Doxorubicin Hydrochloride: Package Insert and Label Information (Page 3 of 5)

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.

8.6 Hepatic Impairment

The clearance of doxorubicin hydrochloride 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)]. Reduce the dose of Doxorubicin Hydrochloride Injection in patients with serum total bilirubin levels greater than 1.2 mg/dL [see Dosage and Administration (2.4), Warnings and Precautions (5.5)].

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/m2) 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.

11 DESCRIPTION

Doxorubicin hydrochloride, USP is an anthracycline topoisomerase inhibitor isolated from cultures of Streptomyces peucetius var. caesius. The chemical name of doxorubicin hydrochloride, USP is: 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-α-L-lyxo -hexopyranosyl)oxy]-7,8,9,10­ tetrahydro-6,8,11-trihydroxy-8-(hydroxylacetyl)-1-methoxy-, hydrochloride (8S-cis)-. The molecular weight of doxorubicin hydrochloride, USP is 579.98, and the molecular formula is C27 H29 NO11 •HCl. The chemical structure of doxorubicin hydrochloride, USP is:

1

Doxorubicin Hydrochloride Injection USP, for intravenous use, is a clear red, sterile, isotonic aqueous solution provided in vials containing 10 mg/5 mL doxorubicin hydrochloride, USP (equivalent to 9.37 mg of doxorubicin free base), 20 mg/10 mL doxorubicin hydrochloride, USP (equivalent to 18.74 mg of doxorubicin free base), 50 mg/25 mL doxorubicin hydrochloride, USP (equivalent to 46.86 mg of doxorubicin free base), or 200 mg/100 mL of doxorubicin hydrochloride, USP (equivalent to 187.43 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, USP. Inactive ingredients include Sodium Chloride 0.9%, USP, and Water for Injection, USP, quantity sufficient. The pH of the solution is adjusted to 3 with hydrochloric acid, USP.

12 CLINICAL PHARMACOLOGY

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 hydrochloride. Intercalation inhibits nucleotide replication and action of DNA and RNA polymerases. The interaction of doxorubicin hydrochloride with topoisomerase II to form DNA-cleavable complexes appears to be an important mechanism of doxorubicin hydrochloride cytocidal activity.

12.3 Pharmacokinetics

Pharmacokinetic studies conducted in patients with various types of tumors have shown that doxorubicin hydrochloride follows multiphasic disposition after intravenous injection. In four patients, doxorubicin hydrochloride demonstrated dose-independent pharmacokinetics across a dose range of 30 mg/m2 to 70 mg/m2.

Distribution

The distribution half-life is approximately 5 minutes. Steady-state distribution volume ranges from 809 L/m2 to 1214 L/m2. Binding of doxorubicin hydrochloride and its major metabolite, doxorubicinol, to plasma proteins is 75% and is independent of plasma concentration of doxorubicin hydrochloride up to 1.1 mcg/mL.

Doxorubicin hydrochloride does not cross the blood brain barrier.

Elimination

Plasma clearance is ranges from 324 mL/min/m2 to 809 mL/min/m2. The terminal half-life is 20 hours to 48 hours.

Metabolism

Doxorubicin hydrochloride 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 hydrochloride. The relative exposure of doxorubicinol, i.e., the ratio between the AUC of doxorubicinol and the AUC of doxorubicin hydrochloride is approximately 0.5.

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 hydrochloride 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/m2 to 75 mg/m2 of doxorubicin hydrochloride to 60 patients ranging from 2 months to 20 years, doxorubicin hydrochloride clearance averaged 1443 ± 114 mL/min/m2. Further analysis demonstrated that clearance in 52 patients ranging from 2 to 20 years (1540 mL/min/m2) was increased compared with adults. However, clearance in infants younger than 2 years of age (813 mL/min/m2) was decreased compared with older patients (ranging from 2 to 20 years) and approached the range of clearance values determined in adults [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 hydrochloride clearance in men compared to women (1088 mL/min/m2 versus 433 mL/min/m2). However, the terminal half-life of doxorubicin hydrochloride was longer in men compared to women (54 versus 35 hours).

Patients with Hepatic Impairment

The clearance of doxorubicin hydrochloride and doxorubicinol was reduced in patients with elevated serum total bilirubin concentrations [see Dosage and Administration (2.4), Warnings and Precautions (5.5)].

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Doxorubicin hydrochloride treatment can increase the risk of secondary malignancies based on postmarketing reports [see Warnings and Precautions (5.2)]. Doxorubicin hydrochloride was mutagenic in the in vitro Ames assay, and clastogenic in multiple in vitro assays (CHO cell, V79 hamster cell, human lymphoblast, and SCE assays) and the in vivo mouse micronucleus assay.

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.

14 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: 0.82, 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

Regimens

No. of Cycles

No. of

Doxorubicin Hydrochloride-Containing Regimens vs CMF

(starting year)

Patients

HR** (95% CI)

DFS

OS

NSABP B-15 (1984)

AC CMF

4 6

1562* 776

0.93 (0.82, 1.06)

0.97 (0.83, 1.12)

SECSG 2 (1976)

FAC CMF

6 6

260 268

0.86 (0.66, 1.13)

0.93 (0.69, 1.26)

ONCOFRANCE (1978)

FACV CMF

12 12

138 113

0.71 (0.49, 1.03)

0.65 (0.44, 0.96)

SE Sweden BCG A (1980)

AC

CMF

6

6

21

22

0.59 (0.22, 1.61)

0.53 (0.21, 1.37)

NSABC Israel Br0283 (1983)

AVbCMF

CMF

4

6

6

55

50

0.91 (0.53, 1.57)

0.88 (0.47, 1.63)

Austrian BCSG 3 (1984)

CMFVA CMF

6 8

121 124

1.07 (0.73, 1.55)

0.93 (0.64, 1.35)

Combined Studies

Doxorubicin Hydrochloride-Containing Regimen

CMF

2157 1353

0.91 (0.82, 1.01)

0.91 (0.81, 1.03)

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

* 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.

** 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.

Patients received alternating cycles of AVb and CMF.

2
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Figure 1. Meta-analysis of Disease-Free Survival

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Figure 2. Meta-analysis of Overall Survival

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