DOXOrubicin HCl 2 MG/ML Injectable Solution
Generic Name: DOXORUBICIN HYDROCHLORIDE
Brand Name: Doxorubicin Hydrochloride
- Substance Name(s):
- DOXORUBICIN HYDROCHLORIDE
DRUG INTERACTIONS
7 Avoid concomitant use of doxorubicin hydrochloride with inhibitors and inducers of CYP3A4, CYP2D6, and/or P-gp ( 7.1 ).
Do not administer doxorubicin hydrochloride in combination with trastuzumab due to increased risk of cardiac dysfunction ( 5.1 , 7.2 ).
7.1 Effect of Other Drugs on Doxorubicin Hydrochloride 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 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 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 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 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/m 2 intravenously daily for 5 days per cycle every 2–3 weeks) and doxorubicin hydrochloride (50 mg/m 2 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.
OVERDOSAGE
10 Few cases of overdose have been described.
A 58-year-old man with acute lymphoblastic leukemia received 10-fold overdose of doxorubicin hydrochloride (300 mg/m 2 ) 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 hydrochloride 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.
DESCRIPTION
11 Doxorubicin hydrochloride is an anthracycline, topoisomerase inhibitor isolated from cultures of Streptomyces peucetius var.
caesius.
The chemical name of doxorubicin hydrochloride is 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-α-L- lyx o-hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxylacetyl)-1-methoxy-, hydrochloride (8S- ci s)-.
The chemical structure of doxorubicin hydrochloride is: Doxorubicin Hydrochloride Injection, for intravenous use is a clear red, sterile, isotonic aqueous solution provided in vials containing 10 mg/5 mL doxorubicin hydrochloride (equivalent to 9.37 mg of doxorubicin free base), 20 mg/10 mL doxorubicin hydrochloride (equivalent to 18.74 mg of doxorubicin free base), 50 mg/25 mL doxorubicin hydrochloride (equivalent to 46.86 mg of doxorubicin free base), 150 mg/75 mL doxorubicin hydrochloride (140.58 mg of doxorubicin free base), or 200 mg/100 mL doxorubicin hydrochloride (equivalent to 187.4 mg of doxorubicin free base).
The drug product has demonstrated inherent antimicrobial activity suitable for a multiple dose presentation.
Each milliliter of solution contains 2 mg of doxorubicin hydrochloride and 9 mg of sodium chloride.
The pH of the solution is adjusted to 3.0 with hydrochloric acid, USP.
Chemical Structure
CLINICAL STUDIES
14 14.1 Adjuvant Breast Cancer The efficacy of doxorubicin hydrochloride-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 fluorouracil (CMF) to no chemotherapy (19 trials including 7523 patients) and doxorubicin hydrochloride-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 hydrochloride-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 hydrochloride-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).
Efficacy results are provided in Table 3 and Figures 1 and 2.
Table 3.
Summary of Randomized Trials Comparing Doxorubicin Hydrochloride-Containing Regimens Versus CMF in Meta-Analysis Study (starting year) Regimens No.
of Cycles No.
of Patients Doxorubicin Hydrochloride-Containing Regimens vs.
CMF HR Hazard ratio of less than 1 indicates that the treatment with doxorubicin hydrochloride-containing regimens is associated with lower risk of disease recurrences or death compared to the treatment with CMF.
(95% CI) DFS OS Abbreviations: DFS = disease free survival; OS = overall survival; AC = doxorubicin hydrochloride, cyclophosphamide; AVbCMF = doxorubicin hydrochloride, vinblastine, cyclophosphamide, methotrexate, fluorouracil; CMF = cyclophosphamide, methotrexate, fluorouracil; CMFVA = cyclophosphamide, methotrexate, fluorouracil, vincristine, doxorubicin hydrochloride; FAC = fluorouracil, doxorubicin hydrochloride, cyclophosphamide; FACV = fluorouracil, doxorubicin hydrochloride, cyclophosphamide, vincristine; HR = hazard ratio; CI = confidence interval NSABP B-15 (1984) AC 4 1562 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.
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 Patients received alternating cycles of AVb and CMF.
4 6 55 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 Hydrochloride-Containing Regimen 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 Figure 1 Figure 2
HOW SUPPLIED
16 /STORAGE AND HANDLING Doxorubicin Hydrochloride Injection Doxorubicin Hydrochloride Injection is a sterile, 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.
Storage 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 Doxorubicin Hydrochloride Injection is a cytotoxic drug.
Follow applicable special handling and disposal procedures.
1
RECENT MAJOR CHANGES
Warnings and Precautions, Embryo-Fetal Toxicity ( 5.8 ) 12/2019
GERIATRIC USE
8.5 Geriatric Use Clinical experience in patients who were 65 years of age and older who received doxorubicin hydrochloride-based chemotherapy regimens for metastatic breast cancer showed no overall differences in safety and effectiveness compared with younger patients.
DOSAGE FORMS AND STRENGTHS
3 Doxorubicin Hydrochloride Injection: 10 mg/5 mL, 20 mg/10 mL, and 50 mg/25 mL (2 mg/mL) clear red solution in a single-dose vial.
200 mg/100 mL (2 mg/mL) clear red solution in a multiple-dose vial.
Injection: 10 mg/5 mL, 20 mg/10 mL, 50 mg/25 mL in single-dose vial ( 3 ).
200 mg/100 mL in multiple-dose vial ( 3 ).
MECHANISM OF ACTION
12.1 Mechanism of Action The cytotoxic effect of doxorubicin hydrochloride on malignant cells and its toxic effects on various organs are thought to be related to nucleotide base intercalation and cell membrane lipid binding activities of doxorubicin.
Intercalation inhibits nucleotide replication and action of DNA and RNA polymerases.
The interaction of doxorubicin with topoisomerase II to form DNA-cleavable complexes appears to be an important mechanism of doxorubicin hydrochloride cytocidal activity.
INDICATIONS AND USAGE
1 Doxorubicin Hydrochloride Injection is an anthracycline topoisomerase 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 ).
1.1 Adjuvant Breast Cancer Doxorubicin Hydrochloride Injection 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 .
1.2 Other Cancers Doxorubicin Hydrochloride Injection 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
PEDIATRIC USE
8.4 Pediatric Use Based on postmarketing reports, pediatric patients treated with doxorubicin hydrochloride are at risk for developing late cardiovascular dysfunction.
Risk factors include young age at treatment (especially <5 years), high cumulative doses and receipt of combined modality therapy.
Long-term periodic cardiovascular monitoring is recommended for all pediatric patients who have received doxorubicin hydrochloride.
Doxorubicin hydrochloride, as a component of intensive chemotherapy regimens administered to pediatric patients, may contribute to prepubertal growth failure and may also contribute to gonadal impairment, which is usually temporary.
There are no recommended dose adjustments based on age.
Doxorubicin clearance was increased in patients aged 2 years to 20 years as compared to adults, while doxorubicin clearance was similar in infants less than 2 years as compared to adults [see Clinical Pharmacology (12.3) ] .
PREGNANCY
8.1 Pregnancy Risk Summary Based on findings in animals and its mechanism of action, Doxorubicin Hydrochloride Injection can cause fetal harm when administered to a pregnant woman; avoid the use of Doxorubicin Hydrochloride Injection during the 1 st trimester.
Available human data do not establish the presence or absence of major birth defects and miscarriage related to the use of doxorubicin hydrochloride during the 2 nd and 3 rd trimesters.
Doxorubicin hydrochloride was teratogenic and embryotoxic in rats and embryotoxic in rabbits when administered during organogenesis at doses approximately 0.07 times (based on body surface area) the recommended human dose of 60 mg/m 2 (see Data ) .
Advise pregnant women of the potential risk to a fetus.
In the U.S.
general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Data Animal Data Doxorubicin hydrochloride was teratogenic and embryotoxic at doses of 0.8 mg/kg/day (about 0.07 times the recommended human dose based on body surface area) when administered during the period of organogenesis in rats.
Teratogenicity and embryotoxicity were also seen using discrete periods of treatment.
The most susceptible was the 6- to 9-day gestation period at doses of 1.25 mg/kg/day and greater.
Characteristic malformations included esophageal and intestinal atresia, tracheo-esophageal fistula, hypoplasia of the urinary bladder, and cardiovascular anomalies.
Doxorubicin hydrochloride was embryotoxic (increase in embryo-fetal 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.
BOXED WARNING
WARNING: CARDIOMYOPATHY, SECONDARY MALIGNANCIES, EXTRAVASATION AND TISSUE NECROSIS, and SEVERE MYELOSUPPRESSION Cardiomyopathy: Myocardial damage, including acute left ventricular failure, can occur with doxorubicin hydrochloride.
The risk of cardiomyopathy is proportional to the cumulative exposure with incidence rates from 1% – 20% for cumulative doses ranging from 300 mg/m 2 to 500 mg/m 2 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 [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 hydrochloride [see Warnings and Precautions (5.2) ] .
Extravasation and Tissue Necrosis: Extravasation of doxorubicin hydrochloride 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) ] .
WARNING: CARDIOMYOPATHY, SECONDARY MALIGNANCIES, EXTRAVASATION AND TISSUE NECROSIS, and SEVERE MYELOSUPPRESSION See full prescribing information for complete boxed warning.
Cardiomyopathy: Myocardial damage can occur with doxorubicin hydrochloride with incidences from 1% – 20% for cumulative doses from 300 mg/m 2 to 500 mg/m 2 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 )
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Radiation-Induced Toxicity : Can be increased by the administration of Doxorubicin Hydrochloride Injection.
Radiation recall can occur in patients who receive Doxorubicin Hydrochloride Injection after prior radiation therapy ( 5.7 ).
Embryo-Fetal Toxicity : Can cause fetal harm.
Advise females of reproductive potential of the potential risk to a fetus and on the use of effective contraception.
Advise males with female partners of reproductive potential to use effective contraception.
Advise males with pregnant partners to use condoms ( 5.8 , 8.1 , 8.3 ).
5.1 Cardiomyopathy and Arrhythmias Cardiomyopathy Doxorubicin hydrochloride can result in myocardial damage, including acute left ventricular failure.
The risk of cardiomyopathy is generally proportional to the cumulative exposure.
Include prior doses of other anthracyclines or anthracenediones in calculations of total cumulative dosage for doxorubicin hydrochloride.
Cardiomyopathy may develop during treatment or up to several years after completion of treatment and can include decrease in LVEF and signs and symptoms of congestive heart failure (CHF).
The probability of developing cardiomyopathy is estimated to be 1 to 2% at a total cumulative dose of 300 mg/m 2 of doxorubicin hydrochloride, 3 to 5% at a dose of 400 mg/m 2 , 5 to 8% at a dose of 450 mg/m 2 , and 6 to 20% at a dose of 500 mg/m 2 , when doxorubicin hydrochloride is administered every 3 weeks.
There is an additive or potentially synergistic increase in the risk of cardiomyopathy in patients who have received radiotherapy to the mediastinum or concomitant therapy with other known cardiotoxic agents such as cyclophosphamide and trastuzumab.
Pericarditis and myocarditis have also been reported during or following doxorubicin hydrochloride treatment.
Assess left ventricular cardiac function (e.g., MUGA or echocardiogram) prior to initiation of Doxorubicin Hydrochloride Injection, 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/m 2 .
Use the same method of assessment of LVEF at all time points [see Use in Specific Populations (8.4) ] .
Discontinue Doxorubicin Hydrochloride Injection in patients who develop signs or symptoms of cardiomyopathy [see Dosage and Administration (2.3) ] .
Consider the use of dexrazoxane to reduce the incidence and severity of cardiomyopathy due to doxorubicin hydrochloride administration in patients who have received a cumulative doxorubicin hydrochloride dose of 300 mg/m 2 and who will continue to receive doxorubicin hydrochloride.
Arrhythmias Doxorubicin hydrochloride can result in arrhythmias, including life-threatening arrhythmias, during or within a few hours after doxorubicin hydrochloride administration and at any time point during treatment.
Tachyarrhythmias, including sinus tachycardia, premature ventricular contractions, and ventricular tachycardia, as well as bradycardia, can 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 a dosage modification of doxorubicin hydrochloride.
5.2 Secondary Malignancies The risk of developing secondary acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) is increased following treatment with doxorubicin hydrochloride.
Cumulative incidences ranged from 0.2% at five years to 1.5% at 10 years in two separate trials involving the adjuvant treatment of women with breast cancer.
These leukemias generally occur within 1 to 3 years of treatment.
5.3 Extravasation and Tissue Necrosis Extravasation of doxorubicin hydrochloride can cause severe local tissue injury manifesting as blistering, ulceration, and necrosis requiring wide excision of the affected area and skin grafting.
Extravasation should be considered if a patient experiences a burning or stinging sensation or shows other evidence indicating peri-venous infiltration or extravasation; however, 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.
When given via a peripheral venous line, infuse Doxorubicin Hydrochloride Injection over 10 minutes or less to minimize the risk of thrombosis or perivenous extravasation.
If extravasation is suspected, immediately discontinue the intravenous injection or continuous intravenous infusion [see Dosage and Administration (2.5) ] .
Apply ice to the site intermittently for 15 minutes, 4 times a day for 3 days.
In adults, if appropriate, administer dexrazoxane at the site of extravasation as soon as possible and within the first 6 hours after extravasation.
5.4 Severe Myelosuppression Doxorubicin hydrochloride can cause myelosuppression.
In Study 1, the incidence of severe myelosuppression was: grade 4 leukopenia (0.3%), grade 3 leukopenia (3%), and grade 4 thrombocytopenia (0.1%).
A dose-dependent, reversible neutropenia is the predominant manifestation of myelosuppression from doxorubicin hydrochloride.
When doxorubicin hydrochloride is administered every 21 days, the neutrophil count reaches its nadir 10 to 14 days after administration with recovery usually occurring by day 21.
Obtain complete blood counts prior to each treatment and carefully monitor patients during treatment for possible clinical complications due to myelosuppression.
Delay next dose of Doxorubicin Hydrochloride Injection if severe myelosuppression has not improved.
Consider dose reduction for patients with prolonged myelosuppression based on severity of reaction.
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 (8.6) , Clinical Pharmacology (12.3) ] .
Doxorubicin Hydrochloride Injection 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) ].
Reduce the dose of Doxorubicin Hydrochloride Injection in patients with serum bilirubin levels of 1.2 to 5 mg/dL [see Dosage and Administration (2.4) ] .
Obtain liver tests including ALT, AST, alkaline phosphatase, and bilirubin prior to and during therapy.
5.6 Tumor Lysis Syndrome Doxorubicin hydrochloride can 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 Potentiation of Radiation Toxicity and Radiation Recall Doxorubicin hydrochloride can increase radiation-induced toxicity to the myocardium, mucosa, skin, and liver.
Radiation recall, including but not limited to cutaneous and pulmonary toxicity, can occur in patients who receive doxorubicin hydrochloride after prior radiation therapy.
5.8 Embryo-Fetal Toxicity Based on findings in animals and its mechanism of action, Doxorubicin Hydrochloride Injection can cause fetal harm when administered to a pregnant woman; avoid the use of Doxorubicin Hydrochloride Injection during the 1 st trimester.
Available human data do not establish the presence or absence of major birth defects and miscarriage related to the use of doxorubicin hydrochloride during the 2 nd and 3 rd trimesters.
Doxorubicin hydrochloride was teratogenic and embryotoxic in rats and rabbits at doses lower than the recommended human dose.
Advise pregnant women of the potential risk to a fetus.
Advise females of reproductive potential to use effective contraception during treatment with Doxorubicin Hydrochloride Injection and for 6 months after treatment.
Advise males with female partners of reproductive potential to use effective contraception during treatment with Doxorubicin Hydrochloride Injection and for 3 months after treatment.
Advise males with pregnant partners to use condoms during treatment with Doxorubicin Hydrochloride Injection and for at least 10 days after the final dose [see Use in Specific Populations (8.1 , 8.3) , Nonclinical Toxicology (13.1) ] .
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information).
Cardiomyopathy Advise patients that Doxorubicin Hydrochloride Injection can cause irreversible myocardial damage and to contact a healthcare provider for symptoms of heart failure during or after treatment [see Warnings and Precautions (5.1) ] .
Secondary Malignancy Advise patients of the increased risk of treatment-related leukemia [see Warnings and Precautions (5.2) ] .
Myelosuppression Advise patients that Doxorubicin Hydrochloride Injection can reduce the absolute neutrophil count resulting in an increased risk of infection and to contact a healthcare provider for new onset fever or symptoms of infection [see Warnings and Precautions (5.4) ] .
Embryo-Fetal Toxicity Advise pregnant women and females of reproductive potential of the potential risk to a fetus, and to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.8) , Use in Specific Populations (8.1) ] .
Advise females of reproductive potential to use effective contraception during treatment with Doxorubicin Hydrochloride Injection and for 6 months after treatment [see Warnings and Precautions (5.8) , Use in Specific Populations (8.3) ] .
Advise patients that Doxorubicin Hydrochloride Injection may induce chromosomal damage in sperm, which may lead to loss of fertility and offspring with birth defects.
Advise males with female partners of reproductive potential to use effective contraception during treatment with Doxorubicin Hydrochloride Injection and for 3 months after treatment [see Warnings and Precautions (5.8) , Use in Specific Populations (8.3) , Nonclinical Toxicology (13.1) ] .
Advise males with pregnant partners to use condoms during treatment with Doxorubicin Hydrochloride Injection and for at least 10 days after the final dose [see Use in Specific Populations (8.3) ] .
Lactation Advise females not to breastfeed during treatment with Doxorubicin Hydrochloride Injection and for 10 days after the final dose [see Use in Specific Populations (8.2) ] .
Infertility Advise females and males of the potential loss of fertility from Doxorubicin Hydrochloride Injection [see Use in Specific Populations (8.3) ] .
Gastrointestinal and Dermatologic Adverse Reactions Advise patients that Doxorubicin Hydrochloride Injection can cause nausea, vomiting, diarrhea, mouth/oral pain and sores and to contact a healthcare provider should they develop any severe symptoms that prevent them from eating and drinking [see Adverse Reactions (6) ] .
Advise patients that Doxorubicin Hydrochloride Injection can cause alopecia [see Adverse Reactions (6.1) ] .
Administration Advise patients that Doxorubicin Hydrochloride Injection 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.
DOSAGE AND ADMINISTRATION
2 Single agent : 60 to 75 mg/m 2 given intravenously every 21 days ( 2.1 ).
In combination : 40 to 75 mg/m 2 given intravenously every 21 to 28 days ( 2.1 ).
Discontinue Doxorubicin Hydrochloride Injection in patients who develop signs or symptoms of cardiomyopathy ( 2.2 ).
Reduce dose in patients with hepatic impairment ( 2.3 ).
2.1 Recommended Dosage for Adjuvant Breast Cancer The recommended dosage of Doxorubicin Hydrochloride Injection is 60 mg/m 2 administered as an intravenous bolus on day 1 of each 21-day treatment cycle, in combination with cyclophosphamide, for a total of four cycles .
2.2 Recommended Dosage for Other Cancers The recommended dosage of Doxorubicin Hydrochloride Injection when used as a single agent is 60 mg/m 2 to 75 mg/m 2 intravenously every 21 days.
The recommended dosage of Doxorubicin Hydrochloride Injection, when administered in combination with other chemotherapy drugs, is 40 mg/m 2 to 75 mg/m 2 intravenously every 21 to 28 days.
Consider use of the lower Doxorubicin Hydrochloride Injection dose in the recommended dosage range or longer intervals between cycles for heavily pretreated patients, elderly patients, or obese patients.
Cumulative doses above 550 mg/m 2 are associated with an increased risk of cardiomyopathy [see Warnings and Precautions (5.1) ].
2.3 Dosage Modifications for Adverse Reactions Cardiomyopathy Discontinue Doxorubicin Hydrochloride Injection in patients who develop signs or symptoms of cardiomyopathy [see Warnings and Precautions (5.1) ] .
2.4 Dosage Modifications for Hepatic Impairment Doxorubicin Hydrochloride Injection is contraindicated in patients with severe hepatic impairment (Child-Pugh Class C or serum bilirubin greater than 5 mg/dL) [see Contraindications (4) ].
Dosage modifications for Doxorubicin Hydrochloride Injection in patients with elevated serum total bilirubin concentrations [see Warnings and Precautions (5.5) , Use in Specific Populations (8.6) ] are provided in Table 1.
Table 1.
Recommended Dosage Modification for Elevated Serum Total Bilirubin Serum total bilirubin concentration Dosage Modification 1.2 – 3 mg/dL 50% 3.1 – 5 mg/dL 75% greater than 5 mg/dL Do not initiate Doxorubicin Hydrochloride Injection; discontinue Doxorubicin Hydrochloride Injection 2.5 Preparation and Administration Doxorubicin Hydrochloride Injection is a cytotoxic drug.
Follow applicable special handling and disposal procedures.
1 Preparation Dilution of Doxorubicin Hydrochloride Injection Dilute Doxorubicin Hydrochloride Injection in 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP.
Protect from light following preparation until completion of infusion.
Use within 1 hour.
If not used within 1 hour, discard the diluted product.
Administration Visually inspect for particulate matter and discoloration prior to administration, whenever solution and container permit.
Discard if the solution is discolored, cloudy, or contains particulate matter.
Administration by Intravenous Injection Administer diluted Doxorubicin Hydrochloride Injection 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 intravenously over 3 to 10 minutes.
Decrease the rate of infusion if erythematous streaking along the vein proximal to the site of infusion or facial flushing occur.
Administration by Continuous Intravenous Infusion Administer diluted Doxorubicin Hydrochloride Injection solution only through a central intravenous line.
Decrease the rate of infusion 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 Immediately discontinue Doxorubicin Hydrochloride Injection 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 minutes, 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) ] .
Management of Contact with Skin or Eyes 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.
Incompatibility with Other Drugs Do not admix Doxorubicin Hydrochloride Injection with other drugs.
If Doxorubicin Hydrochloride Injection is mixed with heparin or fluorouracil, a precipitate may form.
Avoid contact with alkaline solutions which can lead to hydrolysis of doxorubicin hydrochloride.