DOXOrubicin Hydrochloride

Sun Pharmaceutical Industries Limited

DOXOrubicin Hydrochloride Injection, USPFor Intravenous Use Only

FULL PRESCRIBING INFORMATION: CONTENTS*

• WARNINGS
• DOXORUBICIN HYDROCHLORIDE DESCRIPTION
• CLINICAL PHARMACOLOGY
  • Pharmacokinetics
  • Pharmacokinetics in Special Populations
• CLINICAL STUDIES
• DOXORUBICIN HYDROCHLORIDE INDICATIONS AND USAGE
• DOXORUBICIN HYDROCHLORIDE CONTRAINDICATIONS
• WARNINGS
  • General
  • Cardiac Function
  • Hematologic Toxicity
  • Secondary Leukemia
  • Effects at Site of Injection
  • Extravasation
  • Hepatic Impairment
  • Immunosuppressant Effects/Increased Susceptibility to Infections
  • Pregnancy Category D
• PRECAUTIONS
  • General
  • Information for Patients
  • Drug Interactions
  • Laboratory Tests
  • Carcinogenesis, Mutagenesis, and Impairment of Fertility
  • Pregnancy Category D
  • Nursing Mothers
  • Pediatric Use
  • Geriatric Use
• DOXORUBICIN HYDROCHLORIDE ADVERSE REACTIONS
• OVERDOSAGE
• DOXORUBICIN HYDROCHLORIDE DOSAGE AND ADMINISTRATION
  • Dose Modifications
  • Directions for Use
  • Handling and Disposal
• HOW SUPPLIED
• REFERENCES
• PATIENT INFORMATION
• PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - LABEL 25ML
• PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - CARTON 25ML
• PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - LABEL 100ML
• PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - CARTON 100ML

FULL PRESCRIBING INFORMATION

DOXORUBICIN HYDROCHLORIDE DESCRIPTION

CLINICAL PHARMACOLOGY

Pharmacokinetics

Pharmacokinetics in Special Populations

CLINICAL STUDIES

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
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
NSABP B-15 (1984)	AC CMF	4 6	1562Includes 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. 776	0.93 (0.82 to 1.06)	0.97 (0.83 to 1.12)
SECSG 2 (1976)	FAC CMF	6 6	260 268	0.86 (0.66 to 1.13)	0.93 (0.69 to 1.26)
ONCOFRANCE (1978)	FACV CMF	12 12	138 113	0.71 (0.49 to 1.03)	0.65 (0.44 to 0.96)
SE Sweden BCG A (1980)	AC CMF	6 6	21 22	0.59 (0.22 to 1.61)	0.53 (0.21 to 1.37)
NSABC Israel Br0283 (1983)	AVbPatients received alternating cycles of AVb and CMF. CMF CMF	4 6   6	55     50	0.91 (0.53 to 1.57)	0.88 (0.47 to 1.63)
Austrian BCSG 3 (1984)	CMFVA CMF	6 8	121 124	1.07 (0.73 to 1.55)	0.93 (0.64 to 1.35)
Combined Studies	Doxorubicin-Containing Regimens CMF		2157 1353	0.91 (0.82 to 1.01)	0.91 (0.81 to 1.03)

DOXORUBICIN HYDROCHLORIDE INDICATIONS AND USAGE

DOXORUBICIN HYDROCHLORIDE CONTRAINDICATIONS

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

Hematologic Toxicity

Secondary Leukemia

Effects at Site of Injection

Extravasation

Hepatic Impairment

Immunosuppressant Effects/Increased Susceptibility to Infections

Pregnancy Category D

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

Laboratory Tests

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Pregnancy Category D

Nursing Mothers

Pediatric Use

Geriatric Use

DOXORUBICIN HYDROCHLORIDE ADVERSE REACTIONS

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

	ACIncludes 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	Conventional CMF
	N=1492	N=739
Treatment administration
Mean number of cycles	3.8	5.5
Total cycles	5676	4068
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

OVERDOSAGE

Acute overdosage with doxorubicin enhances the toxic effect 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 100 mL (2 mg/mL) doxorubicin hydrochloride injection vials are packaged as multiple dose vials 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.

DOXORUBICIN HYDROCHLORIDE DOSAGE AND ADMINISTRATION

Dose Modifications

Directions for Use

Handling and Disposal

• Personnel should be trained in good technique for 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.
• All items used for 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.

HOW SUPPLIED

REFERENCES

• 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.
• OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html
• American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. 2006; 63:1172-1193.
• Polovich, M., White, J. M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd. ed.) Pittsburgh , PA : Oncology Nursing Society.

PATIENT INFORMATION

• Heart problems. Doxorubicin may cause heart problems that may lead to death. These problems can happen during your treatment or months to years after stopping treatment. In some cases heart problems are irreversible. Your chance of heart problems is higher if you:
  • already have heart problems
  • have a history of radiation therapy or are currently receiving radiation therapy to your chest
  • have had treatment with certain other anti-cancer medicines
  • take other medicines that can affect your heart

• shortness of breath
• swelling of your feet and ankles
• cough
• 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.

• 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. See the end of this leaflet for a complete list of ingredients in doxorubicin hydrochloride injection.

• 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. See “What should I avoid while receiving doxorubicin?”
• have any other medical conditions
• are pregnant or plan to become pregnant. Doxorubicin can harm your unborn baby. Women who may become pregnant should use effective birth control (contraception). Talk to your doctor about the best way to prevent pregnancy while receiving doxorubicin.
• 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.

• 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.

• Avoid receiving live vaccines during treatment with doxorubicin. Talk to your doctor to find out which vaccines are safe for you while receiving doxorubicin. See “What should I tell my doctor before receiving doxorubicin?”

• See “What is the most important information I should know about doxorubicin?”

• pain at injection site
• skin redness or swelling
• burning or stinging
• open skin sores at injection site

• fever (temperature of 100.4 F or greater) chills or shivering
• cough that brings up mucus
• burning or pain with urination

• hair loss (alopecia). Your hair may re-grow after your treatment.
• darkening of your nails or separation of your nails from your nailbed
• nausea
• vomiting
• lack of appetite or increased thirst
• bruise or bleed more easily
• abnormal heart beat
• a secondary cancer may occur when doxorubicin is combined with other chemotherapy agents.
• mouth sores
• weight changes
• stomach (abdominal) pain
• diarrhea
• eye problems
• allergic reactions. Call your doctor right away if you have any of the following symptoms of an allergic reaction
  • rash
  • fever
  • flushed face
  • dizziness or feel faint
  • hives
  • shortness of breath or trouble breathing
  • itching
  • swelling of your lips or tongue

What are the ingredients of doxorubicin hydrochloride injection?

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - LABEL 25ML

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - CARTON 25ML

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - LABEL 100ML

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - CARTON 100ML