxorubicin, mainly in combination therapies. This effect may be permanent. However, sperm counts have been reported to return to normal levels in some instances. This may occur several years after the end of the therapy. Men undergoing doxorubicin treatment should use effective contraceptive methods.

In women, doxorubicin may cause infertility during the time of drug administration. Doxorubicin may cause amenorrhea. Ovulation and menstruation may return after termination of therapy, although premature menopause can occur. Recovery of menses is related to age at treatment.

Secondary acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) have been reported in patients treated with anthracycline-containing adjuvant combination chemotherapy regimens (see WARNINGS, Hematologic Toxicity).

Pregnancy

Teratogenic Effects: Pregnancy Category D

(See WARNINGS).

Nursing Mothers

Doxorubicin and its major metabolite, doxorubicinol have been detected in the milk of at least one lactating patient (see CLINICAL PHARMACOLOGY, Pharmacokinetics). Because of the potential for serious adverse reactions in nursing infants from doxorubicin, mothers should be advised to discontinue nursing during doxorubicin therapy.

Pediatric Use

Pediatric patients are at increased risk for developing delayed cardiotoxicity. Follow-up cardiac evaluations are recommended periodically to monitor for this delayed cardiotoxicity (see WARNINGS). Doxorubicin, as a component of intensive chemotherapy regimens administered to pediatric patients, may contribute to prepubertal growth failure. It may also contribute to gonadal impairment, which is usually temporary. Pediatric patients treated with doxorubicin or other topoisomerase II inhibitors are at a risk for developing acute myelogenous leukemia and other neoplasms. Pediatric patients receiving concomitant doxorubicin and actinomycin-D have manifested acute "recall" pneumonitis at variable times after local radiation therapy.

Geriatric Use

An estimated 4,600 patients who were 65 and over were included in the reported clinical experience of doxorubicin use for various indications. No overall differences in safety and effectiveness were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out. The decision to use doxorubicin in the treatment of older patients should be based upon a consideration of overall performance status and concurrent illnesses, in addition to age of the individual patient.

Adverse Reactions: ⮝

Dose limiting toxicities of therapy are myelosuppression and cardiotoxicity. Other reactions reported are:

Cardiotoxicity

(See WARNINGS).

Cutaneous

Reversible complete alopecia occurs in most cases. Hyperpigmentation of nailbeds and dermal creases, primarily in pediatric patients, and onycholysis have been reported in a few cases. Radiation recall reaction has occurred with doxorubicin administration. Rash, itching, or photosensitivity may occur.

Gastrointestinal

Acute nausea and vomiting occurs frequently and may be severe. This may be alleviated by antiemetic therapy. Mucositis (stomatitis and esophagitis) may occur within 5 to 10 days of beginning therapy, and most patients recover from this adverse event within another 5 to 10 days. The effect may be severe leading to ulceration and represents a site of origin for severe infections. The dosage regimen consisting of administration of doxorubicin on three successive days results in greater incidence and severity of mucositis. Ulceration and necrosis of the colon, especially the cecum, may occur leading to bleeding or severe infections which can be fatal. This reaction has been reported in patients with acute non-lymphocytic leukemia treated with a 3-day course of doxorubicin combined with cytarabine. Anorexia, abdominal pain, dehydration, diarrhea, and hyperpigmentation of the oral mucosa have been occasionally reported.

Hematologic

(See WARNINGS).

Hypersensitivity

Fever, chills and urticaria have been reported occasionally. Anaphylaxis may occur. A case of apparent cross sensitivity to lincomycin has been reported.

Neurological

Peripheral neurotoxicity in the form of local-regional sensory and/or motor disturbances have been reported in patients treated intra-arterially with doxorubicin, mostly in combination with cisplatin. Animal studies have demonstrated seizures and coma in rodents and dogs treated with intra-carotid doxorubicin. Seizures and coma have been reported in patients treated with doxorubicin in combination with cisplatin or vincristine.

Ocular

Conjunctivitis, keratitis, and lacrimation occur rarely.

Other

Malaise/asthenia have been reported.

Adverse Reactions in Patients with Early Breast Cancer Receiving Doxorubicin-Containing Adjuvant Therapy

Safety data were collected from approximately 2,300 women who participated in a randomized, open-label trial (NSABP B-15) evaluating the use of AC versus CMF in the treatment of early breast cancer involving axillary lymph nodes. In the safety analysis, the follow-up data from all patients receiving AC were combined (N=1,492 evaluable patients) and compared with data from patients receiving conventional CMF (i.e., oral cyclophosphamide; N=739 evaluable patients). The most relevant adverse events reported in this study are provided in Table 2.

Table 2. Relevant Adverse Events in Patients with Early Breast Cancer Involving Axillary Lymph Nodes

	AC*	Conventional CMF
	N=1,492	N=739
Treatment administration
Mean number of cycles	3.8	5.5
Total cycles	5,676	4,068
Adverse events, % of patients
Leukopenia
Grade 3 (1,000 to 1,999 /mm3)	3.4	9.4
Grade 4 (<1000/mm3)	0.3	0.3
Thrombocytopenia
Grade 3 (25,000 to 49,999 /mm3)	0	0.3
Grade 4 (<25,000 /mm3)	0.1	0
Shock, sepsis	1.5	0.9
Systemic infection	2.4	1.2
Nausea and vomiting
Nausea only	15.5	42.8
Vomiting 12 hours	34.4	25.2
Vomiting >12 hours	36.8	12
Intractable	4.7	1.6
Alopecia	92.4	71.4
Partial	22.9	56.3
Complete	69.5	15.1
Weight loss
5 to 10%	6.2	5.7
>10%	2.4	2.8
Weight gain
5 to 10%	10.6	27.9
>10%	3.8	14.3
Cardiac function
Asymptomatic	0.2	0.1
Transient	0.1	0
Symptomatic	0.1	0
Treatment-related death	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

Overdosage: ⮝

Acute overdosage with doxorubicin enhances the toxic effects of mucositis, leukopenia and thrombocytopenia. Treatment of acute overdosage consists of treatment of the severely myelosuppressed patient with hospitalization, antimicrobials, platelet transfusions and symptomatic treatment of mucositis. Use of hemopoietic growth factor (G-CSF, GM-CSF) may be considered.

The 200 mg doxorubicin hydrochloride injection vial is packaged as a multiple dose vial and caution should be exercised to prevent inadvertent overdosage.

Cumulative dosage with doxorubicin increases the risk of cardiomyopathy and resultant congestive heart failure (see WARNINGS). Treatment consists of vigorous management of congestive heart failure with digitalis preparations, diuretics, and after-load reducers such as ACE inhibitors.

Dosage And Administration: ⮝

When possible, to reduce the risk of developing cardiotoxicity in patients receiving doxorubicin after stopping treatment with other cardiotoxic agents, especially those with long half-lives such as trastuzumab, doxorubicin-based therapy should be delayed until the other agents have cleared from the circulation (see WARNINGS and PRECAUTIONS, General).

Care in the administration of doxorubicin will reduce the chance of perivenous infiltration (see WARNINGS). It may also decrease the chance of local reactions such as urticaria and erythematous streaking. On intravenous administration of doxorubicin, extravasation may occur with or without an accompanying burning or stinging sensation, even if blood returns well on aspiration of the infusion needle. If any signs or symptoms of extravasation have occurred, the injection or infusion should be immediately terminated and restarted in another vein. If extravasation is suspected, intermittent application of ice to the site for 15 min. q.i.d. x 3 days may be useful. The benefit of local administration of drugs has not been clearly established. Because of the progressive nature of extravasation reactions, close observation and plastic surgery consultation is recommended. Blistering, ulceration and/or persistent pain are indications for wide excision surgery, followed by split-thickness skin grafting.

The most commonly used dose schedule when used as a single agent is 60 to 75 mg/m2 as a single intravenous injection administered at 21-day intervals. The lower dosage should be given to patients with inadequate marrow reserves due to old age, or prior therapy, or neoplastic marrow infiltration.

Doxorubicin has been used concurrently with other approved chemotherapeutic agents. Evidence is available that in some types of neoplastic disease, combination chemotherapy is superior to single agents. The benefits and risks of such therapy continue to be elucidated. When used in combination with other chemotherapy drugs, the most commonly used dosage of doxorubicin is 40 to 60 mg/m2 given as a single intravenous injection every 21 to 28 days.

In a large randomized study (NSABP B-15) of patients with early breast cancer involving axillary lymph nodes (see CLINICAL PHARMACOLOGY, CLINICAL STUDIES and ADVERSE REACTIONS, Adverse Reactions in Patients with Early Breast Cancer Receiving Doxorubicin-Containing Adjuvant Therapy), the combination dosage regimen of AC (doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2) was administered intravenously on day 1 of each 21-day treatment cycle. Four cycles of treatment were administered.

Dose Modifications

Patients in the NSABP B-15 study could have dose modifications of AC to 75% of the starting doses for neutropenic fever/infection. When necessary, the next cycle of treatment cycle was delayed until the absolute neutrophil count (ANC) was 1,000 cells/mm3 and the platelet count was 100,000 cells/mm3 and nonhematologic toxicities had resolved.

Doxorubicin dosage must be reduced in case of hyperbilirubinemia as follows:

Plasma bilirubin concentration (mg/dL)	Dosage reduction (%)
1.2 to 3	50
3.1 to 5	75

Reconstitution Directions

It is recommended that doxorubicin be slowly administered into the tubing of a freely running intravenous infusion of Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP. The tubing should be attached to a Butterfly needle inserted preferably into a large vein. If possible, avoid veins over joints or in extremities with compromised venous or lymphatic drainage. The rate of administration is dependent on the size of the vein and the dosage. However, the dose should be administered in not less than 3 to 5 minutes. Local erythematous streaking along the vein as well as facial flushing may be indicative of too rapid an administration. A burning or stinging sensation may be indicative of perivenous infiltration and, if this occurs, the infusion should be immediately terminated and restarted in another vein. Perivenous infiltration may occur painlessly.

Doxorubicin should not be mixed with heparin or fluorouracil since it has been reported that these drugs are incompatible to the extent that a precipitate may form. Contact with alkaline solutions should be avoided since this can lead to hydrolysis of doxorubicin. Until specific compatibility data are available, it is not recommended that doxorubicin be mixed with other drugs.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Handling and Disposal

Procedures for proper handling and disposal of anti-cancer drugs should be considered. Several guidelines on this subject have been published.1-4 There is no general agreement that all the procedures recommended in the guidelines are necessary or appropriate. However, given the toxic nature of this substance, the following protective recommendations are provided:

• Personnel should be trained in good technique for reconstitution and handling.
• Pregnant staff should be excluded from working with this drug.
• Personnel handling doxorubicin should wear protective clothing: goggles, gowns and disposable gloves and masks.
• A designated area should be defined for reconstitution (preferably under a laminar flow system). The work surface should be protected by disposable, plastic-backed, absorbent paper.
• All items used for reconstitution, administration or cleaning, including gloves, should be placed in high-risk waste-disposal bags for high-temperature incineration.
• Spillage or leakage should be treated with dilute sodium hypochlorite (1% available chlorine) solution, preferably by soaking, and then water.
• All cleaning materials should be disposed of as indicated previously.
• In case of skin contact, thoroughly wash the affected area with soap and water or sodium bicarbonate solution. However, do not abrade the skin by using a scrub brush.
• In case of contact with the eye(s), hold back the eyelid(s) and flush the affected eye(s) with copious amounts of water for at least 15 minutes. Then seek medical evaluation by a physician.
• Always wash hands after removing gloves.

Caregivers of pediatric patients receiving doxorubicin should be counseled to take precautions (such as wearing latex gloves) to prevent contact with the patient s urine and other body fluids for at least 5 days after each treatment.

How Supplied: ⮝

Doxorubicin Hydrochloride Injection, USP, 2 mg per mL, a sterile product which contains no preservatives, is available as follows:

Product No.	NDC No.
88305	63323-883-05	Doxorubicin hydrochloride 10 mg in a 5 mL single dose flip-top vial, packaged individually.
88310	63323-883-10	Doxorubicin hydrochloride 20 mg in a 10 mL single dose flip-top vial, packaged individually.
88330	63323-883-30	Doxorubicin hydrochloride 50 mg in a 25 mL single dose flip-top vial, packaged individually.
100161	63323-101-61	Doxorubicin hydrochloride 200 mg in a 100 mL multiple dose vial, packaged individually.

REFRIGERATE AT: 2 to 8 C (36 to 46 F).

Protect from light (keep in outer carton). Preservative Free. Discard unused portion.

The container closure is not made with natural rubber latex.

References: ⮝

1. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165.
2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://osha.gov/dts/osta/otm/otm_vi/otm _vi_2.html
3. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. 2006; 63:1172-1193.
4. Polovich, M., White, J. M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for human practice (2nd. ed.) Pittsburgh, PA: Oncology Nursing Society.

The brand names mentioned in this document are the trademarks of their respective owners.

Principal Display Panel - 10 Mg/5 Ml Vial Label ⮝

NDC 0069-4004-05

Single-Dose
Discard unused portion

Rx only

DOXOrubicin
HCl Injection, USP

10 mg/5 mL

(2 mg/mL)

For Intravenous Use Only
Caution: Cytotoxic Agent

Principal Display Panel - 10 Mg/5 Ml Vial Carton ⮝

NDC 0069-4004-05
Rx only

SINGLE-DOSE: DISCARD UNUSED PORTION

DOXOrubicin
HCl Injection,
USP

10 mg/5 mL

(2 mg/mL)

For Intravenous Use Only
Cytosafe Vial

Caution: Cytotoxic Agent

PREMIERProRx

Principal Display Panel - 20 Mg/10 Ml Vial Label ⮝

NDC 0069-4015-10

Single-Dose
Discard unused portion

Rx only

DOXOrubicin
HCl Injection, USP

20 mg/10 mL

(2 mg/mL)

For Intravenous Use Only

Caution: Cytotoxic Agent

Principal Display Panel - 20 Mg/10 Ml Vial Carton ⮝

NDC 0069-4015-10
Rx only

SINGLE-DOSE: DISCARD UNUSED PORTION

DOXOrubicin
HCl Injection,
USP

20 mg/10 mL

(2 mg/mL)

For Intravenous Use Only
Cytosafe Vial

Caution: Cytotoxic Agent

PREMIERProRx

Principal Display Panel - 50 Mg/25 Ml Vial Label ⮝

NDC 0069-4026-25

Single-Dose
Discard unused portion

Rx only

DOXOrubicin
HCl Injection, USP

50 mg/25 mL

(2 mg/mL)

For Intravenous Use Only

Caution: Cytotoxic Agent

Principal Display Panel - 50 Mg/25 Ml Vial Carton ⮝

NDC 0069-4026-25
Rx only

SINGLE-DOSE: DISCARD UNUSED PORTION

DOXOrubicin
HCl Injection,
USP

50 mg/25 mL

(2 mg/mL)

For Intravenous Use Only
Cytosafe Vial

Caution: Cytotoxic Agent

PREMIERProRx

Principal Display Panel - 200 Mg/100 Ml Vial Label ⮝

NDC 0069-4037-01

Multiple Dose Vial
Rx only

DOXOrubicin
HCl Injection, USP

200 mg/100 mL

(2 mg/mL)

For Intravenous Use Only

Caution: Cytotoxic Agent

PREMIERProRx

Principal Display Panel - 200 Mg/100 Ml Vial Carton ⮝

NDC 0069-4037-01
Rx only

Multiple Dose Vial

DOXOrubicin
HCl Injection,
USP

200 mg/100 mL

(2 mg/mL)

For Intravenous Use Only
Cytosafe Vial

Caution: Cytotoxic Agent

PREMIERProRx

DOXORUBICIN HYDROCHLORIDE doxorubicin hydrochloride injection, solution

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0069-4004 Route of Administration INTRAVENOUS

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength DOXORUBICIN HYDROCHLORIDE (UNII: 82F2G7BL4E) (DOXORUBICIN - UNII:80168379AG) DOXORUBICIN HYDROCHLORIDE 2 mg in 1 mL

Inactive Ingredients Ingredient Name Strength SODIUM CHLORIDE (UNII: 451W47IQ8X) HYDROCHLORIC ACID (UNII: QTT17582CB)

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0069-4004-05 1 in 1 CARTON 03/17/2013 1 5 mL in 1 VIAL, SINGLE-DOSE; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA050629 03/17/2013

DOXORUBICIN HYDROCHLORIDE doxorubicin hydrochloride injection, solution

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0069-4015 Route of Administration INTRAVENOUS

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength DOXORUBICIN HYDROCHLORIDE (UNII: 82F2G7BL4E) (DOXORUBICIN - UNII:80168379AG) DOXORUBICIN HYDROCHLORIDE 2 mg in 1 mL

Inactive Ingredients Ingredient Name Strength SODIUM CHLORIDE (UNII: 451W47IQ8X) HYDROCHLORIC ACID (UNII: QTT17582CB)

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0069-4015-10 1 in 1 CARTON 03/17/2014 1 10 mL in 1 VIAL, SINGLE-DOSE; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA050629 03/17/2014

DOXORUBICIN HYDROCHLORIDE doxorubicin hydrochloride injection, solution

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0069-4026 Route of Administration INTRAVENOUS

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength DOXORUBICIN HYDROCHLORIDE (UNII: 82F2G7BL4E) (DOXORUBICIN - UNII:80168379AG) DOXORUBICIN HYDROCHLORIDE 2 mg in 1 mL

Inactive Ingredients Ingredient Name Strength SODIUM CHLORIDE (UNII: 451W47IQ8X) HYDROCHLORIC ACID (UNII: QTT17582CB)

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0069-4026-25 1 in 1 CARTON 03/17/2014 1 25 mL in 1 VIAL, SINGLE-DOSE; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA050629 03/17/2014

DOXORUBICIN HYDROCHLORIDE doxorubicin hydrochloride injection, solution

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0069-4037 Route of Administration INTRAVENOUS

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength DOXORUBICIN HYDROCHLORIDE (UNII: 82F2G7BL4E) (DOXORUBICIN - UNII:80168379AG) DOXORUBICIN HYDROCHLORIDE 2 mg in 1 mL

Inactive Ingredients Ingredient Name Strength SODIUM CHLORIDE (UNII: 451W47IQ8X) HYDROCHLORIC ACID (UNII: QTT17582CB)

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0069-4037-01 1 in 1 CARTON 03/17/2014 1 100 mL in 1 VIAL, MULTI-DOSE; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA050629 03/17/2014

Labeler - Pfizer Laboratories Div Pfizer Inc (134489525)

Registrant - Pfizer Inc (113480771)

Establishment
Name	Address	ID/FEI	Business Operations
Olon, SpA		543029958	API MANUFACTURE(0069-4037, 0069-4026, 0069-4015, 0069-4004)

Establishment
Name	Address	ID/FEI	Business Operations
Pfizer (Perth) Pty Ltd		757868963	ANALYSIS(0069-4004, 0069-4015, 0069-4026, 0069-4037) , LABEL(0069-4004, 0069-4015, 0069-4026, 0069-4037) , MANUFACTURE(0069-4004, 0069-4015, 0069-4026, 0069-4037) , PACK(0069-4004, 0069-4015, 0069-4026, 0069-4037)

Revised: 10/2019 Document Id: 237a7dab-efb8-4cc7-ab52-58b1a4a6ce86 34391-3 Set id: 00634b2b-4e48-4178-8877-28582af894ad Version: 5 Effective Time: 20191024 Pfizer Laboratories Div Pfizer Inc