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Doxil

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Doxil

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Cardiac Toxicity

Special attention must be given to the risk of myocardial damage from cumulative doses of doxorubicin HCl. Acute left ventricular failure may occur with doxorubicin, particularly in patients who have received a total cumulative dosage of doxorubicin exceeding the currently recommended limit of 550 mg/m². Lower (400 mg/m²) doses appear to cause heart failure in patients who have received radiotherapy to the mediastinal area or concomitant therapy with other potentially cardiotoxic agents such as cyclophosphamide.

Prior use of other anthracyclines or anthracenodiones should be included in calculations of total cumulative dosage. Congestive heart failure or cardiomyopathy may be encountered after discontinuation of anthracycline therapy. Patients with a history of cardiovascular disease should be administered DOXIL (doxorubicin hcl liposome injection) only when the potential benefit of treatment outweighs the risk.

Cardiac function should be carefully monitored in patients treated with DOXIL (doxorubicin hcl liposome injection) . The most definitive test for anthracycline myocardial injury is endomyocardial biopsy. Other methods, such as echocardiography or multigated radionuclide scans, have been used to monitor cardiac function during anthracycline therapy. Any of these methods should be employed to monitor potential cardiac toxicity in patients treated with DOXIL (doxorubicin hcl liposome injection) . If these test results indicate possible cardiac injury associated with DOXIL (doxorubicin hcl liposome injection) therapy, the benefit of continued therapy must be carefully weighed against the risk of myocardial injury.

In a clinical study in patients with advanced breast cancer, 250 patients received DOXIL (doxorubicin hcl liposome injection) at starting dose of 50 mg/m² every 4 weeks. At all cumulative anthracycline doses between 450-500 mg/m², or between 500-550 mg/m², the risk of cardiac toxicity for patients treated with DOXIL (doxorubicin hcl liposome injection) was 11%. In this study, cardiotoxicity was defined as a decrease of > 20% from baseline if the resting left ventricular ejection fraction (LVEF) remained in the normal range, or a decrease of > 10% if the resting LVEF became abnormal (less than the institutional lower limit of normal). The data on left ventricular ejection fraction (LVEF) defined cardiotoxicity and congestive heart failure (CHF) are in the table below.

Table 5: Number of Patients With Advanced Breast Cancer

  DOXIL (n=250)
Patients who Developed Cardiotoxicity (LVEF Defined) 10
Cardiotoxicity (With Signs & Symptoms of CHF) 0
Cardiotoxicity (no Signs & Symptoms of CHF) 10
Patients With Signs and Symptoms of CHF Only 2

In the randomized multiple myeloma study, the incidence of heart failure events (ventricular dysfunction, cardiac failure, right ventricular failure, congestive cardiac failure, chronic cardiac failure, acute pulmonary edema and pulmonary edema) was similar in the DOXIL (doxorubicin hcl liposome injection) +bortezomib group and the bortezomib monotherapy group, 3% in each group. LVEF decrease was defined as an absolute decrease of ≥ 15% over baseline or a ≥ 5% decrease below the institutional lower limit of normal. Based on this definition, 25 patients in the bortezomib arm (8%) and 42 patients in the DOXIL (doxorubicin hcl liposome injection) + bortezomib arm (13%) experienced a reduction in LVEF.

Infusion Reactions

Acute infusion-related reactions were reported in 7.1% of patients treated with DOXIL (doxorubicin hcl liposome injection) in the randomized ovarian cancer study. These reactions were characterized by one or more of the following symptoms: flushing, shortness of breath, facial swelling, headache, chills, chest pain, back pain, tightness in the chest and throat, fever, tachycardia, pruritus, rash, cyanosis, syncope, bronchospasm, asthma, apnea, and hypotension. In most patients, these reactions resolve over the course of several hours to a day once the infusion is terminated. In some patients, the reaction resolved when the rate of infusion was slowed. In this study, two patients treated with DOXIL (doxorubicin hcl liposome injection) (0.8%) discontinued due to infusion-related reactions. In clinical studies, six patients with AIDS-related Kaposi's sarcoma (0.9%) and 13 (1.7%) solid tumor patients discontinued DOXIL (doxorubicin hcl liposome injection) therapy because of infusion-related reactions.

Serious and sometimes life-threatening or fatal allergic/anaphylactoid-like infusion reactions have been reported. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use.

The majority of infusion-related events occurred during the first infusion. Similar reactions have not been reported with conventional doxorubicin and they presumably represent a reaction to the DOXIL (doxorubicin hcl liposome injection) liposomes or one of its surface components.

The initial rate of infusion should be 1 mg/min to help minimize the risk of infusion reactions [see DOSAGE AND ADMINISTRATION].

Myelosuppression

Because of the potential for bone marrow suppression, careful hematologic monitoring is required during use of DOXIL (doxorubicin hcl liposome injection) , including white blood cell, neutrophil, platelet counts, and Hgb/Hct. With the recommended dosage schedule, leukopenia is usually transient. Hematologic toxicity may require dose reduction or delay or suspension of DOXIL (doxorubicin hcl liposome injection) therapy. Persistent severe myelosuppression may result in superinfection, neutropenic fever, or hemorrhage. Development of sepsis in the setting of neutropenia has resulted in discontinuation of treatment and, in rare cases, death.

DOXIL (doxorubicin hcl liposome injection) may potentiate the toxicity of other anticancer therapies. In particular, hematologic toxicity may be more severe when DOXIL (doxorubicin hcl liposome injection) is administered in combination with other agents that cause bone marrow suppression.

In patients with relapsed ovarian cancer, myelosuppression was generally moderate and reversible. In the three single-arm studies, anemia was the most common hematologic adverse reaction (52.6%), followed by leukopenia (WBC < 4,000 mm³; 42.2%), thrombocytopenia (24.2%), and neutropenia (ANC < 1,000; 19.0%). In the randomized study, anemia was the most common hematologic adverse reaction (40.2%), followed by leukopenia (WBC < 4,000 mm³; 36.8%), neutropenia (ANC < 1,000; 35.1%), and thrombocytopenia (13.0%) [see ADVERSE REACTIONS].

In patients with relapsed ovarian cancer, 4.6% received G-CSF (or GM-CSF) to support their blood counts [see DOSAGE AND ADMINISTRATIONS].

For patients with AIDS-related Kaposi's sarcoma who often present with baseline myelosuppression due to such factors as their HIV disease or concomitant medications, myelosuppression appears to be the dose-limiting adverse reaction at the recommended dose of 20 mg/m² [see ADVERSE REACTIONS]. Leukopenia is the most common adverse reaction experienced in this population; anemia and thrombocytopenia can also be expected. Sepsis occurred in 5% of patients; for 0.7% of patients the event was considered possibly or probably related to DOXIL (doxorubicin hcl liposome injection) . Eleven patients (1.6%) discontinued study because of bone marrow suppression or neutropenia.

Table 10 presents data on myelosuppression in patients with multiple myeloma receiving DOXIL and bortezomib in combination [see ADVERSE REACTIONS].

Hand-Foot Syndrome (HFS)

In the randomized ovarian cancer study, 50.6% of patients treated with DOXIL (doxorubicin hcl liposome injection) at 50 mg/m² every 4 weeks experienced HFS (developed palmar-plantar skin eruptions characterized by swelling, pain, erythema and, for some patients, desquamation of the skin on the hands and the feet), with 23.8% of the patients reporting HFS Grade 3 or 4 events. Ten subjects (4.2%) discontinued treatment due to HFS or other skin toxicity. HFS toxicity grades are described above [see definitions of HFS grades in DOSAGE AND ADMINISTRATION].

Among 705 patients with AIDS-related Kaposi's sarcoma treated with DOXIL (doxorubicin hcl liposome injection) at 20 mg/m² every 2 weeks, 24 (3.4%) developed HFS, with 3 (0.9%) discontinuing.

In the randomized multiple myeloma study, 19% of patients treated with DOXIL (doxorubicin hcl liposome injection) at 30 mg/m² every three weeks experienced HFS.

HFS was generally observed after 2 or 3 cycles of treatment but may occur earlier. In most patients the reaction is mild and resolves in one to two weeks so that prolonged delay of therapy need not occur. However, dose modification may be required to manage HFS [see DOSAGE AND ADMINISTRATION]. The reaction can be severe and debilitating in some patients and may require discontinuation of treatment.

Radiation Recall Reaction

Recall reaction has occurred with DOXIL (doxorubicin hcl liposome injection) administration after radiotherapy.

Fetal Mortality

Pregnancy Category D

DOXIL (doxorubicin hcl liposome injection) can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies in pregnant women. If DOXIL (doxorubicin hcl liposome injection) 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. If pregnancy occurs in the first few months following treatment with DOXIL (doxorubicin hcl liposome injection) , the prolonged half-life of the drug must be considered. Women of childbearing potential should be advised to avoid pregnancy during treatment with Doxil (doxorubicin hcl liposome injection) . [see Use in Specific Populations].

Toxicity Potentiation

The doxorubicin in DOXIL (doxorubicin hcl liposome injection) may potentiate the toxicity of other anticancer therapies. Exacerbation of cyclophosphamide-induced hemorrhagic cystitis and enhancement of the hepatotoxicity of 6-mercaptopurine have been reported with the conventional formulation of doxorubicin HCl. Radiation-induced toxicity to the myocardium, mucosae, skin, and liver have been reported to be increased by the administration of doxorubicin HCl.

Monitoring: Laboratory Tests

Complete blood counts, including platelet counts, should be obtained frequently and at a minimum prior to each dose of DOXIL (doxorubicin hcl liposome injection) [see WARNINGS and PRECAUTIONS].

Non-Clinical Toxicology

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Although no studies have been conducted with DOXIL (doxorubicin hcl liposome injection) , doxorubicin HCl and related compounds have been shown to have mutagenic and carcinogenic properties when tested in experimental models.

STEALTH® liposomes without drug were negative when tested in Ames, mouse lymphoma and chromosomal aberration assays in vitro, and mammalian micronucleus assay in vivo.

The possible adverse effects on fertility in males and females in humans or experimental animals have not been adequately evaluated. However, DOXIL (doxorubicin hcl liposome injection) resulted in mild to moderate ovarian and testicular atrophy in mice after a single dose of 36 mg/kg (about twice the 50 mg/m² human dose on a mg/m² basis). Decreased testicular weights and hypospermia were present in rats after repeat doses ≥ 0.25 mg/kg/day (about one thirtieth the 50 mg/m² human dose on a mg/m² basis), and diffuse degeneration of the seminiferous tubules and a marked decrease in spermatogenesis were observed in dogs after repeat doses of 1 mg/kg/day (about one half the 50 mg/m² human dose on a mg/m² basis).

Use In Specific Populations

Pregnancy

Pregnancy Category D

[see WARNINGS and PRECAUTIONS].

DOXIL (doxorubicin hcl liposome injection) is embryotoxic at doses of 1 mg/kg/day in rats and is embryotoxic and abortifacient at 0.5 mg/kg/day in rabbits (both doses are about one-eighth the 50 mg/m² human dose on a mg/m² basis). Embryotoxicity was characterized by increased embryo-fetal deaths and reduced live litter sizes.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs, including anthracyclines, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from DOXIL (doxorubicin hcl liposome injection) , mothers should discontinue nursing prior to taking this drug.

Pediatric Use

The safety and effectiveness of DOXIL (doxorubicin hcl liposome injection) in pediatric patients have not been established.

Geriatric Use

Of the patients treated with DOXIL (doxorubicin hcl liposome injection) in the randomized ovarian cancer study, 34.7% (n=83) were 65 years of age or older while 7.9% (n=19) were 75 years of age or older. Of the 318 patients treated with DOXIL (doxorubicin hcl liposome injection) in combination with bortezomib for multiple myeloma, 37% were 65 years of age or older and 8% were 75 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients.

Hepatic Impairment

The pharmacokinetics of DOXIL (doxorubicin hcl liposome injection) has not been adequately evaluated in patients with hepatic impairment. Doxorubicin is eliminated in large part by the liver. Thus, DOXIL (doxorubicin hcl liposome injection) dosage should be reduced in patients with impaired hepatic function [see DOSAGE AND ADMINISTRATION].

Prior to DOXIL (doxorubicin hcl liposome injection) administration, evaluation of hepatic function is recommended using conventional clinical laboratory tests such as SGOT, SGPT, alkaline phosphatase, and bilirubin [see DOSAGE AND ADMINISTRATION].

Last reviewed on RxList: 7/8/2008
This monograph has been modified to include the generic and brand name in many instances.

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