Doxorubicin

Description

11 DESCRIPTION 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]-7,8,9,10tetrahydro-6,8,11-trihydroxy-8-(hydroxylacetyl)-1-methoxy-, hydrochloride (8S- ci s)-. The chemical structure of doxorubicin hydrochloride is: Doxorubicin Hydrochloride for Injection, USP, for intravenous use is a sterile red to orange-red lyophilized cake or powder, provided in single-dose vials. Each 20 mg/vial contains 20 mg of doxorubicin hydrochloride, USP (equivalent to 18.74 mg of doxorubicin free base) and 100 mg of lactose monohydrate. Each 50 mg/vial contains 50 mg of doxorubicin hydrochloride, USP (equivalent to 46.86 mg of doxorubicin free base) and 250 mg of lactose monohydrate. formula_

What Is Doxorubicin Used For?

1 INDICATIONS AND USAGE Doxorubicin hydrochloride for 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 for 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 for 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

Dosage and Administration

2 DOSAGE AND ADMINISTRATION 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 for 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 for 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 for 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 for 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 for 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 for 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 for 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 for 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 to 3 mg/dL 50% 3.1 to 5 mg/dL 75% greater than 5 mg/dL Do not initiate doxorubicin hydrochloride for injection; discontinue doxorubicin hydrochloride for injection 2.5 Preparation and Administration Doxorubicin hydrochloride for injection is a cytotoxic drug. Follow applicable special handling and disposal procedures. 1 Preparation Reconstitution of Doxorubicin Hydrochloride for Injection Reconstitute doxorubicin hydrochloride for injection with 0.9% Sodium Chloride Injection to obtain a final concentration of 2 mg per mL as follows: 10 mL 0.9% Sodium Chloride Injection, USP to reconstitute 20 mg vial 25 mL 0.9% Sodium Chloride Injection, USP to reconstitute 50 mg vial Gently shake vial until the contents have dissolved. Protect reconstituted solution from light. Dilution of Reconstituted Doxorubicin Hydrochloride...

Side Effects (Adverse Reactions)

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in 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) ] The most common (> 10%) adverse reactions are alopecia, nausea and vomiting ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience 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 practice. Breast Cancer The safety data below were collected from 1,492 women who received doxorubicin hydrochloride at a dose of 60 mg/m 2 and cyclophosphamide at a dose of 600 mg/m 2 (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 2. No treatment-related deaths were reported in patients on either arm of the study. Table 2. Selected Adverse Reactions in Patients with Early Breast Cancer Involving Axillary Lymph Nodes Adverse Reactions AC* N=1,492 Conventional CMF N=739 % % Alopecia 92 71 Vomiting Vomiting ≤ 12 hours Vomiting > 12 hours Intractable 34 37 5 25 12 2 Leukopenia Grade 3 (1,000 to 1,999 /mm 3 ) Grade 4 (< 1,000 /mm 3 ) 3.4 0.3 9.4 0.3 Shock, sepsis 2 1 Systemic infection 2 1 Cardiac dysfunction Asymptomatic Transient Symptomatic 0.2 0.1 0.1 0.1 0 0 Thrombocytopenia Grade 3 (25,000 to 49,999 /mm 3 ) Grade 4 (< 25,000 /mm 3 ) 0 0.1 0.3 0 AC = doxorubicin hydrochloride, cyclophosphamide; CMF = cyclophosphamide, methotrexate, fluorouracil * Includes pooled data from patients who received either AC for 4 cycles or AC for 4 cycles followed by CMF for 3 cycles 6.2 Post-marketing Experience The following adverse reactions have been identified during post-approval use of doxorubicin hydrochloride for injection. 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 ALT, increased AST 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

Drug Interactions

7 DRUG INTERACTIONS 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 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 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 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 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 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/m 2 intravenously daily for 5 days per cycle every 2 to 3 weeks) and doxorubicin hydrochloride (50 mg/m 2 intravenous once per cycle every 2 to 3 weeks) alone or with vincristine and prednisone, all developed hepatic dysfunction manifested by increased total serum bilirubin, alkaline phosphatase and aspartate aminotransferase.

Contraindications

4 CONTRAINDICATIONS Doxorubicin hydrochloride for injection 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 hydrochloride, including anaphylaxis [see Adverse Reactions (6.2) ] Severe myocardial insufficiency ( 4 ). Recent myocardial infarction ( 4 ). Severe persistent drug-induced myelosuppression ( 4 ). Severe hepatic impairment ( 4 ). Severe hypersensitivity to doxorubicin hydrochloride ( 4 ).

Pregnancy and Breastfeeding

8.1 Pregnancy Risk Summary Based on findings in animals and its mechanism of action, doxorubicin hydrochloride for injection can cause fetal harm when administered to a pregnant woman; avoid the use of doxorubicin hydrochloride for 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 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 Females and Males of Reproductive Potential Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating doxorubicin hydrochloride for injection. Contraception Females Doxorubicin hydrochloride for injection can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1) ] . Advise female patients of reproductive potential to use highly effective contraception during treatment with doxorubicin hydrochloride for injection and for 6 months after treatment [see Use in Specific Populations (8.1) ] . Males Doxorubicin hydrochloride may damage spermatozoa and testicular tissue, resulting in possible genetic fetal abnormalities. Due to the potential for genotoxicity, advise males with female partners of reproductive potential to use effective contraception during treatment with doxorubicin hydrochloride for injection and for 3 months after treatment [see Nonclinical Toxicology (13.1) ] . Males with pregnant partners should use condoms during treatment and for at least 10 days after the final dose [see Nonclinical Toxicology (13.1) , Use in Specific Populations (8.1) ] . Infertility Females In females of reproductive potential, doxorubicin hydrochloride 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 hydrochloride may result in oligospermia, azoospermia,...

Overdosage

10 OVERDOSAGE 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 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.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING Doxorubicin Hydrochloride for Injection, USP is a sterile red to orange-red lyophilized cake or powder, available in Type 1 glass vials in single vial packs or 10 vial packs as: 20 mg/vial : Single-Dose Vial in mono-carton NDC 70121-1218-1 10 mono-cartons in Outer Carton NDC 70121-1218-7 50 mg/vial: Single-Dose Vial in a Carton NDC 70121-1219-1 Storage Store all vials at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Protect from light. Retain in carton until time of use. Discard unused portion. Handling and Disposal Doxorubicin Hydrochloride for Injection, USP is a cytotoxic drug. Follow applicable special handling and disposal procedures. 1