DOXORUBICIN HYDROCHLORIDE- doxorubicin hydrochloride_injection, solution

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. Pharmacokinetic studies conducted in patients with various types of tumors have shown that doxorubicin follows multiphasic disposition after intravenous injection. In four patients, doxorubicin demonstrated dose-independent pharmacokinetics across a dose range of 30 mg/m 2 2 Distribution The distribution half-life is approximately 5 minutes. Steady-state distribution volume ranges from 809 L/m 2 2 Doxorubicin does not cross the blood brain barrier. Elimination Plasma clearance is ranges from 324 mL/min/m 2 2 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 hydrochloride. 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. , the ratio between the AUC of doxorubicinol and the AUC of doxorubicin is approximately 0. Excretion Plasma clearance 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. Specific Populations Weight 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 mg/m 2 2 2 2 2 [see Use in Specific Populations ( 8. 4 Sex 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/m 2 2 Patients with Hepatic Impairment The clearance of doxorubicin and doxorubicinol was reduced in patients with elevated serum total bilirubin concentrations [see Dosage and Administration ( 2.

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 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. 2 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. 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.

Single agent 2 2. 1 In combination 2 2. 1 Discontinue Doxorubicin Hydrochloride Injection in patients who develop signs or symptoms of cardiomyopathy. 2 Reduce dose in patients with hepatic impairment. 3 The recommended dosage of Doxorubicin Hydrochloride Injection is 60 mg/m 2 The recommended dosage of Doxorubicin Hydrochloride Injection when used as a single agent is 60 mg/m 2 2 The recommended dosage of Doxorubicin Hydrochloride Injection, when administered in combination with other chemotherapy drugs, is 40 mg/m 2 2 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 [see Warnings and Precautions ( 5. 1 Cardiomyopathy Discontinue Doxorubicin Hydrochloride Injection in patients who develop signs or symptoms of cardiomyopathy [see Warnings and Precautions ( 5. 1 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. 6 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 Injection; 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. 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.

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. 1 To report SUSPECTED ADVERSE REACTIONS, contact Athenex Pharmaceutical Division, LLC. at 1-855-273-0154 or FDA at 1-800-FDA-1088 or www. gov/medwatch. 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 1492 women who received doxorubicin hydrochloride at a dose of 60 mg/m 2 2 Table 2 Table 2: Selected Adverse Reactions in Patients with Early Breast Cancer Involving Axillary Lymph Nodes AC = doxorubicin hydrochloride, cyclophosphamide; CMF = cyclophosphamide, methotrexate, fluorouracil * Adverse Reactions AC * N=1492 Conventional CMF N=739 % % Alopecia 92 71 Vomiting 34 25 Leukopenia 3 3 3. 4 Shock, sepsis 2 1 Systemic infection 2 1 Cardiac dysfunction Thrombocytopenia 3 3 The following adverse reactions have been identified during postapproval use of Doxorubicin Hydrochloride 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 en dash Cutaneous Gastrointestinal Hypersensitivity Laboratory Abnormalities Neurological Ocular Vascular Other.

Doxorubicin Hydrochloride 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.

Lactation 8. 2 Females and Males of Reproductive Potential 8. 3 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 nd rd 2 (see Data In the U. 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. Risk Summary Doxorubicin was measured in the milk of one lactating patient after therapy with 70 mg/m 2 Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating Doxorubicin Hydrochloride Injection. Contraception Females Doxorubicin Hydrochloride Injection can cause fetal harm when administered to pregnant women [see Use in Specific Populations ( 8. 1 [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 Injection and for 3 months after treatment [see Nonclinical Toxicology ( 13. 1 [see Nonclinical Toxicology ( 13. 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, 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 [see Nonclinical Toxicology ( 13. 1 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 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. The clearance of doxorubicin was reduced in patients with elevated serum total bilirubin levels. Doxorubicin Hydrochloride Injection 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 [see Dosage and Administration ( 2.

Avoid concomitant use of doxorubicin hydrochloride with inhibitors and inducers of CYP3A4, CYP2D6, and/or P-gp. 1 Do not administer doxorubicin hydrochloride in combination with trastuzumab due to increased risk of cardiac dysfunction. 2 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. 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. 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. 007) and shorter time to progression compared to doxorubicin hydrochloride-based chemotherapy alone. Doxorubicin hydrochloride may potentiate 6-mercaptopurine-induced hepatotoxicity. In 11 patients with refractory leukemia treated with 6-mercaptopurine (500 mg/m 2 2.

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
NONCLINICAL TOXICOLOGY
Doxorubicin hydrochloride treatment can increase the risk of secondary malignancies based on postmarketing reports [see Warnings and Precautions ( 5.2 in vitro in vitro in vivo Doxorubicin hydrochloride 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 hydrochloride (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 hydrochloride induces DNA damage in rabbit spermatozoa and dominant lethal mutations in mice.
CLINICAL STUDIES
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. 01) and on OS with a HR of 0. Efficacy results are provided in Table 3 Figures 1 2 Table 3: Summary of Randomized Trials Comparing Doxorubicin Hydrochloride-Containing Regimens Versus CMF in Meta-Analysis Abbreviations: * ** dagger Study (starting year) Regimens No. of Cycles No. of Patients Doxorubicin Hydrochloride-Containing Regimens vs. CMF HR ** (95% CI) DFS OS NSABP B-15 (1984) AC 4 1562 * 0. 12) SECSG 2 FAC 6 260 0. 26) ONCOFRANCE (1978) FACV 12 138 0. 96) SE Sweden BCG A AC 6 21 0. 37) NSABC Israel Br0283 AVbCMF dagger 4 55 0. 63) Austrian BCSG 3 (1984) CMFVA 6 121 1. 35) Combined Studies Doxorubicin Hydrochloride-Containing Regimen 2157 0. 03) CMF 1353 Figure 1. Meta-analysis of Disease-Free Survival Figure 2. Meta-analysis of Overall Survival Figure 1 Figure 2.
REFERENCES
“Hazardous Drugs”. OSHA http://www.osha.gov/SLTC/hazardousdrugs/index.html

Athenex Pharmaceutical Division, LLC.

DOXORUBICIN HYDROCHLORIDE- doxorubicin hydrochloride_injection, solution Product manual source documgent