Doxorubicin Hydrochloride

Description

11 DESCRIPTION Doxorubicin is a cytotoxic anthracycline antibiotic isolated from cultures of Streptomyces peucetius var. caesius . Doxorubicin consists of a naphthacenequinone nucleus linked through a glycosidic bond at ring atom 7 to an amino sugar, daunosamine. Chemically, doxorubicin hydrochloride is (8S,10S)-10-[(3-Amino-2,3,6-trideoxy-a-L-lyxo-hexopyranosyl)-oxy]-8-glycoloyl-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12-naphthacenedione hydrochloride. The structural formula is as follows: Doxorubicin binds to nucleic acids, presumably by specific intercalation of the planar anthracycline nucleus with the DNA double helix. The anthracycline ring is lipophilic, but the saturated end of the ring system contains abundant hydroxyl groups adjacent to the amino sugar, producing a hydrophilic center. The molecule is amphoteric, containing acidic functions in the ring phenolic groups and a basic function in the sugar amino group. It binds to cell membranes as well as plasma proteins. It is supplied in the hydrochloride form as a sterile red-orange lyophilized powder containing lactose for intravenous use only. DOXOrubicin HCl for Injection, USP: Each 10 mg lyophilized vial contains 10 mg of Doxorubicin Hydrochloride, USP and 50 mg of Lactose Monohydrate, NF. Each 50 mg lyophilized vial contains 50 mg of Doxorubicin Hydrochloride, USP and 250 mg of Lactose Monohydrate, NF. structure

What Is Doxorubicin Hydrochloride Used For?

1 INDICATIONS AND USAGE Doxorubicin is an anthracycline topoisomerase II inhibitor indicated: as a component of multiagent adjuvant chemotherapy for treatment of women with axillary lymph node involvement following resection of primary breast cancer (1.1) . for the treatment of: acute lymphoblastic leukemia, acute myeloblastic leukemia, Hodgkin lymphoma, Non-Hodgkin lymphoma, metastatic breast cancer, metastatic Wilms’ tumor, metastatic neuroblastoma, metastatic soft tissue sarcoma, metastatic bone sarcomas, metastatic ovarian carcinoma, metastatic transitional cell bladder carcinoma, metastatic thyroid carcinoma, metastatic gastric carcinoma, metastatic bronchogenic carcinoma (1.2) . 1.1 Adjuvant Breast Cancer DOXOrubicin HCl for Injection, USP is indicated as a component of multi-agent adjuvant chemotherapy for treatment of women with axillary lymph node involvement following resection of primary breast cancer [see Clinical Studies (14.1 )]. 1.2 Other Cancers Doxorubicin is indicated for the treatment of acute lymphoblastic leukemia acute myeloblastic leukemia Hodgkin lymphoma non-Hodgkin lymphoma (NHL) metastatic breast cancer metastatic Wilms’ tumor metastatic neuroblastoma metastatic soft tissue sarcoma metastatic bone sarcoma metastatic ovarian carcinoma 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 therapy: 40 to 75 mg/m 2 given intravenously every 21 to 28 days (2.1) . Discontinue doxorubicin in patients who develop signs or symptoms of cardiomyopathy (2.2) . Reduce dose in patients with hepatic impairment (2.2) . 2.1 Recommended Dose Adjuvant Breast Cancer The recommended dose of doxorubicin 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 [see Clinical Studies (14) ]. Metastatic Disease, Leukemia, or Lymphoma The recommended dose of doxorubicin when used as a single agent is 60 to 75 mg/m 2 intravenously every 21 days. The recommended dose of doxorubicin, when administered in combination with other chemotherapy drugs, is 40 to 75 mg/m 2 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/m 2 are associated with an increased risk of cardiomyopathy [see Warnings and Precautions (5.1) ]. 2.2 Dose Modifications Cardiac Impairment Discontinue doxorubicin in patients who develop signs or symptoms of cardiomyopathy. Hepatic Impairment Doxorubicin is contraindicated in patients with severe hepatic impairment (Child-Pugh Class C or serum bilirubin >5.0 mg/dL) [see Contraindications (4) ]. Decrease the dose of doxorubicin in patients with elevated serum total bilirubin concentrations as follows: Serum bilirubin concentration Doxorubicin Dose reduction 1.2 to 3 mg/dL 50 % 3.1 to 5 mg/dL 75 % greater than 5 mg/dL Do not initiate doxorubicin Discontinue doxorubicin [see Warnings and Precautions (5.5) and Use in Specific Population (8.7) ] 2.3 Preparation and Administration Preparation of DOXOrubicin HCl for Injection, USP; Reconstitute doxorubicin hydrochloride for injection with 0.9% Sodium Chloride Injection to obtain a final concentration of 2 mg per mL as follows: 5 mL 0.9% Sodium Chloride Injection to reconstitute 10 mg doxorubicin HCl vial 25 mL 0.9% Sodium Chloride Injection to reconstitute 50 mg doxorubicin HCl vial Gently shake vial until the contents have dissolved. Protect reconstituted solution from light. Administration Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard if the solution is discolored, cloudy, or contains particulate matter. Storage of vials of DOXOrubicin HCl for Injection, USP following reconstitution under refrigerated conditions can result in the formation of a gelled product. Place gelled product at room temperature [15º to 30ºC (59º to 86ºF)] for 2 to 4 hours to return the product to a slightly viscous, mobile solution. Administration by Intravenous Injection : Administer doxorubicin as an intravenous...

Side Effects (Adverse Reactions)

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) ] The most common (>10%) adverse drug reactions are alopecia, nausea and vomiting ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-877-845-0689, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial Experience in Breast Cancer Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety data below were collected from 1492 women who received doxorubicin at a dose of 60 mg/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 1. No treatment-related deaths were reported in patients on either arm of the study. Table 1. Selected Adverse Reactions in Patients with Early Breast Cancer Involving Axillary Lymph Nodes Adverse reactions, % of patients AC* N=1492 Conventional CMF N=739 Leukopenia Grade 3 (1,000 to 1,999 /mm 3 ) Grade 4 (<1000 /mm 3 ) 3.4 0.3 9.4 0.3 Thrombocytopenia Grade 3 (25,000 to 49,999 /mm 3 ) Grade 4 (<25,000 /mm 3 ) 0 0.1 3.0 0 Shock, sepsis 2 1 Systemic infection 2 1 Vomiting Vomiting ≤12 hours Vomiting >12 hours Intractable 34 37 5 25 12 2 Alopecia 92 71 Cardiac dysfunction Asymptomatic Transient Symptomatic 0.2 0.1 0.1 0.1 0 0 * Includes pooled data from patients who received either AC alone for 4 cycles, or who were treated with AC for 4 cycles followed by 3 cycles of CMF 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of doxorubicin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiac – cardiogenic shock Cutaneous – Skin and nail hyperpigmentation, oncolysis, rash, itching, photosensitivity, urticaria, acral erythema, palmar plantar erythrodysesthesia Gastrointestinal – Nausea, mucositis, stomatitis, necrotizing colitis, typhlitis, gastric erosions, gastrointestinal tract bleeding, hematochezia, esophagitis, anorexia, abdominal pain, dehydration, diarrhea, hyperpigmentation of the oral mucosa Hypersensitivity – Anaphylaxis Laboratory Abnormalities –Increased alanine aminotransferase, increased aspartate aminotransferase Neurological – Peripheral sensory and motor neuropathy, seizures, coma Ocular – Conjunctivitis, keratitis, lacrimation Vascular – Phlebosclerosis, phlebitis/thrombophlebitis, hot flashes, thromboembolism Other – Malaise/asthenia, fever, chills, weight gain

Drug Interactions

7 DRUG INTERACTIONS Avoid concurrent use of doxorubicin with inhibitors and inducers of CYP3A4, CYP2D6, and/or P-gp (7.1) . Do not administer doxorubicin in combination with trastuzumab due to increased risk of cardiac dysfunction (5.1 , 7.2) . 7.1 Effect of CYP3A4 Inhibitors, Inducers and P-gp Doxorubicin is a major substrate of cytochrome P450 CYP3A4 and CYP2D6, and P-glycoprotein (P-gp). Clinically significant interactions have been reported with inhibitors of CYP3A4, CYP2D6, and/or P-gp (e.g., verapamil), resulting in increased concentration and clinical effect of doxorubicin. Inducers of CYP3A4 (e.g., phenobarbital, phenytoin, St. John’s Wort) and P-gp inducers may decrease the concentration of doxorubicin. Avoid concurrent use of doxorubicin with inhibitors and inducers of CYP3A4, CYP2D6, or P-gp. 7.2 Trastuzumab Concurrent use of trastuzumab and doxorubicin results in an increased risk of cardiac dysfunction. Avoid concurrent administration of doxorubicin and trastuzumab. The appropriate interval for administering doxorubicin following trastuzumab therapy has not been determined [see Warnings and Precautions (5.1) ]. 7.3 Paclitaxel Paclitaxel, when given prior to doxorubicin, increases the plasma-concentrations of doxorubicin and its metabolites. Administer doxorubicin prior to paclitaxel if used concomitantly. 7.4 Dexrazoxane Do not administer dexrazoxane as a cardioprotectant at the initiation of doxorubicin containing chemotherapy regimens. In a randomized trial in women with metastatic breast cancer, initiation of dexrazoxane with doxorubicin based chemotherapy resulted in a significantly lower tumor response rate (48% vs. 63%; p=0.007) and shorter time to progression than in women who received doxorubicin based chemotherapy alone. 7.5 6-Mercaptopurine Doxorubicin may potentiate 6-mercaptopurine-induced hepatotoxicity. In 11 patients with refractory leukemia treated with 6-mercaptopurine (500 mg/m 2 intravenously daily for 5 days per cycle every 2 to 3 weeks) and doxorubicin (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 elevations of total serum bilirubin, alkaline phosphatase and aspartate aminotransferase.

Contraindications

4 CONTRAINDICATIONS Doxorubicin 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 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 ) Hypersensitivity to doxorubicin HCl ( 4 )

Pregnancy and Breastfeeding

8.1 Pregnancy Pregnancy Category D Risk Summary Doxorubicin can cause fetal harm when administered to a pregnant woman. Doxorubicin was teratogenic and embryotoxic in rats and rabbits at doses approximately 0.07 times (based on body surface area) the recommended human dose of 60 mg/m 2 . If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus. Animal Data Doxorubicin was teratogenic and embryotoxic at doses of 0.8 mg/kg/day (about 0.07 times the recommended human dose based on body surface area) when administered during the period of organogenesis in rats. Teratogenicity and embryotoxicity were also seen using discrete periods of treatment. The most susceptible was the 6- to 9-day gestation period at doses of 1.25 mg/kg/day and greater. Characteristic malformations included esophageal and intestinal atresia, tracheo-esophageal fistula, hypoplasia of the urinary bladder, and cardiovascular anomalies. Doxorubicin was embryotoxic (increase in embryofetal deaths) and abortifacient at 0.4 mg/kg/day (about 0.07 times the recommended human dose based on body surface area) in rabbits when administered during the period of organogenesis.

8.3 Nursing Mothers Doxorubicin has been detected in the milk of at least one lactating patient [see Clinical Pharmacology (12.3) ] . Because of the potential for serious adverse reactions in nursing infants from doxorubicin , a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

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 (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 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 HCI for Injection, USP is supplied as a sterile red-orange lyophilized powder in single dose flip-top vials in the following package strengths: NDC 0143-9092-01 : 10 mg vial; individually boxed. NDC 0143-9093-01 : 50 mg vial; individually boxed. Store all vials at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Protect from light. Retain in carton until time of use. Discard unused portion. Reconstituted Solution Stability After adding the diluent, the vial should be shaken and the contents allowed to dissolve. The reconstituted solution is stable for 7 days at room temperature and under normal room light (100 foot-candles) and 15 days under refrigeration (2° to 8°C). It should be protected from exposure to sunlight. Discard any unused solution from the 10 mg and 50 mg single dose vials. Handling and Disposal Handle and dispose of DOXOrubicin HCl for Injection, USP consistent with recommendations for the handling and disposal of hazardous drugs. 1