Doxorubicin liposome

Doxorubicin liposome
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

For patient information regarding Doxorubicin liposome, click here.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];

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Black Box Warning

WARNING: CARDIOMYOPATHY AND INFUSION-RELATED REACTIONS See full prescribing information for complete Boxed Warning. * DOXIL (doxorubicin HCl liposome injection) can cause myocardial damage, including congestive heart failure, as the total cumulative dose of doxorubicin HCl approaches 550 mg/m2. In a clinical study of 250 patients with advanced cancer who were treated with DOXIL, the risk of cardiotoxicity was 11% when the cumulative anthracycline dose was between 450–550 mg/m2. Prior use of other anthracyclines or anthracenediones should be included in calculations of total cumulative dosage. The risk of cardiomyopathy may be increased at lower cumulative doses in patients with prior mediastinal irradiation. Acute infusion-related reactions consisting of, but not limited to, flushing, shortness of breath, facial swelling, headache, chills, back pain, tightness in the chest or throat, and/or hypotension occurred in 11% of patients with solid tumors treated with DOXIL. Serious, life-threatening and fatal infusion reactions have been reported.

Overview

Doxorubicin liposome is an anthracycline that is FDA approved for the treatment of ovarian cancer, AIDS-related Kaposi's sarcoma, and multiple myeloma. There is a Black Box Warning for this drug as shown here. Common adverse reactions include asthenia, fatigue, fever, stomatitis, nausea, vomiting, diarrhea, constipation, anorexia, hand-foot syndrome, rash, neutropenia, thrombocytopenia, and anemia.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Indications

Ovarian Cancer

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

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.

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.

Dosage

Important Use Information

Do not substitute DOXIL for doxorubicin HCl injection.

Do not administer as an undiluted suspension or as an intravenous bolus.

Ovarian Cancer

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

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.

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.

Dose Modifications for Adverse Reactions

Do not increase DOXIL after a dose reduction for toxicity.

This image is provided by the National Library of Medicine.

This image is provided by the National Library of Medicine.

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

Preparation and Administration

Preparation

Dilute DOXIL doses up to 90 mg in 250 mL of 5% Dextrose Injection, USP prior to administration. Dilute doses exceeding 90 mg in 500 mL of 5% Dextrose Injection, USP prior to administration. Refrigerate diluted DOXIL at 2°C to 8°C (36°F to 46°F) and administer within 24 hours.

Administration

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if a precipitate or foreign matter is present.

Do not use with in-line filters.

Administer the first dose of DOXIL at an initial rate of 1 mg/min. If no infusion-related adverse reactions are observed, increase the infusion rate to complete the administration of the drug over one hour. Do not rapidly flush the infusion line.

Do not mix DOXIL with other drugs.

Management of Suspected Extravasation

Discontinue DOXIL for burning or stinging sensation or other evidence indicating perivenous 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 min 4 times a day for 3 days

• If the extravasation is in an extremity, elevate the extremity

Procedure for Proper Handling and Disposal

Handle and dispose of DOXIL in accordance with recommendations for the handling and disposal of hazardous drugs.

If DOXIL comes into contact with skin or mucosa, immediately wash thoroughly with soap and water.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Doxorubicin liposome in adult patients.

Non–Guideline-Supported Use

Mycosis fungoides

• Dosing Information

• In observational, single-arm studies, pegylated liposomal DOXOrubicin 20 to 40 mg/m(2) IV every 4 weeks was administered for patients with refractory mycosis fungoides.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

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

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Doxorubicin liposome in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Doxorubicin liposome in pediatric patients.

Contraindications

• DOXIL is contraindicated in patients who have a history of severe hypersensitivity reactions, including anaphylaxis, to doxorubicin HCl.

Warnings

Cardiomyopathy

Doxorubicin HCl can result in myocardial damage, including acute left ventricular failure. The risk of cardiomyopathy with doxorubicin HCl is generally proportional to the cumulative exposure. The relationship between cumulative DOXIL dose and the risk of cardiac toxicity has not been determined.

In a clinical study in 250 patients with advanced cancer who were treated with DOXIL, the risk of cardiotoxicity was 11% when the cumulative anthracycline dose was between 450–550 mg/m2. Cardiotoxicity 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 cardiotoxicity.

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 cardiotoxicity. Administer DOXIL to patients with a history of cardiovascular disease only when the potential benefit of treatment outweighs the risk.

Infusion-Related Reactions

Serious and sometimes life-threatening 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. The majority of infusion-related events occurred during the first infusion. 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.

Ensure that medications to treat infusion-related reactions and cardiopulmonary resuscitative equipment is available for immediate use prior to initiation of DOXIL. Initiate DOXIL infusions at a rate of 1 mg/min and increase rate as tolerated. In the event of an infusion-related reaction, temporarily stop the drug until resolution then resume at a reduced infusion rate. Discontinue DOXIL infusion for serious or life-threatening infusion-related reactions.

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. Discontinue DOXIL if HFS is severe and debilitating.

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.

Embryofetal Toxicity

Based on animal data, DOXIL can cause fetal harm when administered to a pregnant woman. 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.

Adverse Reactions

Clinical Trials Experience

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.

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

Patients With Ovarian Cancer

The safety data described below are from Trial 4, which included 239 patients with ovarian cancer treated with DOXIL 50 mg/m2 once every 4 weeks for a minimum of four courses in a randomized, multicenter, open-label study. In this trial, patients received DOXIL for a median number of 3.2 months (range 1 day to 25.8 months). The median age of the patients is 60 years (range 27 to 87), with 91% Caucasian, 6% Black, and 3% Hispanic or Other.

Table 3 presents the hematologic adverse reactions from Trial 4.

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Table 4 presents the non-hematologic adverse reactions from Trial 4.

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The following additional adverse reactions were observed in patients with ovarian cancer with doses administered every four weeks (Trial 4).

Incidence 1% to 10%

Cardiovascular: vasodilation, tachycardia, deep vein thrombosis, hypotension, cardiac arrest.

Digestive: oral moniliasis, mouth ulceration, esophagitis, dysphagia, rectal bleeding, ileus.

Hematologic and Lymphatic: ecchymosis.

Metabolic and Nutritional: dehydration, weight loss, hyperbilirubinemia, hypokalemia, hypercalcemia, hyponatremia.

Nervous: somnolence, dizziness, depression.

Respiratory: rhinitis, pneumonia, sinusitis, epistaxis.

Skin and Appendages: pruritus, skin discoloration, vesiculobullous rash, maculopapular rash, exfoliative dermatitis, herpes zoster, dry skin, herpes simplex, fungal dermatitis, furunculosis, acne.

Special Senses: conjunctivitis, taste perversion, dry eyes.

Urinary: urinary tract infection, hematuria, vaginal moniliasis.

Patients With AIDS-Related Kaposi's Sarcoma

The safety data described is based on the experience reported in 753 patients with AIDS-related Kaposi's sarcoma (KS) enrolled in four open-label, uncontrolled trials of DOXIL administered at doses ranging from 10 to 40 mg/m2 every 2 to 3 weeks. Demographics of the population were: median age 38.7 years (range 24–70); 99% male; 88% Caucasian, 6% Hispanic, 4% Black, and 2% Asian/other/unknown. The majority of patients were treated with 20 mg/m2 of DOXIL every 2 to 3 weeks with a median exposure of 4.2 months (range 1 day to 26.6 months). The median cumulative dose was 120 mg/m2 (range 3.3 to 798.6 mg/m2); 3% received cumulative doses of greater than 450 mg/m2.

Disease characteristics were: 61% poor risk for KS tumor burden, 91% poor risk for immune system, and 47% poor risk for systemic illness; 36% were poor risk for all three categories; median CD4 count 21 cells/mm3 (51% less than 50 cells/mm3); mean absolute neutrophil count at study entry approximately 3,000 cells/mm3.

Of the 693 patients with concomitant medication information, 59% were on one or more antiretroviral medications [35% zidovudine (AZT), 21% didanosine (ddI), 16% zalcitabine (ddC), and 10% stavudine (D4T)]; 85% received PCP prophylaxis (54% sulfamethoxazole/trimethoprim); 85% received antifungal medications (76% fluconazole); 72% received antivirals (56% acyclovir, 29% ganciclovir, and 16% foscarnet) and 48% patients received colony-stimulating factors (sargramostim/filgrastim) during their course of treatment.

Adverse reactions led to discontinuation of treatment in 5% of patients with AIDS-related Kaposi's sarcoma and included myelosuppression, cardiac adverse reactions, infusion-related reactions, toxoplasmosis, HFS, pneumonia, cough/dyspnea, fatigue, optic neuritis, progression of a non-KS tumor, allergy to penicillin, and unspecified reasons. Tables 5 and 6 summarize adverse reactions reported in patients treated with DOXIL for AIDS-related Kaposi's sarcoma in a pooled analysis of the four trials.

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The following additional adverse reactions were observed in 705 patients with AIDS-related Kaposi's sarcoma.

Incidence 1% to 5%

Body as a Whole: headache, back pain, infection, allergic reaction, chills.

Cardiovascular: chest pain, hypotension, tachycardia.

Cutaneous: herpes simplex, rash, itching.

Digestive: mouth ulceration, anorexia, dysphagia.

Metabolic and Nutritional: SGPT increase, weight loss, hyperbilirubinemia.

Other: dyspnea, pneumonia, dizziness, somnolence.

Incidence Less Than 1%

Body As A Whole: sepsis, moniliasis, cryptococcosis.

Cardiovascular: thrombophlebitis, cardiomyopathy, palpitation, bundle branch block, congestive heart failure, heart arrest, thrombosis, ventricular arrhythmia.

Digestive: hepatitis.

Metabolic and Nutritional Disorders: dehydration

Respiratory: cough increase, pharyngitis.

Skin and Appendages: maculopapular rash, herpes zoster.

Special Senses: taste perversion, conjunctivitis.

Patients With Multiple Myeloma

The safety data described are from 318 patients treated with DOXIL (30 mg/m2) administered on day 4 following bortezomib (1.3 mg/m2 i.v. bolus on days 1, 4 , 8 and 11) every 3 weeks, in a randomized, open-label, multicenter study (Trial 6). In this trial, patients in the DOXIL + bortezomib combination group were treated for a median number of 4.5 months (range 21 days to 13.5 months). The population was 28 to 85 years of age (median age 61), 58% male, 90% Caucasian, 6% Black, and 4% Asian and Other. Table 7 lists adverse reactions reported in 10% or more of patients treated with DOXIL in combination with bortezomib for multiple myeloma.

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Postmarketing Experience

The following additional adverse reactions have been identified during post approval 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

Drug Interactions

No formal drug interaction studies have been conducted with DOXIL.

Use in Specific Populations

Pregnancy

Risk Summary

Based on findings in animals, DOXIL can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, DOXIL was embryotoxic in rats and abortifacient in rabbits following intravenous administration during organogenesis at doses approximately 0.12 times the recommended clinical dose. There are no available human data informing the drug-associated risk. Advise pregnant women of the potential risk to a fetus.

The background risk of major birth defects and miscarriage for the indicated populations are unknown. However, the background risk in the U.S. general population of major birth defects is 2–4% and of miscarriage is 15–20% of clinically recognized pregnancies.

Animal Data

DOXIL was embryotoxic at doses of 1 mg/kg/day in rats and was embryotoxic and abortifacient at 0.5 mg/kg/day in rabbits (both doses are about 0.12 times the recommended dose of 50 mg/m2 human dose on a mg/m2 basis). Embryotoxicity was characterized by increased embryo-fetal deaths and reduced live litter sizes.

Labor and Delivery

There is no FDA guidance on use of Doxorubicin liposome during labor and delivery.

Nursing Mothers

It is not known whether DOXIL is present 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, discontinue breastfeeding during treatment with DOXIL.

Pediatric Use

There is no FDA guidance on the use of Doxorubicin liposome with respect to pediatric patients.

Geriatic Use

There is no FDA guidance on the use of Doxorubicin liposome with respect to geriatric patients.

Gender

Contraception

Females

DOXIL can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during and for 6 months after treatment with DOXIL.

Males

DOXIL may damage spermatozoa and testicular tissue, resulting in possible genetic fetal abnormalities. Males with female sexual partners of reproductive potential should use effective contraception during and for 6 months after treatment with DOXIL.

Infertility

Females

In females of reproductive potential, DOXIL may cause infertility and result in amenorrhea. Premature menopause can occur with doxorubicin HCl. Recovery of menses and ovulation is related to age at treatment.

Males

DOXIL 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.

Race

There is no FDA guidance on the use of Doxorubicin liposome with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Doxorubicin liposome in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Doxorubicin liposome in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Doxorubicin liposome in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Doxorubicin liposome in patients who are immunocompromised.

Administration and Monitoring

Administration

• Oral
• Intravenous

Monitoring

• Description

There is limited information regarding Monitoring of Doxorubicin liposome in the drug label.

Overdosage

• Description

There is limited information regarding Chronic Overdose of Doxorubicin liposome in the drug label.

Pharmacology

drugbox2

Mechanism of Action

mechanismofaction

Structure

File:Doxorubicin liposome01.png

This image is provided by the National Library of Medicine.

Pharmacodynamics

There is limited information regarding Pharmacodynamics of Doxorubicin liposome in the drug label.

Pharmacokinetics

There is limited information regarding Pharmacokinetics of Doxorubicin liposome in the drug label.

Nonclinical Toxicology

There is limited information regarding Nonclinical Toxicology of Doxorubicin liposome in the drug label.

Clinical Studies

There is limited information regarding Clinical Studies of Doxorubicin liposome in the drug label.

How Supplied

• Description

There is limited information regarding How Supplied of Doxorubicin liposome in the drug label.

Images

Package and Label Display Panel

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This image is provided by the National Library of Medicine.

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This image is provided by the National Library of Medicine.

Patient Counseling Information

There is limited information regarding Patient Counseling Information of Doxorubicin liposome in the drug label.

Precautions with Alcohol

Alcohol-Doxorubicin liposome interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

Doxil, Lipodox

Look-Alike Drug Names

Drug Shortage Status

References

The contents of this FDA label are provided by the National Library of Medicine.