1.1 Ovarian Cancer

DOXIL is indicated for the treatment of patients with ovarian cancer whose disease has progressed or recurred after platinum-based chemotherapy.

1.2 AIDS-Related Kaposi's Sarcoma

DOXIL is indicated for the treatment of AIDS-related Kaposi's sarcoma in patients after failure of prior systemic chemotherapy or intolerance to such therapy.

1.3 Multiple Myeloma

DOXIL, in combination with bortezomib, is indicated for the treatment of patients with multiple myeloma who have not previously received bortezomib and have received at least one prior therapy.

2.1 Important Use Information

Do not substitute DOXIL for other doxorubicin hydrochloride products.

Do not administer as an undiluted suspension or as an intravenous bolus [see Warnings and Precautions (5.2)].

2.2 Ovarian Cancer

The recommended dose of DOXIL is 50 mg/m2 intravenously over 60 minutes every 28 days until disease progression or unacceptable toxicity.

2.3 AIDS-Related Kaposi's Sarcoma

The recommended dose of DOXIL is 20 mg/m2 intravenously over 60 minutes every 21 days until disease progression or unacceptable toxicity.

2.4 Multiple Myeloma

The recommended dose of DOXIL is 30 mg/m2 intravenously over 60 minutes on day 4 of each 21-day cycle for eight cycles or until disease progression or unacceptable toxicity. Administer DOXIL after bortezomib on day 4 of each cycle [see Clinical Studies (14.3)].

2.5 Dose Modifications for Adverse Reactions

Do not increase DOXIL after a dose reduction for toxicity.

For neuropathic pain or peripheral neuropathy, no dosage adjustments are required for DOXIL. Refer to bortezomib manufacturer's prescribing information.

2.6 Preparation and Administration

2.7 Procedure for Proper Handling and Disposal

DOXIL is a cytotoxic drug. Follow applicable special handling and disposal procedures.1 If DOXIL comes into contact with skin or mucosa, immediately wash thoroughly with soap and water.

5.1 Cardiomyopathy

Doxorubicin hydrochloride can cause myocardial damage, including acute left ventricular failure. The risk of cardiomyopathy with doxorubicin hydrochloride is generally proportional to the cumulative exposure. Include prior use of other anthracyclines or anthracenediones in calculations of cumulative dose. The risk of cardiomyopathy may be increased at lower cumulative doses in patients with prior mediastinal irradiation.

In a clinical study in 250 patients with advanced cancer who were treated with DOXIL, the risk of cardiomyopathy was 11% when the cumulative anthracycline dose was between 450 mg/m2 to 550 mg/m2. Cardiomyopathy was defined as >20% decrease in resting left ventricular ejection fraction (LVEF) from baseline where LVEF remained in the normal range or a >10% decrease in LVEF from baseline where LVEF was less than the institutional lower limit of normal. Two percent of patients developed signs and symptoms of congestive heart failure without documented evidence of cardiomyopathy.

Assess left ventricular cardiac function (e.g. MUGA or echocardiogram) prior to initiation of DOXIL, during treatment to detect acute changes, and after treatment to detect delayed cardiomyopathy. Administer DOXIL to patients with a history of cardiovascular disease only when the potential benefit of treatment outweighs the risk.

5.2 Infusion-Related Reactions

Serious, life-threatening, and fatal infusion-related reactions characterized by one or more of the following symptoms can occur with DOXIL: 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. Of 239 patients with ovarian cancer treated with DOXIL in Trial 4, 7% of patients experienced acute infusion-related reactions resulting in dose interruption. All occurred during cycle 1 and none during subsequent cycles. Across multiple studies of DOXIL monotherapy including this and other studies enrolling 760 patients with various solid tumors, 11% of patients had infusion-related reactions. The majority of infusion-related events occurred during the first infusion.

Ensure that medications to treat infusion-related reactions and cardiopulmonary resuscitative equipment are available for immediate use prior to initiation of DOXIL. Initiate DOXIL infusions at a rate of 1 mg/min and increase rate as tolerated [see Dosage and Administration (2.6)]. Withhold DOXIL for Grade 1, 2, or 3 infusion-related reactions and resume at a reduced infusion rate. Discontinue DOXIL for serious or life-threatening infusion-related reactions.

5.3 Hand-Foot Syndrome (HFS)

In Trial 4, the incidence of HFS was 51% of patients in the DOXIL arm and 0.9% of patients in the topotecan arm, including 24% Grade 3 or 4 cases of HFS in DOXIL-treated patients and no Grade 3 or 4 cases in topotecan-treated patients. HFS or other skin toxicity required discontinuation of DOXIL in 4.2% of patients.

HFS was generally observed after 2 or 3 cycles of treatment but may occur earlier. Delay DOXIL for the first episode of Grade 2 or greater HFS [see Dosage and Administration (2.5)]. Discontinue DOXIL if HFS is severe and debilitating.

5.4 Secondary Oral Neoplasms

Secondary oral cancers, primarily squamous cell carcinoma, have been reported from post-marketing experience in patients with long-term (more than one year) exposure to DOXIL. These malignancies were diagnosed both during treatment with DOXIL and up to 6 years after the last dose. Examine patients at regular intervals for the presence of oral ulceration or with any oral discomfort that may be indicative of secondary oral cancer.

The altered pharmacokinetics and preferential tissue distribution of liposomal doxorubicin that contributes to enhanced skin toxicity and mucositis compared to free doxorubicin may play a role in the development of oral secondary malignancies with long-term use.

5.5 Embryo-Fetal Toxicity

Based on findings in animals and its mechanism of action, DOXIL can cause fetal harm when administered to a pregnant woman; avoid the use of DOXIL during the 1st trimester. Available human data do not establish the presence or absence of major birth defects and miscarriage related to the use of doxorubicin hydrochloride during the 2nd and 3rd trimesters. At doses approximately 0.12 times the recommended clinical dose, DOXIL was embryotoxic and abortifacient in rabbits. Advise pregnant women of the potential risk to a fetus. Advise females and males of reproductive potential to use effective contraception during and for 6 months after treatment with DOXIL [see Use in Specific Populations (8.1, 8.3)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates on other clinical trials and may not reflect the rates observed in clinical practice.

The safety data reflect exposure to DOXIL in 1310 patients including: 239 patients with ovarian cancer, 753 patients with AIDS-related Kaposi's sarcoma, and 318 patients with multiple myeloma. The most common adverse reactions (>20%) observed with DOXIL are asthenia, fatigue, fever, nausea, stomatitis, vomiting, diarrhea, constipation, anorexia, hand-foot syndrome, rash and neutropenia, thrombocytopenia and anemia.

The following tables present adverse reactions from clinical trials of single-agent DOXIL in ovarian cancer and AIDS-Related Kaposi's sarcoma.

6.2 Postmarketing Experience

The following additional adverse reactions have been identified during postapproval use of DOXIL. 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.

Musculoskeletal and Connective Tissue Disorders: muscle spasms

Respiratory, Thoracic and Mediastinal Disorders: pulmonary embolism (in some cases fatal)

Hematologic Disorders: Secondary acute myelogenous leukemia

Skin and Subcutaneous Tissue Disorders: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, lichenoid keratosis

Secondary Oral Neoplasms: [see Warnings and Precautions (5.4)].

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

The safety and effectiveness of DOXIL in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of DOXIL conducted in patients with either epithelial ovarian cancer (Trial 4) or with AIDS-related Kaposi's sarcoma (Trial 5) did not contain sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger subjects.

In Trial 6, of 318 patients treated with DOXIL 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.

8.6 Hepatic Impairment

The pharmacokinetics of DOXIL has not been adequately evaluated in patients with hepatic impairment. Doxorubicin is eliminated in large part by the liver. Reduce DOXIL for serum bilirubin of 1.2 mg/dL or higher.

12.1 Mechanism of Action

The active ingredient of DOXIL is doxorubicin hydrochloride. The mechanism of action of doxorubicin hydrochloride is thought to be related to its ability to bind DNA and inhibit nucleic acid synthesis. Cell structure studies have demonstrated rapid cell penetration and perinuclear chromatin binding, rapid inhibition of mitotic activity and nucleic acid synthesis, and induction of mutagenesis and chromosomal aberrations.

12.3 Pharmacokinetics

The pharmacokinetic parameters for total doxorubicin following a single dose of DOXIL infused over 30 minutes are presented in Table 8.

DOXIL displayed linear pharmacokinetics over the range of 10 to 20 mg/m2. Relative to DOXIL doses at or below 20 mg/m2, the pharmacokinetics of total doxorubicin following a 50 mg/m2 DOXIL dose are nonlinear. At this dose, the elimination half-life of DOXIL is longer and the clearance lower compared to a 20 mg/m2 dose.

13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility

Mutagenicity or carcinogenicity studies have not been conducted with DOXIL, however doxorubicin was shown to be 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. The possible adverse effects on fertility in animals have not been adequately evaluated. DOXIL resulted in mild to moderate ovarian and testicular atrophy in mice after administration of a single dose of 36 mg/kg (about 2 times the 50 mg/m2 human dose on a mg/m2 basis). Decreased testicular weights and hypospermia were observed in rats after repeat doses ≥ 0.25 mg/kg/day (about 0.03 times 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 0.4 times the 50 mg/m2 human dose on a mg/m2 basis).

14.1 Ovarian Cancer

DOXIL was studied in three open-label, single-arm, clinical studies of 176 patients with metastatic ovarian cancer (Trials 1, 2, and 3). One hundred forty-five of these patients were refractory to both paclitaxel- and platinum-based chemotherapy regimens, defined as disease progression while on treatment or relapse within 6 months of completing treatment. Patients received DOXIL at 50 mg/m2 every 3 or 4 weeks for 3–6+ cycles in the absence of dose-limiting toxicity or disease progression.

The median age at diagnosis ranged from 52 to 64 years in the 3 studies, and the range was 22 to 85. Most patients had International Federation of Obstetricians and Gynecologists (FIGO) stage III or IV disease (ranging from 83% to 93%). Approximately one third of the patients had three or more prior lines of therapy (ranging from 22% to 33%).

The primary outcome measure was confirmed response rate based on Southwestern Oncology Group (SWOG) criteria for patients refractory to both paclitaxel- and a platinum-containing regimen. Secondary efficacy parameters were time to response, duration of response, and time to progression.

The response rates for the individual single arm trials are given in Table 9 below.

In a pooled analysis of Trials 1–3, the response rate for all patients refractory to paclitaxel and platinum agents was 13.8% (95% CI 8.1% to 19.3%). The median time to progression was 15.9 weeks, the median time to response was 17.6 weeks, and the duration of response was 39.4 weeks.

In Trial 4, a randomized, multicenter, open-label, trial in 474 patients with epithelial ovarian cancer after platinum-based chemotherapy, patients were randomized to receive either DOXIL 50 mg/m2 every 4 weeks (n=239) or topotecan 1.5 mg/m2 daily for 5 consecutive days every 3 weeks (n=235). Patients were stratified according to platinum sensitivity (response to initial platinum-based therapy and a progression-free interval of greater than 6 months off treatment) and the presence of bulky disease (tumor mass greater than 5 cm in size). The primary outcome measure was time to progression (TTP). Other endpoints included overall survival and objective response rate.

Of the 474 patients, the median age at diagnosis was 60 years (range 25 to 87), 90% were FIGO stage III and IV; 46% were platinum sensitive; and 45% had bulky disease.

There was no statistically significant difference in TTP between the two arms. Results are provided in Table 10.

14.2 AIDS-Related Kaposi's Sarcoma

DOXIL was studied in an open-label, single-arm, multicenter study at a dose of 20 mg/m2 every 3 weeks, until disease progression or unacceptable toxicity (Trial 5).

Data is described for a cohort of 77 patients retrospectively identified as having disease progression on prior systemic combination chemotherapy (at least two cycles of a regimen containing at least two of three treatments: bleomycin, vincristine or vinblastine, or doxorubicin) or as being intolerant to such therapy. Forty-nine of the 77 (64%) patients had received prior doxorubicin hydrochloride.

The median time on study was 5.1 months (range 1 day to 15 months). The median cumulative dose of DOXIL was 154 mg/m2 (range 20 to 620 mg/m2). Among the 77 patients, mean age was 38 years (range 24 to 54); 87% were Caucasian, 5% Hispanic, 4% Black, and 4% Asian/Other/Unknown; median CD4 count was 10 cells/mm3; ACTG staging criteria were 78% poor risk for tumor burden, 96% poor risk for immune system, and 58% poor risk for systemic illness at baseline; and mean Karnofsky status score was 74%. All patients had cutaneous or subcutaneous lesions, 40% also had oral lesions, 26% pulmonary lesions, and 14% had lesions of the stomach/intestine.

Two analyses of tumor response were used: one based on investigator assessment of changes in lesions based on modified ACTG criteria (partial response defined as no new lesions, sites of disease, or worsening edema; flattening of ≥50% of previously raised lesions or area of indicator lesions decreasing by ≥50%; and response lasting at least 21 days with no prior progression), and one based on changes in up to five prospectively indentified representative indicator lesions (partial response defined as flattening of ≥50% of previously raised indicator lesions, or >50% decrease in the area of indicator lesions and lasting at least 21 days with no prior progression).

Of the 77 patients, 34 were evaluable for investigator assessment and 42 were evaluable for indicator lesion assessment; analyses of tumor responses are shown in Table 11.

Retrospective efficacy analyses were performed in two trials that had subsets of patients who received single-agent DOXIL and who were on stable antiretroviral therapy for at least 60 days prior to enrollment and until a response was demonstrated. In one trial, 7 of 17 (40%) patients had a durable response (median duration not reached but was longer than 11.6 months). In the second trial, 4 of 11 patients (40%) on a stable antiretroviral therapy demonstrated durable responses.

14.3 Multiple Myeloma

The efficacy of DOXIL in combination with bortezomib was evaluated in Trial 6, a randomized, open-label, international, multicenter study in 646 patients who had not previously received bortezomib and whose disease progressed during or after at least one prior therapy. Patients were randomized (1:1) to receive either DOXIL (30 mg/m2) administered IV on day 4 following bortezomib (1.3 mg/m2 IV on days 1, 4, 8 and 11) or bortezomib alone every 3 weeks for up to 8 cycles or until disease progression or unacceptable toxicity. Patients who maintained a response were allowed to receive further treatment. The median number of cycles in each treatment arm was 5 (range 1–18).

The baseline demographics and clinical characteristics of the patients with multiple myeloma were similar between treatment arms (Table 12).

The primary outcome measure was time to progression (TTP). TTP was defined as the time from randomization to the first occurrence of progressive disease or death due to progressive disease. The combination arm demonstrated significant improvement in TTP. As the prespecified primary objective was achieved at the interim analysis, patients in the bortezomib monotherapy group were then allowed to receive the DOXIL + bortezomib combination. Efficacy results are as shown in Table 13 and Figure 1.

Figure 1- Time to Progression Kaplan-Meier Curve

At the final analysis of survival, 78% of subjects in the DOXIL and bortezomib combination therapy group and 80% of subjects in the bortezomib monotherapy group had died after a median follow up of 8.6 years. The median survival was 33 months in the DOXIL and bortezomib combination therapy group and 31 months in the bortezomib monotherapy group. There was no difference observed in overall survival at the final analysis [HR for DOXIL + bortezomib vs. bortezomib = 0.96 (95% CI 0.80, 1.14)].

Seventy-eight percent of subjects in the DOXIL and bortezomib combination therapy group and 80% of subjects in the bortezomib monotherapy group had received subsequent therapy.

Refrigerate unopened vials of DOXIL at 2°C– 8°C (36°F– 46°F). Do not freeze. Discard unused portion.

DOXIL is a cytotoxic drug. Follow applicable special handling and disposal procedures.1

Cardiomyopathy

Advise patients to contact their healthcare provider if they develop symptoms of heart failure [see Warnings and Precautions (5.1)].

Infusion-Related Reactions

Advise patients about the symptoms of infusion-related reactions and to seek immediate medical attention if they develop any of these symptoms [see Warnings and Precautions (5.2)].

Myelosuppression

Advise patients to contact their healthcare provider for a new onset fever or symptoms of infection.

Hand-Foot Syndrome

Advise patients to notify their healthcare provider if they experience tingling or burning, redness, flaking, bothersome swelling, small blisters, or small sores on the palms of their hands or soles of their feet (symptoms of Hand-Foot Syndrome) [see Warnings and Precautions (5.3)].

Stomatitis

Advise patients to notify their healthcare provider if they develop painful redness, swelling, or sores in the mouth (symptoms of stomatitis).

Embryo-Fetal Toxicity

Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider with a known or suspected pregnancy [see Warnings and Precautions (5.5) and Use in Specific Populations (8.1)].

Advise females and males of reproductive potential to use effective contraception during and for 6 months following treatment with DOXIL [see Use in Specific Populations (8.3)].

Lactation

Advise females not to breastfeed during treatment with DOXIL [see Use in Specific Populations (8.2)].

Infertility

Advise females and males of reproductive potential that DOXIL may cause temporary or permanent infertility [see Use in Specific Populations (8.3)].

Discoloration of Urine and Body Fluids

Inform patients that following DOXIL administration, a reddish-orange color to the urine and other body fluids may be observed. This nontoxic reaction is due to the color of the product and will dissipate as the drug is eliminated from the body.