Doxorubicin Hydrochloride 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.

Pharmacokinetics

Pharmacokinetic studies, determined in patients with various types of tumors undergoing either single or multi-agent therapy have shown that doxorubicin follows a multiphasic disposition after intravenous injection. In four patients, doxorubicin has demonstrated dose-independent pharmacokinetics in the dose range of 30 to 70 mg/m2.

Pharmacokinetics in Special Populations

General

Doxorubicin should be administered only under the supervision of qualified physicians experienced in the use of cytotoxic therapy. Patients should recover from acute toxicities of prior cytotoxic treatment (such as stomatitis, neutropenia, thrombocytopenia, and generalized infections) before beginning treatment with doxorubicin. Also, initial treatment with doxorubicin should be preceded by a careful baseline assessment of blood counts; serum levels of total bilirubin, AST, and creatinine; and cardiac function as measured by left ventricular ejection function (LVEF). Patients should be carefully monitored during treatment for possible clinical complications due to myelosuppression. Supportive care may be necessary for the treatment of severe neutropenia and severe infectious complications. Monitoring for potential cardiotoxicity is also important, especially with greater cumulative exposure to doxorubicin. Doxorubicin may potentiate the toxicity of other anticancer therapies (see PRECAUTIONS, Drug Interactions).

Cardiac Function

Cardiotoxicity is a known risk of anthracycline treatment. Anthracycline-induced cardiotoxicity may be manifested by early (or acute) or late (delayed) events. Early cardiotoxicity of doxorubicin consists mainly of sinus tachycardia and/or electrocardiogram (ECG) abnormalities such as non-specific ST-T wave changes. Tachyarrhythmias, including premature ventricular contractions and ventricular tachycardia, bradycardia, as well as atrioventricular and bundle-branch block have also been reported. These effects do not usually predict subsequent development of delayed cardiotoxicity, are rarely of clinical importance, and are generally not considered an indication for the suspension of doxorubicin treatment.

Delayed cardiotoxicity usually develops late in the course of therapy with doxorubicin or within 2 to 3 months after treatment termination, but later events, several months to years after completion of treatment, have also been reported. Delayed cardiomyopathy is manifested by a reduction in LVEF and/or signs and symptoms of congestive heart failure (CHF) such as tachycardia, dyspnea, pulmonary edema, dependent edema, cardiomegaly and hepatomegaly, oliguria, ascites, pleural effusion, and gallop rhythm.  Subacute effects such as pericarditis/myocarditis have also been reported. Life- threatening CHF is the most severe form of anthracycline-induced cardiomyopathy and represents the cumulative dose-limiting toxicity of the drug.

The probability of developing impaired myocardial function, based on a combined index of signs, symptoms, and decline in left ventricular ejection fraction (LVEF) is estimated to be 1 to 2% at a total cumulative dose of 300 mg/m2 of doxorubicin, 3 to 5% at a dose of 400 mg/m2, 5 to 8% at a dose of 450 mg/m2, and 6 to 20% at a dose of 500 mg/m2, given in a schedule of a bolus injection once every 3 weeks. In a retrospective review, the probability of developing congestive heart failure was reported to be 5/168 (3%) at a cumulative dose of 430 mg/m2 of doxorubicin, 8/110 (7%) at 575 mg/m2, and 3/14 (21%) at 728 mg/m2. In a prospective study of doxorubicin in combination with cyclophosphamide, fluorouracil, and/or vincristine in patients with breast cancer or small cell lung cancer, the probability of CHF at various cumulative doses of doxorubicin was 1.5% at 300 mg/m2, 4.9% at 400 mg/m2, 7.7% at 450 mg/m2, and 20.5% at 500 mg/m2. The risk of developing CHF increases rapidly with increasing total cumulative doses of doxorubicin in excess of 400 mg/m2.

Cardiotoxicity may occur at lower doses in patients with prior mediastinal/pericardial irradiation, concomitant use of other cardiotoxic drugs, doxorubicin exposure at an early age, and advanced age. Data also suggest that pre-existing heart disease is a cofactor for increased risk of doxorubicin cardiotoxicity. In such cases, cardiac toxicity may occur at doses lower than the recommended cumulative dose of doxorubicin. Studies have suggested that concomitant administration of doxorubicin and calcium channel entry blockers or cardiotoxic drugs, especially those with long half-lives, e.g., trastuzumab) may increase the risk of doxorubicin cardiotoxicity (see PRECAUTIONS, General; DOSAGE AND ADMINISTRATION). The total dose of doxorubicin administered to the individual patient should also take into account previous or concomitant therapy with related compounds such as daunorubicin, idarubicin and mitoxantrone. Although not formally tested, it is probable that the toxicity of doxorubicin and other anthracyclines or anthracenediones is additive. Cardiomyopathy and/or congestive heart failure may be encountered several months or years after discontinuation of doxorubicin therapy.

The risk of acute manifestations of doxorubicin cardiotoxicity in pediatric patients may be as much or lower than in adults. Pediatric patients appear to be at particular risk for developing delayed cardiac toxicity in that doxorubicin-induced cardiomyopathy impairs myocardial growth as pediatric patients mature, subsequently leading to possible development of congestive heart failure during early adulthood. As many as 40% of pediatric patients may have subclinical cardiac dysfunction and 5 to 10% of pediatric patients may develop congestive heart failure on long-term follow-up. This late cardiac toxicity may be related to the dose of doxorubicin. The longer the length of follow-up, the greater the increase in the detection rate. Treatment of doxorubicin-induced congestive heart failure includes the use of digitalis, diuretics, after load reducers such as angiotensin I converting enzyme (ACE) inhibitors, low salt diet, and bed rest. Such intervention may relieve symptoms and improve the functional status of the patient.

Hematologic Toxicity

As with other cytotoxic agents, doxorubicin may produce myelosuppression. Myelosuppression requires careful monitoring. Total and differential WBC, red blood cell (RBC), and platelet counts should be assessed before and during each cycle of therapy with doxorubicin. A dose-dependent, reversible leukopenia and/or granulocytopenia (neutropenia) are the predominant manifestations of doxorubicin hematologic toxicity and are the most common acute dose-limiting toxicities of this drug. With the recommended dose schedule, leukopenia is usually transient, reaching its nadir 10 to 14 days after treatment with recovery usually occurring by the 21st day. Thrombocytopenia and anemia may also occur. Clinical consequences of severe myelosuppression include fever, infections, sepsis/septicemia, septic shock, hemorrhage, tissue hypoxia, or death.

Secondary Leukemia

The occurrence of secondary AML or MDS has been reported most commonly in patients treated with chemotherapy regimens containing anthracyclines (including doxorubicin) and DNA-damaging antineoplastic agents, in combination with radiotherapy, when patients have been heavily pretreated with cytotoxic drugs, or when doses of anthracyclines have been escalated. Such cases generally have a 1–3 year latency period. The rate of developing secondary AML or MDS has been estimated in an analysis of 8563 patients with early breast cancer treated in 6 studies conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP), including NSABP B-15. Patients in these studies received standard doses of doxorubicin and standard or escalated doses of cyclophosphamide (AC) adjuvant chemotherapy and were followed for 61,810 patient years. Among 4483 such patients who received conventional doses of AC, 11 cases of AML or MDS were identified, for an incidence of 0.32 cases per 1000 patient years (95% CI, 0.16 to 0.57) and a cumulative incidence at 5 years of 0.21% (95% CI, 0.11 to 0.41%). In another analysis of 1474 patients with breast cancer who received adjuvant treatment with doxorubicin-containing regimens in clinical trials conducted at University of Texas M.D. Anderson Cancer Center, the incidence was estimated at 1.5% at 10 years. In both experiences, patients who received regimens with higher cyclophosphamide dosages, who received radiotherapy, or who were aged 50 or older had an increased risk of secondary AML or MDS.

Pediatric patients are also at risk of developing secondary AML.

Effects at Site of Injection

Phlebosclerosis may result from an injection into a small vessel or from repeated injections into the same vein. Following the recommended administration procedures may minimize the risk of phlebitis/thrombophlebitis at the injection site (see DOSAGE AND ADMINISTRATION, Instruction for Use/Handling).

Extravasation

On intravenous administration of doxorubicin, extravasation may occur with or without an accompanying stinging or burning sensation, even if blood returns well on aspiration of the infusion needle. If any signs or symptoms of extravasation have occurred, the injection or infusion should be immediately terminated and restarted in another vein (see DOSAGE AND ADMINISTRATION).

Hepatic Impairment

Since metabolism and excretion of doxorubicin occurs predominantly by the hepatobiliary route, toxicity of recommended doses of doxorubicin can be enhanced by hepatic impairment; therefore, prior to individual dosing, evaluation of hepatic function is recommended using conventional laboratory tests such as SGOT, SGPT, alkaline phosphatase, and bilirubin (see DOSAGE AND ADMINISTRATION).

Immunosuppressant Effects/Increased Susceptibility to Infections

Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including doxorubicin, may result in serious or fatal infections. Vaccination with a live vaccine should be avoided in patients receiving doxorubicin. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.

Pregnancy Category D

Doxorubicin can cause fetal harm when administered to a pregnant woman. Doxorubicin was teratogenic and embryotoxic at doses of 0.8 mg/kg/day (about 1/13 the recommended human dose on a body surface area basis) 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 1/14 the recommended human dose on a body surface area basis) in rabbits when administered during the period of organogenesis.

There are no adequate and well-controlled studies in pregnant women. If doxorubicin is to be used during pregnancy, or if the patient becomes pregnant during therapy, the patient should be apprised of the potential hazard to the fetus. Women of childbearing age should be advised to avoid becoming pregnant.

General

Doxorubicin is not an anti-microbial agent. Doxorubicin is emetigenic. Antiemetics may reduce nausea and vomiting; prophylactic use of antiemetics should be considered before administration of doxorubicin, particularly when given in conjunction with other emetigenic drugs. Doxorubicin should not be administered in combination with other cardiotoxic agents unless the patient’s cardiac function is closely monitored. Patients receiving doxorubicin after stopping treatment with other cardiotoxic agents, especially those with long half-lives such as trastuzumab, may also be at an increased risk of developing cardiotoxicity. Physicians should avoid doxorubicin-based therapy for up to 24 weeks after stopping trastuzumab when possible. If doxorubicin used before this time, careful monitoring of cardiac function is recommended (see WARNINGS,  DOSAGE AND ADMINISTRATION).

Information for Patients

Patients should be informed of the expected adverse effects of doxorubicin, including gastrointestinal symptoms (nausea, vomiting, diarrhea, and stomatitis) and potential neutropenic complications. Patients should consult their physician if vomiting, dehydration, fever, evidence of infection, symptoms of CHF, or injection-site pain occurs following therapy with doxorubicin. Patients should be informed that they will almost certainly develop alopecia. Patients should be advised that their urine may appear red for 1 to 2 days after administration of doxorubicin and that they should not be alarmed. Patients should understand that there is a risk of irreversible myocardial damage associated with treatment with doxorubicin, as well as a risk of treatment-related leukemia. Because doxorubicin may induce chromosomal damage in sperm, men undergoing treatment with doxorubicin should use effective contraceptive methods. Women treated with doxorubicin may develop irreversible amenorrhea, or premature menopause.

Drug Interactions

Doxorubicin is extensively metabolized by the liver. Changes in hepatic function induced by concomitant therapies may affect doxorubicin metabolism, pharmacokinetics, therapeutic efficacy, and/or toxicity. Toxicities associated with doxorubicin, especially hematologic and gastrointestinal events, may be increased when doxorubicin is used in combination with other cytotoxic drugs.

Laboratory Tests

Initial treatment with doxorubicin requires observation of the patient and periodic monitoring of complete blood counts, hepatic function tests, and left ventricular ejection fraction (see WARNINGS). Abnormalities of hepatic function tests may occur. Like other cytotoxic drugs, doxorubicin may induce "tumor-lysis syndrome" and hyperuricemia in patients with rapidly growing tumors. Blood uric acid levels, potassium, calcium, phosphate, and creatinine should be evaluated after initial treatment. Hydration, urine alkalinization, and prophylaxis with allopurinol to prevent hyperuricemia may minimize potential complications of tumor-lysis syndrome.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Carcinogenicity studies have not been conducted with doxorubicin. Secondary acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) have been reported in patients treated with doxorubicin-containing combination chemotherapy regimens (see WARNINGS). Pediatric patients treated with doxorubicin or other topoisomerase II inhibitors are at risk for developing acute myelogenous leukemia and other neoplasms. Doxorubicin 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 decreased fertility in female rats at the doses of 0.05 and 0.2 mg/kg/day (about 1/200 and 1/50 the recommended human dose on a body surface area basis) when administered from 14 days before mating through late gestation period. A single i.v. dose of doxorubicin at 0.1 mg/kg (about 1/100 the recommended human dose on a body surface area basis) was toxic to male reproductive organs, producing testicular atrophy and oligospermia in rats. Doxorubicin is mutagenic as it induced DNA damage in rabbit spermatozoa and dominant lethal mutations in mice. Therefore, doxorubicin may potentially induce chromosomal damage in human spermatozoa. Oligospermia or azoospermia were evidenced in men treated with doxorubicin, mainly in combination therapies. Men undergoing doxorubicin treatment should use effective contraceptive methods.

Doxorubicin was toxic to male reproductive organs in animal studies, producing testicular atrophy, diffuse degeneration of the seminiferous tubules, and hypospermia. Doxorubicin is mutagenic as it induces DNA damage in rabbit spermatozoa and dominant lethal mutations in mice. Therefore, doxorubicin can potentially induce chromosomal damage in human spermatozoa. Oligospermia or azoospermia were evidenced in men treated with doxorubicin, mainly in combination therapies. This effect may be permanent. However, sperm counts have been reported to return to normal levels in some instances. This may occur several years after the end of therapy. Men undergoing doxorubicin treatment should use effective contraceptive methods.

In women, doxorubicin may cause infertility during the time of drug administration. Doxorubicin may cause amenorrhea. Ovulation and menstruation may return after termination of therapy, although premature menopause can occur. Recovery of menses is related to age at treatment.

Secondary acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) have been reported in patients treated with anthracycline-containing adjuvant combination chemotherapy regimens (see WARNINGS, Hematologic Toxicity).

Pregnancy Category D

(see WARNINGS.)

Nursing Mothers

Doxorubicin and its major metabolite, doxorubicinol, have been detected in the milk of at least one lactating patient (see CLINICAL PHARMACOLOGY, Pharmacokinetics). Because of the potential for serious adverse reactions in nursing infants from doxorubicin, mothers should be advised to discontinue nursing during doxorubicin therapy.

Pediatric Use

Pediatric patients are at increased risk for developing delayed cardiotoxicity. Follow-up cardiac evaluations are recommended periodically to monitor for this delayed cardiotoxicity (see WARNINGS). Doxorubicin, as a component of intensive chemotherapy regimens administered to pediatric patients, may contribute to prepubertal growth failure. It may also contribute to gonadal impairment, which is usually temporary. Pediatric patients treated with doxorubicin or other topoisomerase II inhibitors are at risk for developing acute myelogenous leukemia and other neoplasms. Pediatric patients receiving concomitant doxorubicin and actinomycin-D have manifested acute "recall" pneumonitis at variable times after local radiation therapy.

Geriatric Use

An estimated 4600 patients who were 65 and over were included in the reported clinical experience of doxorubicin use for various indications. No overall differences in safety and effectiveness were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out. The decision to use doxorubicin in the treatment of older patients should be based upon a consideration of overall performance status and concurrent illnesses, in addition to age of the individual patient.

Cardiotoxicity

(see WARNINGS).

Cutaneous

Reversible complete alopecia occurs in most cases. Hyperpigmentation of nailbeds and dermal creases, primarily in pediatric patients, and onycholysis have been reported in a few cases. Radiation recall reaction has occurred with doxorubicin administration. Rash, itching, or photosensitivity may occur.

Gastrointestinal

Acute nausea and vomiting occurs frequently and may be severe. This may be alleviated by antiemetic therapy. Mucositis (stomatitis and esophagitis) may occur within 5 to 10 days of beginning therapy, and most patients recover from this adverse event within another 5 to 10 days. The effect may be severe, leading to ulceration and represents a site of origin for severe infections. The dosage regimen consisting of administration of doxorubicin on three successive days results in greater incidence and severity of mucositis. Ulceration and necrosis of the colon, especially the cecum, may occur, leading to bleeding or severe infections which can be fatal. This reaction has been reported in patients with acute non-lymphocytic leukemia treated with a 3-day course of doxorubicin combined with cytarabine. Anorexia, abdominal pain, dehydration, diarrhea, and hyperpigmentation of the oral mucosa have been occasionally reported.

Hematologic

(see WARNINGS).

Hypersensitivity

Fever, chills, and urticaria have been reported occasionally. Anaphylaxis may occur. A case of apparent cross sensitivity to lincomycin has been reported.

Neurological

Peripheral neurotoxicity in the form of local-regional sensory and/or motor disturbances have been reported in patients treated intra-arterially with doxorubicin, mostly in combination with cisplatin. Animal studies have demonstrated seizures and coma in rodents and dogs treated with intra-carotid doxorubicin. Seizures and coma have been reported in patients treated with doxorubicin in combination with cisplatin or vincristine.

Ocular

Conjunctivitis, keratitis, and lacrimation occur rarely.

Other

Malaise/asthenia have been reported.

Adverse Reactions in Patients with Early Breast Cancer Receiving Doxorubicin-Containing Adjuvant Therapy

Safety data were collected from approximately 2300 women who participated in a randomized, open-label trial (NSABP B-15) evaluating the use of AC versus CMF in the treatment of early breast cancer involving axillary lymph nodes. In the safety analysis, the follow-up data from all patients receiving AC were combined (N=1492 evaluable patients) and compared with data from patients receiving conventional CMF (i.e., oral cyclophosphamide; N=739 evaluable patients). The most relevant adverse events reported in this study are provided in Table 2.

Dose Modifications

Patients in the NSABP B-15 study could have dose modifications of AC to 75% of the starting doses for neutropenic fever/infection. When necessary, the next cycle of treatment cycle was delayed until the absolute neutrophil count (ANC) was ≥1000 cells/mm3 and the platelet count was ≥100,000 cells/mm3 and nonhematologic toxicities had resolved.

Doxorubicin dosage must be reduced in case of hyperbilirubinemia as follows:

Reconstitution Directions

It is recommended that doxorubicin be slowly administered into the tubing of a freely running intravenous infusion of Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP. The tubing should be attached to a Butterfly® needle inserted preferably into a large vein. If possible, avoid veins over joints or in extremities with compromised venous or lymphatic drainage. The rate of administration is dependent on the size of the vein, and the dosage. However, the dose should be administered in not less than 3 to 5 minutes. Local erythematous streaking along the vein as well as facial flushing may be indicative of too rapid an administration. A burning or stinging sensation may be indicative of perivenous infiltration and, if this occurs, the infusion should be immediately terminated and restarted in another vein. Perivenous infiltration may occur painlessly.

Doxorubicin should not be mixed with heparin or fluorouracil since it has been reported that these drugs are incompatible to the extent that a precipitate may form. Contact with alkaline solutions should be avoided since this can lead to hydrolysis of doxorubicin. Until specific compatibility data are available, it is not recommended that doxorubicin be mixed with other drugs.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Handling and Disposal

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published. 1-4 There is no general agreement that all the procedures recommended in the guidelines are necessary or appropriate. However, given the toxic nature of this substance, the following protective recommendations are provided:

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Personnel should be trained in good technique for reconstitution and handling.

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Pregnant staff should be excluded from working with this drug.

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Personnel handling doxorubicin should wear protective clothing: goggles, gowns, and disposable gloves and masks.

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A designated area should be defined for reconstitution (preferably under a laminar flow system). The work surface should be protected by disposable, plastic-backed, absorbent paper.

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All items used for reconstitution, administration, or cleaning, including gloves,    should be placed in high-risk waste-disposal bags for high-temperature incineration.

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Spillage or leakage should be treated with dilute sodium hypochlorite (1% available chlorine) solution, preferably by soaking, and then water.

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All cleaning materials should be disposed of as indicated previously.

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In case of skin contact, thoroughly wash the affected area with soap and water or  sodium bicarbonate solution. However, do not abrade the skin by using a scrub brush.

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In case of contact with the eye(s), hold back the eyelid(s) and flush the affected eye(s) with copious amounts of water for at least 15 minutes. Then seek medical evaluation by a physician.

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Always wash hands after removing gloves.

Caregivers of pediatric patients receiving doxorubicin should be counseled to take precautions (such as wearing latex gloves) to prevent contact with the patient’s urine and other body fluids for at least 5 days after each treatment.

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.