Doxorubicin liposome: Difference between revisions

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

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Latest revision as of 20:14, 18 August 2015

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.

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.^[1]^[2]

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.

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

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.

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, achycardia.

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.

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

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

Geriatic 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.

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

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.

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

Intravenous

Monitoring

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

Overdosage

Acute overdosage with doxorubicin HCl causes increased risk of severe mucositis, leukopenia, and thrombocytopenia.

Pharmacology



Doxorubicin liposome
Systematic (IUPAC) name
(7S,9S)-7-[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7H-tetracene-5,12-dione
Identifiers
CAS number	23214-92-8
ATC code	L01DB01
PubChem	31703
DrugBank	DB00997
Chemical data
Formula	Template:OrganicBox atom Template:OrganicBox atom Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox atom Template:OrganicBox Template:OrganicBox atom Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox
Mol. mass	543.52 g/mol
SMILES	eMolecules & PubChem
Pharmacokinetic data
Bioavailability	5% (Oral)
Protein binding	75%^[3]
Metabolism	Hepatic
Half life	Triphasic; 12 minutes, 3.3 hours, 30 hours. Mean: 1-3 hours^[3]^[4]
Excretion	Urine (5-12%), faeces (40-50%)^[3]
Therapeutic considerations
Pregnancy cat.	D(AU) D(US)
Legal status	Prescription Only (S4)(AU) ?(CA) POM(UK) [[Prescription drug\|Template:Unicode-only]](US)
Routes	Intravenous, intravesical

Mechanism of Action

The active ingredient of Doxil is doxorubicin HCl. The mechanism of action of doxorubicin HCl 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.

Structure

Doxil (doxorubicin HCl liposome injection) is doxorubicin hydrochloride (HCl), an anthracycline topoisomerase II inhibitor, that is encapsulated in STEALTH® liposomes for intravenous use.

The chemical name of doxorubicin HCl is (8S,10S)-10-[(3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl)oxy]-8-glycolyl-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12-naphthacenedione hydrochloride. The molecular formula is C27-H29 -NO11∙HCl; its molecular weight is 579.99.

Doxil is a sterile, translucent, red liposomal dispersion in 10-mL or 30-mL glass, single use vials. Each vial contains 20 mg or 50 mg doxorubicin HCl at a concentration of 2 mg/mL and a pH of 6.5. The STEALTH liposome carriers are composed of cholesterol, 3.19 mg/mL; fully hydrogenated soy phosphatidylcholine (HSPC), 9.58 mg/mL; and N-(carbonyl-methoxypolyethylene glycol 2000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine sodium salt (MPEG-DSPE), 3.19 mg/mL. Each mL also contains ammonium sulfate, approximately 2 mg; histidine as a buffer; hydrochloric acid and/or sodium hydroxide for pH control; and sucrose to maintain isotonicity. Greater than 90% of the drug is encapsulated in the STEALTH liposomes.

MPEG-DSPE has the following structural formula:

HSPC has the following structural formula:

Representation of a STEALTH liposome:

Pharmacodynamics

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

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.

Distribution:

Direct measurement of liposomal doxorubicin shows that at least 90% of the drug (the assay used cannot quantify less than 5–10% free doxorubicin) remains liposome-encapsulated during circulation.

In contrast to doxorubicin, which displays a large volume of distribution (range 700 to 1100 L/m2), the small steady state volume of distribution of liposomal doxorubicin suggests that Doxil is largely confined to vascular fluid. Doxorubicin becomes available after the liposomes are extravasated. Plasma protein binding of Doxil has not been determined; the plasma protein binding of doxorubicin is approximately 70%.

Metabolism:

Doxorubicinol, the major metabolite of doxorubicin, was detected at concentrations of 0.8 to 26.2 ng/mL in the plasma of patients who received 10 or 20 mg/m2 Doxil.

Elimination:

The plasma clearance of total doxorubicin from Doxil was 0.041 L/h/m2 at a dose of 20 mg/m2. Following administration of doxorubicin HCl, the plasma clearance of doxorubicin is 24 to 35 L/h/m2.`

Nonclinical Toxicology

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).

Clinical Studies

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.

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 HCl.

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.

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. Survival continued to be followed after the interim analysis and survival data are not mature at this time. Efficacy results are as shown in Table 13 and Figure 1.

How Supplied

Doxil is a sterile, translucent, red liposomal dispersion in 10-mL or 30-mL glass, single use vials.

Each 10-mL vial contains 20 mg doxorubicin HCl at a concentration of 2 mg/mL.

Each 30-mL vial contains 50 mg doxorubicin HCl at a concentration of 2 mg/mL.

The following individually cartoned vials are available:

Images

Package and Label Display Panel

Patient Counseling Information

Cardiomyopathy

Advise patients to contact their healthcare provider if they develop symptoms of heart failure.

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.

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).

Stomatitis

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

Embryofetal 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.

Advise females and males of reproductive potential to use effective contraception during and for 6 months following treatment with Doxil.

Lactation

Advise females not to breastfeed during treatment with Doxil.

Infertility

Advise females and males of reproductive potential that Doxil may cause temporary or permanent infertility.

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.

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 ®^[5]
Lipodox

Look-Alike Drug Names

Drug Shortage Status

References

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

↑ Pulini, Stefano; Rupoli, Serena; Goteri, Gaia; Pimpinelli, Nicola; Alterini, Renato; Tassetti, Angela; Scortechini, Anna Rita; Offidani, Massimo; Mulattieri, Simonetta; Stronati, Andrea; Brandozzi, Giuliano; Giacchetti, Alfredo; Mozzicafreddo, Giorgio; Ricotti, Giuseppe; Filosa, Giorgio; Bettacchi, Alberta; Simonacci, Marco; Novelli, Nicolino; Leoni, Pietro (2007-05). "Pegylated liposomal doxorubicin in the treatment of primary cutaneous T-cell lymphomas". Haematologica. 92 (5): 686–689. ISSN 1592-8721. PMID 17488695. Check date values in: |date= (help)
↑ Quereux, Gaëlle; Marques, Sonia; Nguyen, Jean-Michel; Bedane, Christophe; D'incan, Michel; Dereure, Olivier; Puzenat, Elisabeth; Claudy, Alain; Martin, Ludovic; Joly, Pascal; Delaunay, Michele; Beylot-Barry, Marie; Vabres, Pierre; Celerier, Philippe; Sasolas, Bruno; Grange, Florent; Khammari, Amir; Dreno, Brigitte (2008-06). "Prospective multicenter study of pegylated liposomal doxorubicin treatment in patients with advanced or refractory mycosis fungoides or Sézary syndrome". Archives of Dermatology. 144 (6): 727–733. doi:10.1001/archderm.144.6.727. ISSN 1538-3652. PMID 18559761. Check date values in: |date= (help)
↑ ^3.0 ^3.1 ^3.2 "(doxorubicin) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 15 April 2014.
↑ Brayfield, A, ed. (19 December 2013). "Doxorubicin". Martindale: The Complete Drug Reference. Pharmaceutical Press. Retrieved 15 April 2014.
↑ "DOXIL- doxorubicin hydrochloride injection, suspension, liposomal".

[1] Pulini, Stefano; Rupoli, Serena; Goteri, Gaia; Pimpinelli, Nicola; Alterini, Renato; Tassetti, Angela; Scortechini, Anna Rita; Offidani, Massimo; Mulattieri, Simonetta; Stronati, Andrea; Brandozzi, Giuliano; Giacchetti, Alfredo; Mozzicafreddo, Giorgio; Ricotti, Giuseppe; Filosa, Giorgio; Bettacchi, Alberta; Simonacci, Marco; Novelli, Nicolino; Leoni, Pietro (2007-05). "Pegylated liposomal doxorubicin in the treatment of primary cutaneous T-cell lymphomas". Haematologica. 92 (5): 686–689. ISSN 1592-8721. PMID 17488695. Check date values in: |date= (help)

[2] Quereux, Gaëlle; Marques, Sonia; Nguyen, Jean-Michel; Bedane, Christophe; D'incan, Michel; Dereure, Olivier; Puzenat, Elisabeth; Claudy, Alain; Martin, Ludovic; Joly, Pascal; Delaunay, Michele; Beylot-Barry, Marie; Vabres, Pierre; Celerier, Philippe; Sasolas, Bruno; Grange, Florent; Khammari, Amir; Dreno, Brigitte (2008-06). "Prospective multicenter study of pegylated liposomal doxorubicin treatment in patients with advanced or refractory mycosis fungoides or Sézary syndrome". Archives of Dermatology. 144 (6): 727–733. doi:10.1001/archderm.144.6.727. ISSN 1538-3652. PMID 18559761. Check date values in: |date= (help)

[MSR-3] 3.0 ^3.1 ^3.2 "(doxorubicin) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 15 April 2014.

[MD-4] Brayfield, A, ed. (19 December 2013). "Doxorubicin". Martindale: The Complete Drug Reference. Pharmaceutical Press. Retrieved 15 April 2014.

[5] "DOXIL- doxorubicin hydrochloride injection, suspension, liposomal".

[1]

[2]

[3]

[4]

[5]

@@ Line 1: / Line 1: @@
-{{DrugProjectFormSinglePage
+{{DrugProjectFormSinglePage01
-|authorTag={{Steven}}
+|authorTag=<!--Overview-->
 |genericName=Doxorubicin liposome
 |aOrAn=an
-|drugClass=anthracycline
+|drugClass=[[anthracycline]]
 |indicationType=treatment
-|indication=metastatic [[breast cancer]], [[non-small cell lung cancer]], and [[adenocarcinoma]] of the [[pancreas]]
+|indication=[[ovarian cancer]], [[AIDS]]-related [[Kaposi's sarcoma]], and [[multiple myeloma]]
 |hasBlackBoxWarning=Yes
-|adverseReactions=[[alopecia]], [[neutropenia]], [[sensory neuropathy]], [[arrhythmia]], [[fatigue]]/[[asthenia]], [[myalgia]]/[[arthralgia]], [[AST]] elevation, [[alkaline phosphatase]] elevation, [[anemia]], and [[infection]]s
+|adverseReactions=[[asthenia]], [[fatigue]], [[fever]], [[stomatitis]], [[nausea]], [[vomiting]], [[diarrhea]], [[constipation]], [[anorexia]], [[hand-foot syndrome]], [[rash]], [[neutropenia]], [[thrombocytopenia]], and [[anemia]]
-|blackBoxWarningTitle=<span style="color:#FF0000;">WARNING: NEUTROPENIA</span>
-|blackBoxWarningBody=* Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE.
-* Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS.
-|fdaLIADAdult==== Indications ===
-==== Metastatic Breast Cancer ====
+<!--Black Box Warning-->
-ABRAXANE is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.
+|blackBoxWarningTitle=<span style="color:#FF0000;">WARNING: CARDIOMYOPATHY AND INFUSION-RELATED REACTIONS</span>
+|blackBoxWarningBody=* 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.
-==== Non-Small Cell Lung Cancer ====
+<!--Adult Indications and Dosage-->
-ABRAXANE is indicated for the first-line treatment of locally advanced or metastatic non-small cell lung cancer, in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy.
-==== Adenocarcinoma of the Pancreas ====
+<!--FDA-Labeled Indications and Dosage (Adult)-->
-ABRAXANE is indicated for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas, in combination with gemcitabine.
+|fdaLIADAdult=====Indications====
-=== Dosage ===
+======Ovarian Cancer======
+Doxil is indicated for the treatment of patients with [[ovarian cancer]] whose disease has progressed or recurred after [[List of chemotherapeutic agents#Platinum coordination complexes|platinum-based chemotherapy]].
-==== Metastatic Breast Cancer====
+======AIDS-Related Kaposi's Sarcoma======
-After failure of combination chemotherapy for metastatic breast cancer or relapse within 6 months of adjuvant chemotherapy, the recommended regimen for ABRAXANE is 260 mg/m2 administered intravenously over 30 minutes every 3 weeks.
+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.
-==== Non-Small Cell Lung Cancer ====
+======Multiple Myeloma======
-The recommended dose of ABRAXANE is 100 mg/m2 administered as an intravenous infusion over 30 minutes on Days 1, 8, and 15 of each 21-day cycle. Administer carboplatin on Day 1 of each 21 day cycle immediately after ABRAXANE.
+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.
-====Adenocarcinoma of the Pancreas====
+====Dosage====
-The recommended dose of ABRAXANE is 125 mg/m2 administered as an intravenous infusion over 30-40 minutes on Days 1, 8 and 15 of each 28-day cycle. Administer gemcitabine immediately after ABRAXANE on Days 1, 8 and 15 of each 28-day cycle.
-==== Dosage in Patients with Hepatic Impairment====
-For patients with mild hepatic impairment (total bilirubin greater than ULN and less than or equal to 1.5 x ULN and aspartate aminotransferase [AST] less than or equal to 10 x ULN), no dose adjustments are required, regardless of indication.
-Do not administer ABRAXANE to patients with metastatic adenocarcinoma of the pancreas who have moderate to severe hepatic impairment.
+=====Important Use Information=====
-Do not administer ABRAXANE to patients with total bilirubin greater than 5 x ULN or AST greater than 10 x ULN regardless of indication as these patients have not been studied.
+Do not substitute Doxil for [[doxorubicin|doxorubicin HCl]] injection.
-Recommendations for dosage adjustment for the first course of therapy are shown in TABLE 1.
+Do not administer as an undiluted suspension or as an [[intravenous]] bolus.
-[[File:Doxorubicin table01.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]
+=====Ovarian Cancer=====
-==== Dose Reduction/Discontinuation Recommendations====
+The recommended dose of Doxil is 50 mg/m2 intravenously over 60 minutes every 28 days until disease progression or unacceptable toxicity.
-Metastatic Breast Cancer
+=====AIDS-Related Kaposi's Sarcoma=====
-Patients who experience severe neutropenia (neutrophils less than 500 cells/mm3 for a week or longer) or severe sensory neuropathy during ABRAXANE therapy should have dosage reduced to 220 mg/m2 for subsequent courses of ABRAXANE. For recurrence of severe neutropenia or severe sensory neuropathy, additional dose reduction should be made to 180 mg/m2. For Grade 3 sensory neuropathy hold treatment until resolution to Grade 1 or 2, followed by a dose reduction for all subsequent courses of ABRAXANE.
-Non-Small Cell Lung Cancer
+The recommended dose of Doxil is 20 mg/m2 intravenously over 60 minutes every 21 days until disease progression or unacceptable toxicity.
-Do not administer ABRAXANE on Day 1 of a cycle until absolute neutrophil count (ANC) is at least 1500 cells/mm3 and platelet count is at least 100,000 cells/mm3 [see Contraindications (4),Warnings and Precautions (5.1) and Adverse Reactions (6.2)].
+=====Multiple Myeloma=====
-In patients who develop severe neutropenia or thrombocytopenia withhold treatment until counts recover to an absolute neutrophil count of at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an absolute neutrophil count of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle. Upon resumption of dosing, permanently reduce ABRAXANE and carboplatin doses as outlined in TABLE 2.
-Withhold ABRAXANE for Grade 3-4 peripheral neuropathy. Resume ABRAXANE and carboplatin at reduced doses (see TABLE 2) when peripheral neuropathy improves to Grade 1 or completely resolves.
-[[File:Doxorubicin table02.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]
+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.
-Adenocarcinoma of the Pancreas
+=====Dose Modifications for Adverse Reactions=====
-Dose level reductions for patients with adenocarcinoma of the pancreas, as referenced in TABLES 4 and 5, are provided in TABLE 3.
-[[File:Doxorubicin table03.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]
+Do not increase Doxil after a dose reduction for toxicity.
-Recommended dose modifications for neutropenia and thrombocytopenia for patients with adenocarcinoma of the pancreas are provided in TABLE 4.
+[[File:Doxil table01.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
+[[File:Doxil table02.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
-[[File:Doxorubicin table04.jpg|thumb|none|400px|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.
-Recommended dose modifications for other adverse drug reactions in patients with adenocarcinoma of the pancreas are provided in TABLE 5.
+=====Preparation and Administration=====
-[[File:Doxorubicin table05.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]
+======Preparation======
-==== Preparation and Administration Precautions====
+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.
-ABRAXANE is a cytotoxic drug and, as with other potentially toxic paclitaxel compounds, caution should be exercised in handling ABRAXANE. The use of gloves is recommended. If ABRAXANE (lyophilized cake or reconstituted suspension) contacts the skin, wash the skin immediately and thoroughly with soap and water. Following topical exposure to paclitaxel, events may include tingling, burning and redness. If ABRAXANE contacts mucous membranes, the membranes should be flushed thoroughly with water.
-Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration. Limiting the infusion of ABRAXANE to 30 minutes, as directed, reduces the likelihood of infusion-related reactions.
+======Administration======
-Premedication to prevent hypersensitivity reactions is generally not needed prior to the administration of ABRAXANE. Premedication may be needed in patients who have had prior hypersensitivity reactions to ABRAXANE. Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be re-challenged with this drug.
+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.
-==== Preparation for Intravenous Administration====
+Do not use with in-line filters.
-ABRAXANE is supplied as a sterile lyophilized powder for reconstitution before use. AVOID ERRORS, READ ENTIRE PREPARATION INSTRUCTIONS PRIOR TO RECONSTITUTION.
-[[File:Doxorubicin pic01.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]
+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.
-Each mL of the reconstituted formulation will contain 5 mg/mL paclitaxel.
+Do not mix Doxil with other drugs.
-Calculate the exact total dosing volume of 5 mg/mL suspension required for the patient: Dosing volume (mL) = Total dose (mg)/5 (mg/mL).
+Management of Suspected Extravasation
-The reconstituted suspension should be milky and homogenous without visible particulates. If particulates or settling are visible, the vial should be gently inverted again to ensure complete resuspension prior to use. Discard the reconstituted suspension if precipitates are observed. Discard any unused portion.
+Discontinue Doxil for burning or stinging sensation or other evidence indicating perivenous infiltration or [[extravasation]]. Manage confirmed or suspected extravasation as follows:
-Inject the appropriate amount of reconstituted ABRAXANE into an empty, sterile intravenous bag [plasticized polyvinyl chloride (PVC) containers, PVC or non-PVC type intravenous bag]. The use of specialized DEHP-free solution containers or administration sets is not necessary to prepare or administer ABRAXANE infusions. The use of an in-line filter is not recommended.
+* Do not remove the needle until attempts are made to aspirate extravasated fluid
-Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.
+* Do not flush the line
-==== Stability ====
+* Avoid applying pressure to the site
-Unopened vials of ABRAXANE are stable until the date indicated on the package when stored between 20°C to 25°C (68°F to 77°F) in the original package. Neither freezing nor refrigeration adversely affects the stability of the product.
-Stability of Reconstituted Suspension in the Vial
+* Apply ice to the site intermittently for 15 min 4 times a day for 3 days
-Reconstituted ABRAXANE in the vial should be used immediately, but may be refrigerated at 2°C to 8°C (36°F to 46°F) for a maximum of 24 hours if necessary. If not used immediately, each vial of reconstituted suspension should be replaced in the original carton to protect it from bright light. Discard any unused portion.
-Stability of Reconstituted Suspension in the Infusion Bag
+* If the extravasation is in an extremity, elevate the extremity
-The suspension for infusion when prepared as recommended in an infusion bag should be used immediately, but may be refrigerated at 2°C to 8°C (36°F to 46°F) and protected from bright light for a maximum of 24 hours.
-The total combined refrigerated storage time of reconstituted ABRAXANE in the vial and in the infusion bag is 24 hours. This may be followed by storage in the infusion bag at ambient temperature (approximately 25°C) and lighting conditions for a maximum of 4 hours.
+=====Procedure for Proper Handling and Disposal=====
+Handle and dispose of Doxil in accordance with recommendations for the handling and disposal of hazardous drugs.
-Discard any unused portion.
+If Doxil comes into contact with skin or mucosa, immediately wash thoroughly with soap and water.
-|offLabelAdultGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Doxorubicin liposome in adult patients.
-|offLabelAdultNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of Doxorubicin liposome in adult patients.
-|fdaLIADPed=The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated.
-|offLabelPedGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Doxorubicin liposome in pediatric patients.
-|offLabelPedNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of Doxorubicin liposome in pediatric patients.
-|contraindications=* ABRAXANE should not be used in patients who have baseline neutrophil counts of < 1,500 cells/mm3.
-* Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug.
-|warnings=====Hematologic Effects====
-Bone marrow suppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity of ABRAXANE. In clinical studies, Grade 3-4 neutropenia occurred in 34% of patients with metastatic breast cancer (MBC), 47% of patients with non-small cell lung cancer (NSCLC), and 38% of patients with pancreatic cancer.
-Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to dosing on Day 1 (for MBC) and Days 1, 8, and 15 (for NSCLC and for pancreatic cancer). Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1,500 cells/mm3. In the case of severe neutropenia (<500 cells/mm3 for seven days or more) during a course of ABRAXANE therapy, reduce the dose of ABRAXANE in subsequent courses in patients with either MBC or NSCLC.
+<!--Off-Label Use and Dosage (Adult)-->
-In patients with MBC, resume treatment with every-3-week cycles of ABRAXANE after ANC recovers to a level >1,500 cells/mm3 and platelets recover to a level >100,000 cells/mm3.
+<!--Guideline-Supported Use (Adult)-->
+|offLabelAdultGuideSupport=<SMALL>There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in adult patients.</SMALL>
-In patients with NSCLC, resume treatment if recommended (see Dosage and Administration, TABLE 2) at permanently reduced doses for both weekly ABRAXANE and every-3-week carboplatin after ANC recovers to at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an ANC of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle [see Dosage and Administration (2.5)].
+<!--Non–Guideline-Supported Use (Adult)-->
+|offLabelAdultNoGuideSupport======Mycosis fungoides=====
-In patients with adenocarcinoma of the pancreas, withhold ABRAXANE and gemcitabine if the ANC is less than 500 cells/mm3 or platelets are less than 50,000 cells/mm3 and delay initiation of the next cycle if the ANC is less than 1500 cells/mm3 or platelet count is less than 100,000 cells/mm3 on Day 1 of the cycle. Resume treatment with appropriate dose reduction if recommended [see Dosage and Administration (2.5)].
+* Dosing Information
-====Nervous System====
+:* 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]].<ref>{{Cite journal| issn = 1592-8721| volume = 92| issue = 5| pages = 686–689| last1 = Pulini| first1 = Stefano| last2 = Rupoli| first2 = Serena| last3 = Goteri| first3 = Gaia| last4 = Pimpinelli| first4 = Nicola| last5 = Alterini| first5 = Renato| last6 = Tassetti| first6 = Angela| last7 = Scortechini| first7 = Anna Rita| last8 = Offidani| first8 = Massimo| last9 = Mulattieri| first9 = Simonetta| last10 = Stronati| first10 = Andrea| last11 = Brandozzi| first11 = Giuliano| last12 = Giacchetti| first12 = Alfredo| last13 = Mozzicafreddo| first13 = Giorgio| last14 = Ricotti| first14 = Giuseppe| last15 = Filosa| first15 = Giorgio| last16 = Bettacchi| first16 = Alberta| last17 = Simonacci| first17 = Marco| last18 = Novelli| first18 = Nicolino| last19 = Leoni| first19 = Pietro| title = Pegylated liposomal doxorubicin in the treatment of primary cutaneous T-cell lymphomas| journal = Haematologica| date = 2007-05| pmid = 17488695}}</ref><ref>{{Cite journal| doi = 10.1001/archderm.144.6.727| issn = 1538-3652| volume = 144| issue = 6| pages = 727–733| last1 = Quereux| first1 = Gaëlle| last2 = Marques| first2 = Sonia| last3 = Nguyen| first3 = Jean-Michel| last4 = Bedane| first4 = Christophe| last5 = D'incan| first5 = Michel| last6 = Dereure| first6 = Olivier| last7 = Puzenat| first7 = Elisabeth| last8 = Claudy| first8 = Alain| last9 = Martin| first9 = Ludovic| last10 = Joly| first10 = Pascal| last11 = Delaunay| first11 = Michele| last12 = Beylot-Barry| first12 = Marie| last13 = Vabres| first13 = Pierre| last14 = Celerier| first14 = Philippe| last15 = Sasolas| first15 = Bruno| last16 = Grange| first16 = Florent| last17 = Khammari| first17 = Amir| last18 = Dreno| first18 = Brigitte| title = Prospective multicenter study of pegylated liposomal doxorubicin treatment in patients with advanced or refractory mycosis fungoides or Sézary syndrome| journal = Archives of Dermatology| date = 2008-06| pmid = 18559761}}</ref>
-Sensory neuropathy is dose- and schedule-dependent [see Adverse Reactions (6.1, 6.2, 6.3)]. The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification. If ≥ Grade 3 sensory neuropathy develops, withhold ABRAXANE treatment until resolution to Grade 1 or 2 for metastatic breast cancer or until resolution to ≤ Grade 1 for NSCLC and pancreatic cancer followed by a dose reduction for all subsequent courses of ABRAXANE [see Dosage and Administration (2.5)].
-====Sepsis====
+<!--Pediatric Indications and Dosage-->
-Sepsis occurred in 5% of patients with or without neutropenia who received ABRAXANE in combination with gemcitabine. Biliary obstruction or presence of biliary stent were risk factors for severe or fatal sepsis. If a patient becomes febrile (regardless of ANC) initiate treatment with broad spectrum antibiotics. For febrile neutropenia, interrupt ABRAXANE and gemcitabine until fever resolves and ANC ≥ 1500, then resume treatment at reduced dose levels [see Dosage and Administration (2.5)].
-====Pneumonitis====
+<!--FDA-Labeled Indications and Dosage (Pediatric)-->
-Pneumonitis, including some cases that were fatal, occurred in 4% of patients receiving ABRAXANE in combination with gemcitabine. Monitor patients for signs and symptoms of pneumonitis and interrupt ABRAXANE and gemcitabine during evaluation of suspected pneumonitis. After ruling out infectious etiology and upon making a diagnosis of pneumonitis, permanently discontinue treatment with ABRAXANE and gemcitabine.
+|fdaLIADPed=The safety and effectiveness of Doxil in pediatric patients have not been established.
-====Hypersensitivity====
+<!--Off-Label Use and Dosage (Pediatric)-->
-Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported. Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be re-challenged with this drug.
-====Hepatic Impairment====
+<!--Guideline-Supported Use (Pediatric)-->
-Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution. Patients with hepatic impairment may be at increased risk of toxicity, particularly from myelosuppression; such patients should be closely monitored for development of profound myelosuppression. ABRAXANE is not recommended in patients who have total bilirubin >5 x ULN or AST >10 x ULN. In addition, ABRAXANE is not recommended in patients with metastatic adenocarcinoma of the pancreas who have moderate to severe hepatic impairment (total bilirubin >1.5 x ULN and AST ≤10 x ULN). The starting dose should be reduced for patients with moderate or severe hepatic impairment [see Dosage and Administration (2.4), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
+|offLabelPedGuideSupport=<SMALL>There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.</SMALL>
-====Albumin (Human)====
+<!--Non–Guideline-Supported Use (Pediatric)-->
-ABRAXANE contains albumin (human), a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries a remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob Disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin.
+|offLabelPedNoGuideSupport=<SMALL>There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.</SMALL>
-====Use in Pregnancy====
+<!--Contraindications-->
-ABRAXANE can cause fetal harm when administered to a pregnant woman. Administration of paclitaxel formulated as albumin-bound particles to rats during pregnancy at doses lower than the maximum recommended human dose, based on body surface area, caused embryo-fetal toxicities, including intrauterine mortality, increased resorptions, reduced numbers of live fetuses, and malformations.
+|contraindications=Doxil is contraindicated in patients who have a history of severe [[hypersensitivity]] reactions, including [[anaphylaxis]], to doxorubicin HCl.
-There are no adequate and well-controlled studies in pregnant women receiving ABRAXANE. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE [see Use in Specific Populations (8.1)].
+<!--Warnings-->
+|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.
-====Use in Men====
+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.
-Men should be advised not to father a child while receiving ABRAXANE.
-|clinicalTrials=Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
-The most common adverse reactions (≥ 20%) with single-agent use of ABRAXANE in metastatic breast cancer are alopecia, neutropenia, sensory neuropathy, abnormal ECG, fatigue/asthenia, myalgia/arthralgia, AST elevation, alkaline phosphatase elevation, anemia, nausea, infections, and diarrhea [see Adverse Reactions (6.1)].
+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.
-The most common adverse reactions (≥ 20%) of ABRAXANE in combination with carboplatin for non-small cell lung cancer are anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy, nausea, and fatigue [see Adverse Reactions (6.2)] The most common serious adverse reactions of ABRAXANE in combination with carboplatin for non-small cell lung cancer are anemia (4%) and pneumonia (3%). The most common adverse reactions resulting in permanent discontinuation of ABRAXANE are neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%). The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (24%), thrombocytopenia (13%), and anemia (6%). The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (41%), thrombocytopenia (30%), and anemia (16%).
+=====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.
-In a randomized open-label trial of ABRAXANE in combination with gemcitabine for pancreatic adenocarcinoma [see Clinical Studies (14.3)], the most common (≥ 20%) selected (with a ≥ 5% higher incidence) adverse reactions of ABRAXANE are neutropenia, fatigue, peripheral neuropathy, nausea, alopecia, peripheral edema, diarrhea, pyrexia, vomiting, decreased appetite, rash, and dehydration. The most common serious adverse reactions of ABRAXANE (with a ≥ 1% higher incidence) are pyrexia (6%), dehydration (5%), pneumonia (4%) and vomiting (4%). The most common adverse reactions resulting in permanent discontinuation of ABRAXANE are peripheral neuropathy (8%), fatigue (4%) and thrombocytopenia (2%). The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (10%) and peripheral neuropathy (6%). The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (16%), thrombocytopenia (12%), fatigue (8%), peripheral neuropathy (15%), anemia (5%) and diarrhea (5%).
+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.
-==== Clinical Trials Experience in Metastatic Breast Cancer ====
+=====Hand-Foot Syndrome (HFS)=====
-TABLE 6 shows the frequency of important adverse events in the randomized comparative trial for the patients who received either single-agent ABRAXANE or paclitaxel injection for the treatment of metastatic breast cancer.
+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.
-xx
+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.
-Adverse Event Experiences by Body System
+=====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.
-Hematologic Disorders
+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.
-Neutropenia was dose dependent and reversible. Among patients with metastatic breast cancer in the randomized trial, neutrophil counts declined below 500 cells/mm3 (Grade 4) in 9% of the patients treated with a dose of 260 mg/m2 compared to 22% in patients receiving paclitaxel injection at a dose of 175 mg/m2. Pancytopenia has been observed in clinical trials.
-Infections
+=====Embryofetal Toxicity=====
-Infectious episodes were reported in 24% of the patients treated with ABRAXANE. Oral candidiasis, respiratory tract infections and pneumonia were the most frequently reported infectious complications.
+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.
-Hypersensitivity Reactions (HSRs)
+<!--Adverse Reactions-->
-Grade 1 or 2 HSRs occurred on the day of ABRAXANE administration and consisted of dyspnea (1%) and flushing, hypotension, chest pain, and arrhythmia (all <1%). The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied.
-Cardiovascular
+<!--Clinical Trials Experience-->
-Hypotension, during the 30-minute infusion, occurred in 5% of patients. Bradycardia, during the 30-minute infusion, occurred in <1% of patients. These vital sign changes most often caused no symptoms and required neither specific therapy nor treatment discontinuation.
+|clinicalTrials=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.
-Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients. These events included cardiac ischemia/infarction, chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension. Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been reported.
+=====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.
-Electrocardiogram (ECG) abnormalities were common among patients at baseline. ECG abnormalities on study did not usually result in symptoms, were not dose-limiting, and required no intervention. ECG abnormalities were noted in 60% of patients. Among patients with a normal ECG prior to study entry, 35% of all patients developed an abnormal tracing while on study. The most frequently reported ECG modifications were non-specific repolarization abnormalities, sinus bradycardia, and sinus tachycardia.
+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]].
-Respiratory
+The following tables present adverse reactions from clinical trials of single-agent Doxil in ovarian cancer and AIDS-Related [[Kaposi's sarcoma]].
-Dyspnea (12%), cough (7%), and pneumothorax (<1%) were reported after treatment with ABRAXANE.
-Neurologic
+=====Patients With Ovarian Cancer=====
-The frequency and severity of sensory neuropathy increased with cumulative dose. Sensory neuropathy was the cause of ABRAXANE discontinuation in 7/229 (3%) patients. Twenty-four patients (10%) treated with ABRAXANE developed Grade 3 peripheral neuropathy; of these patients, 14 had documented improvement after a median of 22 days; 10 patients resumed treatment at a reduced dose of ABRAXANE and 2 discontinued due to peripheral neuropathy. Of the 10 patients without documented improvement, 4 discontinued the study due to peripheral neuropathy.
-No Grade 4 sensory neuropathies were reported. Only one incident of motor neuropathy (Grade 2) was observed in either arm of the controlled trial.
+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.
-Vision Disorders
+Table 3 presents the hematologic adverse reactions from Trial 4.
-Ocular/visual disturbances occurred in 13% of all patients (n=366) treated with ABRAXANE and 1% were severe. The severe cases (keratitis and blurred vision) were reported in patients who received higher doses than those recommended (300 or 375 mg/m2). These effects generally have been reversible.
-Arthralgia/Myalgia
+[[File:Doxil table03.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
-The symptoms were usually transient, occurred two or three days after ABRAXANE administration, and resolved within a few days.
-Hepatic
+Table 4 presents the non-hematologic adverse reactions from Trial 4.
-Grade 3 or 4 elevations in GGT were reported for 14% of patients treated with ABRAXANE and 10% of patients treated with paclitaxel injection in the randomized trial.
-Renal
+[[File:Doxil table04.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
-Overall 11% of patients experienced creatinine elevation, 1% severe. No discontinuations, dose reductions, or dose delays were caused by renal toxicities.
-Other Clinical Events
+The following additional adverse reactions were observed in patients with ovarian cancer with doses administered every four weeks (Trial 4).
-Nail changes (changes in pigmentation or discoloration of nail bed) have been reported. Edema occurred in 10% of patients; no patients had severe edema. Dehydration and pyrexia were also reported.
-====Clinical Trials Experience in Non-Small Cell Lung Cancer====
+======Incidence 1% to 10%======
-Adverse reactions were assessed in 514 ABRAXANE/carboplatin-treated patients and 524 paclitaxel injection/carboplatin-treated patients receiving first-line systemic treatment for locally advanced (stage IIIB) or metastatic (IV) non-small cell lung cancer (NSCLC) in a multicenter, randomized, open-label trial. ABRAXANE was administered as an intravenous infusion over 30 minutes at a dose of 100 mg/m2 on Days 1, 8, and 15 of each 21-day cycle. Paclitaxel injection was administered as an intravenous infusion over 3 hours at a dose of 200 mg/m2, following premedication. In both treatment arms carboplatin at a dose of AUC = 6 mg•min/mL was administered intravenously on Day 1 of each 21-day cycle after completion of ABRAXANE/paclitaxel infusion.
-The differences in paclitaxel dose and schedule between the two arms limit direct comparison of dose- and schedule-dependent adverse reactions. Among patients evaluable for adverse reactions, the median age was 60 years, 75% were men, 81% were White, 49% had adenocarcinoma, 43% had squamous cell lung cancer, 76% were ECOG PS 1. Patients in both treatment arms received a median of 6 cycles of treatment.
-The following common (≥ 10% incidence) adverse reactions were observed at a similar incidence in ABRAXANE plus carboplatin-treated and paclitaxel injection plus carboplatin-treated patients: alopecia 56%, nausea 27%, fatigue 25%, decreased appetite 17%, asthenia 16%, constipation 16%, diarrhea 15%, vomiting 12%, dyspnea 12%, and rash 10% (incidence rates are for the ABRAXANE plus carboplatin treatment group).
+Cardiovascular: [[vasodilation]], [[tachycardia]], [[deep vein thrombosis]], [[hypotension]], [[cardiac arrest]].
-TABLE 7 provides the frequency and severity of laboratory-detected abnormalities which occurred with a difference of ≥ 5% for all grades (1-4) or ≥ 2% for Grade 3-4 toxicity between ABRAXANE plus carboplatin-treated patients or paclitaxel injection plus carboplatin-treated patients.
+Digestive: oral [[moniliasis]], mouth [[ulceration]], [[esophagitis]], [[dysphagia]], [[rectal bleeding]], [[ileus]].
-xx
+Hematologic and Lymphatic: [[ecchymosis]].
-TABLE 8 provides the frequency and severity of adverse reactions, which occurred with a difference of ≥ 5% for all grades (1-4) or ≥ 2% for Grade 3-4 between either treatment group for the 514 ABRAXANE plus carboplatin-treated patients compared with the 524 patients who received paclitaxel injection plus carboplatin.
+Metabolic and Nutritional: [[dehydration]], [[weight loss]], [[hyperbilirubinemia]], [[hypokalemia]], [[hypercalcemia]], [[hyponatremia]].
-xx
+Nervous: [[somnolence]], [[dizziness]], [[depression]].
-For the ABRAXANE plus carboplatin treated group, 17/514 (3%) patients developed Grade 3 peripheral neuropathy and no patients developed Grade 4 peripheral neuropathy. Grade 3 neuropathy improved to Grade 1 or resolved in 10/17 patients (59%) following interruption or discontinuation of ABRAXANE.
+Respiratory: [[rhinitis]], [[pneumonia]], [[sinusitis]], [[epistaxis]].
-.3 Clinical Trials Experience in Adenocarcinoma of the Pancreas
+Skin and Appendages: [[pruritus]], skin [[discoloration]], vesiculobullous [[rash]], maculopapular rash, [[exfoliative dermatitis]], [[herpes zoster]], dry skin, [[herpes simplex]], [[fungal]] [[dermatitis]], [[furunculosis]], [[acne]].
-Adverse reactions were assessed in 421 patients who received ABRAXANE plus gemcitabine and 402 patients who received gemcitabine for the first-line systemic treatment of metastatic adenocarcinoma of the pancreas in a multicenter, multinational, randomized, controlled, open-label trial. Patients received a median treatment duration of 3.9 months in the ABRAXANE/gemcitabine group and 2.8 months in the gemcitabine group. For the treated population, the median relative dose intensity for gemcitabine was 75% in the ABRAXANE/gemcitabine group and 85% in the gemcitabine group. The median relative dose intensity of ABRAXANE was 81%.
-TABLE 9 provides the frequency and severity of laboratory-detected abnormalities which occurred Additional clinically relevant adverse reactions that were reported in < 10% of the patients with adenocarcinoma of the pancreas who received ABRAXANE/gemcitabine included:
+Special Senses: [[conjunctivitis]], taste perversion, dry eyes.
-Infections & infestations: oral candidiasis, pneumonia
+Urinary: [[urinary tract infection]], [[hematuria]], vaginal moniliasis.
-Vascular disorders: hypertension
-Cardiac disorders: tachycardia, congestive cardiac failure
-Eye disorders: cystoid macular edema
-Peripheral Neuropathy
+=====Patients With AIDS-Related Kaposi's Sarcoma=====
-Grade 3 peripheral neuropathy occurred in 17% of patients who received ABRAXANE/gemcitabine compared to 1% of patients who received gemcitabine only; no patients developed grade 4 peripheral neuropathy. The median time to first occurrence of Grade 3 peripheral neuropathy in the ABRAXANE arm was 140 days. Upon suspension of ABRAXANE dosing, the median time to improvement from Grade 3 peripheral neuropathy to ≤ Grade 1 was 29 days. Of ABRAXANE-treated patients with Grade 3 peripheral neuropathy, 44% resumed ABRAXANE at a reduced dose.
-Sepsis
+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.
-Sepsis occurred in 5% of patients who received ABRAXANE/gemcitabine compared to 2% of patients who received gemcitabine alone. Sepsis occurred both in patients with and without neutropenia. Risk factors for sepsis included biliary obstruction or presence of biliary stent.
-Pneumonitis
+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.
-Pneumonitis occurred in 4% of patients who received ABRAXANE/gemcitabine compared to 1% of patients who received gemcitabine alone. Two of 17 patients in the ABRAXANE arm with pneumonitis died.
-.4 Post-Marketing Experience with ABRAXANE and other Paclitaxel Formulations
+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.
-Unless otherwise noted, the following discussion refers to the adverse reactions that have been identified during post-approval use of ABRAXANE. 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. In some instances, severe events observed with paclitaxel injection may be expected to occur with ABRAXANE.
-Hypersensitivity Reactions
+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.
-Severe and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied.
-Cardiovascular
+[[File:Doxil table05.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
-There have been reports of congestive heart failure, left ventricular dysfunction, and atrioventricular block with ABRAXANE. Most of the individuals were previously exposed to cardiotoxic drugs, such as anthracyclines, or had underlying cardiac history.
-Respiratory
+[[File:Doxil table06.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
-There have been reports of pneumonitis, interstitial pneumonia and pulmonary embolism in patients receiving ABRAXANE and reports of radiation pneumonitis in patients receiving concurrent radiotherapy. Reports of lung fibrosis have been received as part of the continuing surveillance of paclitaxel injection safety and may also be observed with ABRAXANE.
-Neurologic
+The following additional adverse reactions were observed in 705 patients with AIDS-related Kaposi's sarcoma.
-Cranial nerve palsies and vocal cord paresis have been reported, as well as autonomic neuropathy resulting in paralytic ileus.
-Vision Disorders
+======Incidence 1% to 5%======
-Reports in the literature of abnormal visual evoked potentials in patients treated with paclitaxel injection suggest persistent optic nerve damage. These may also be observed with ABRAXANE.
-Reduced visual acuity due to cystoid macular edema (CME) has been reported during treatment with ABRAXANE as well as with other taxanes. After cessation of treatment, CME improves and visual acuity may return to baseline.
+Body as a Whole: [[headache]], [[back pain]], [[infection]], [[allergic reaction]], [[chills]].
-Hepatic
+Cardiovascular: [[chest pain]], [[hypotension]], [[achycardia]].
-Reports of hepatic necrosis and hepatic encephalopathy leading to death have been received as part of the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANE treatment.
-Gastrointestinal (GI)
+Cutaneous: [[herpes simplex]], [[rash]], [[itching]].
-There have been reports of intestinal obstruction, intestinal perforation, pancreatitis, and ischemic colitis following ABRAXANE treatment. There have been reports of neutropenic enterocolitis (typhlitis), despite the coadministration of G-CSF, occurring in patients treated with paclitaxel injection alone and in combination with other chemotherapeutic agents.
-Injection Site Reaction
+Digestive: mouth [[ulceration]], [[anorexia]], [[dysphagia]].
-There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible infiltration during drug administration.
-Severe events such as phlebitis, cellulitis, induration, necrosis, and fibrosis have been reported as part of the continuing surveillance of paclitaxel injection safety. In some cases the onset of the injection site reaction in paclitaxel injection patients either occurred during a prolonged infusion or was delayed by a week to ten days. Recurrence of skin reactions at a site of previous extravasation following administration of paclitaxel injection at a different site, i.e., “recall”, has been reported.
+Metabolic and Nutritional: [[SGPT]] increase, [[weight loss]], [[hyperbilirubinemia]].
-Other Clinical Events
+Other: [[dyspnea]], [[pneumonia]], [[dizziness]], [[somnolence]].
-Skin reactions including generalized or maculopapular rash, erythema, and pruritus have been observed with ABRAXANE. There have been case reports of photosensitivity reactions, radiation recall phenomenon, and in some patients previously exposed to capecitabine, reports of palmar-plantar erythrodysesthesia. Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported.
-There have been reports of conjunctivitis, cellulitis, and increased lacrimation with paclitaxel injection.
+======Incidence Less Than 1%======
-.5 Accidental Exposure
+Body As A Whole: [[sepsis]], [[moniliasis]], [[cryptococcosis]].
-No reports of accidental exposure to ABRAXANE have been received. However, upon inhalation of paclitaxel, dyspnea, chest pain, burning eyes, sore throat, and nausea have been reported. Following topical exposure, events have included tingling, burning, and redness.at a higher incidence for Grades 1-4 (≥ 5%) or for Grade 3-4 (≥ 2%) toxicity in ABRAXANE plus gemcitabine-treated patients.
-xx
+Cardiovascular: [[thrombophlebitis]], [[cardiomyopathy]], [[palpitation]], [[bundle branch block]], [[congestive heart failure]], [[heart arrest]], [[thrombosis]], [[ventricular arrhythmia]].
-TABLE 10 provides the frequency and severity of adverse reactions which occurred with a difference of ≥ 5% for all grades or ≥ 2% for Grade 3 or higher in the ABRAXANE plus gemcitabine-treated group compared to the gemcitabine group.
+Digestive: [[hepatitis]].
-xx
+Metabolic and Nutritional Disorders: [[dehydration]]
-Additional clinically relevant adverse reactions that were reported in < 10% of the patients with adenocarcinoma of the pancreas who received ABRAXANE/gemcitabine included:
+Respiratory: [[cough]] increase, [[pharyngitis]].
-Infections & infestations: oral candidiasis, pneumonia
+Skin and Appendages: maculopapular [[rash]], [[herpes zoster]].
-Vascular disorders: hypertension
-Cardiac disorders: tachycardia, congestive cardiac failure
-Eye disorders: cystoid macular edema
-Peripheral Neuropathy
+Special Senses: taste perversion, [[conjunctivitis]].
-Grade 3 peripheral neuropathy occurred in 17% of patients who received ABRAXANE/gemcitabine compared to 1% of patients who received gemcitabine only; no patients developed grade 4 peripheral neuropathy. The median time to first occurrence of Grade 3 peripheral neuropathy in the ABRAXANE arm was 140 days. Upon suspension of ABRAXANE dosing, the median time to improvement from Grade 3 peripheral neuropathy to ≤ Grade 1 was 29 days. Of ABRAXANE-treated patients with Grade 3 peripheral neuropathy, 44% resumed ABRAXANE at a reduced dose.
-Sepsis
+=====Patients With Multiple Myeloma=====
-Sepsis occurred in 5% of patients who received ABRAXANE/gemcitabine compared to 2% of patients who received gemcitabine alone. Sepsis occurred both in patients with and without neutropenia. Risk factors for sepsis included biliary obstruction or presence of biliary stent.
-Pneumonitis
+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]].
-Pneumonitis occurred in 4% of patients who received ABRAXANE/gemcitabine compared to 1% of patients who received gemcitabine alone. Two of 17 patients in the ABRAXANE arm with pneumonitis died.
+[[File:Doxil table06.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
-|postmarketing=====Post-Marketing Experience with ABRAXANE and other Paclitaxel Formulations====
+<!--Postmarketing Experience-->
-Unless otherwise noted, the following discussion refers to the adverse reactions that have been identified during post-approval use of ABRAXANE. 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. In some instances, severe events observed with paclitaxel injection may be expected to occur with ABRAXANE.
+|postmarketing=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.
-Hypersensitivity Reactions
+Musculoskeletal and Connective Tissue Disorders: [[muscle spasms]]
-Severe and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied.
-Cardiovascular
+Respiratory, Thoracic and Mediastinal Disorders: [[pulmonary embolism]] (in some cases fatal)
-There have been reports of congestive heart failure, left ventricular dysfunction, and atrioventricular block with ABRAXANE. Most of the individuals were previously exposed to cardiotoxic drugs, such as anthracyclines, or had underlying cardiac history.
-Respiratory
+Hematologic disorders: Secondary [[acute myelogenous leukemia]]
-There have been reports of pneumonitis, interstitial pneumonia and pulmonary embolism in patients receiving ABRAXANE and reports of radiation pneumonitis in patients receiving concurrent radiotherapy. Reports of lung fibrosis have been received as part of the continuing surveillance of paclitaxel injection safety and may also be observed with ABRAXANE.
-Neurologic
+Skin and subcutaneous tissue disorders: [[erythema multiforme]], [[Stevens-Johnson syndrome]], [[toxic epidermal necrolysis]]
-Cranial nerve palsies and vocal cord paresis have been reported, as well as autonomic neuropathy resulting in paralytic ileus.
-Vision Disorders
+<!--Drug Interactions-->
-Reports in the literature of abnormal visual evoked potentials in patients treated with paclitaxel injection suggest persistent optic nerve damage. These may also be observed with ABRAXANE.
+|drugInteractions=No formal drug interaction studies have been conducted with Doxil.
-Reduced visual acuity due to cystoid macular edema (CME) has been reported during treatment with ABRAXANE as well as with other taxanes. After cessation of treatment, CME improves and visual acuity may return to baseline.
+<!--Use in Specific Populations-->
+|useInPregnancyFDA======Risk Summary=====
-Hepatic
+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.
-Reports of hepatic necrosis and hepatic encephalopathy leading to death have been received as part of the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANE treatment.
-Gastrointestinal (GI)
+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.
-There have been reports of intestinal obstruction, intestinal perforation, pancreatitis, and ischemic colitis following ABRAXANE treatment. There have been reports of neutropenic enterocolitis (typhlitis), despite the coadministration of G-CSF, occurring in patients treated with paclitaxel injection alone and in combination with other chemotherapeutic agents.
-Injection Site Reaction
+=====Animal Data=====
-There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible infiltration during drug administration.
-Severe events such as phlebitis, cellulitis, induration, necrosis, and fibrosis have been reported as part of the continuing surveillance of paclitaxel injection safety. In some cases the onset of the injection site reaction in paclitaxel injection patients either occurred during a prolonged infusion or was delayed by a week to ten days. Recurrence of skin reactions at a site of previous extravasation following administration of paclitaxel injection at a different site, i.e., “recall”, has been reported.
+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.
+|useInLaborDelivery=<SMALL>There is no FDA guidance on use of {{PAGENAME}} during labor and delivery.</SMALL>
+|useInNursing=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.
+|useInPed=The safety and effectiveness of Doxil in pediatric patients have not been established.
+|useInGeri=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.
-Other Clinical Events
+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.
-Skin reactions including generalized or maculopapular rash, erythema, and pruritus have been observed with ABRAXANE. There have been case reports of photosensitivity reactions, radiation recall phenomenon, and in some patients previously exposed to capecitabine, reports of palmar-plantar erythrodysesthesia. Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported.
+|useInGender======Contraception=====
-There have been reports of conjunctivitis, cellulitis, and increased lacrimation with paclitaxel injection.
+======Females======
-==== Accidental Exposure====
+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.
-No reports of accidental exposure to ABRAXANE have been received. However, upon inhalation of paclitaxel, dyspnea, chest pain, burning eyes, sore throat, and nausea have been reported. Following topical exposure, events have included tingling, burning, and redness.
-|alcohol=Alcohol-Doxorubicin liposome interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
+======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.
+|useInRace=<SMALL>There is no FDA guidance on the use of {{PAGENAME}} with respect to specific racial populations.</SMALL>
+|useInRenalImpair=<SMALL>There is no FDA guidance on the use of {{PAGENAME}} in patients with renal impairment.</SMALL>
+|useInHepaticImpair=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.
+|useInReproPotential=<SMALL>There is no FDA guidance on the use of {{PAGENAME}} in women of reproductive potentials and males.</SMALL>
+|useInImmunocomp=<SMALL>There is no FDA guidance one the use of {{PAGENAME}} in patients who are immunocompromised.</SMALL>
+<!--Administration and Monitoring-->
+|administration=Intravenous
+|monitoring=<SMALL>There is limited information regarding <i>Monitoring</i> of {{PAGENAME}} in the drug label.</SMALL>
+<!--IV Compatibility-->
+|overdose=Acute overdosage with doxorubicin HCl causes increased risk of severe mucositis, leukopenia, and thrombocytopenia.
+<!--Pharmacology-->
+<!--Drug box 2-->
+|drugBox={{Drugbox2
+| Verifiedfields = changed
+| verifiedrevid = 458446335
+| IUPAC_name = (7S,9S)-7-[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7H-tetracene-5,12-dione
+| image = Doxorubicin2DCSD.png
+| image2 = Doxorubicin 3D ball.png
+<!--Clinical data-->
+| tradename = Adriamycin
+| Drugs.com = {{drugs.com|monograph|doxorubicin-hydrochloride}}
+| MedlinePlus = a682221
+| pregnancy_AU = D
+| pregnancy_US = D
+| pregnancy_category =
+| legal_AU = S4
+| legal_CA = Rx-only
+| legal_UK = POM
+| legal_US = Rx-only
+| legal_status =
+| routes_of_administration = [[Intravenous therapy|Intravenous]], intravesical
+<!--Pharmacokinetic data-->
+| bioavailability = 5% (Oral)
+| protein_bound = 75%<ref name = MSR/>
+| metabolism = Hepatic
+| elimination_half-life = Triphasic; 12 minutes, 3.3 hours, 30 hours. Mean: 1-3 hours<ref name = MSR>{{cite web|title=(doxorubicin) dosing, indications, interactions, adverse effects, and more|work=Medscape Reference|publisher=WebMD|accessdate=15 April 2014|url=http://reference.medscape.com/drug/doxorubicin-342120#showall}}</ref><ref name = MD>{{cite web|title=Doxorubicin|work=Martindale: The Complete Drug Reference|publisher=Pharmaceutical Press|date=19 December 2013|accessdate=15 April 2014|editor=Brayfield, A|url=http://www.medicinescomplete.com/mc/martindale/current/ms-21514-e.htm}}</ref>
+| excretion = Urine (5-12%), faeces (40-50%)<ref name = MSR/>
+<!--Identifiers-->
+| CASNo_Ref = {{cascite|correct|CAS}}
+| CAS_number_Ref = {{cascite|correct|??}}
+| CAS_number = 23214-92-8
+| ATC_prefix = L01
+| ATC_suffix = DB01
+| PubChem = 31703
+| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
+| DrugBank = DB00997
+| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
+| ChemSpiderID = 29400
+| UNII_Ref = {{fdacite|correct|FDA}}
+| UNII = 80168379AG
+| KEGG_Ref = {{keggcite|correct|kegg}}
+| KEGG = D03899
+| ChEBI_Ref = {{ebicite|correct|EBI}}
+| ChEBI = 28748
+| ChEMBL_Ref = {{ebicite|changed|EBI}}
+| ChEMBL = 53463
+<!--Chemical data-->
+| C=27 | H=29 | N=1 | O=11
+| molecular_weight = 543.52 [[Gram|g]]/[[Mole (unit)|mol]]
+| smiles = C[C@H]1[C@H]([C@H](C[C@@H](O1)O[C@H]2C[C@@](Cc3c2c(c4c(c3O)C(=O)c5cccc(c5C4=O)OC)O)(C(=O)CO)O)N)O
+| InChI = 1/C27H29NO11/c1-10-22(31)13(28)6-17(38-10)39-15-8-27(36,16(30)9-29)7-12-19(15) 26(35)21-20(24(12)33)23(32)11-4-3-5-14(37-2)18(11)25(21)34/h3-5,10,13,15, 17,22,29,31,33,35-36H,6-9,28H2,1-2H3/t10-,13-,15-,17-,22+,27-/m0/s1
+| InChIKey = AOJJSUZBOXZQNB-TZSSRYMLBG
+| StdInChI_Ref = {{stdinchicite|changed|chemspider}}
+| StdInChI = 1S/C27H29NO11/c1-10-22(31)13(28)6-17(38-10)39-15-8-27 (36,16(30)9-29)7-12-19(15)26(35)21-20(24(12)33)23 (32)11-4-3-5-14(37-2)18(11)25(21)34/h3-5,10,13,15, 17,22,29,31,33,35-36H,6-9,28H2,1-2H3/t10-,13-,15-,17-,22+,27-/m0/s1
+| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
+| StdInChIKey = AOJJSUZBOXZQNB-TZSSRYMLSA-N
+}}
+<!--Mechanism of Action-->
+|mechAction=The active ingredient of Doxil is doxorubicin HCl. The mechanism of action of doxorubicin HCl 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.
+<!--Structure-->
+|structure=Doxil (doxorubicin HCl liposome injection) is doxorubicin hydrochloride (HCl), an anthracycline topoisomerase II inhibitor, that is encapsulated in STEALTH® liposomes for intravenous use.
+The chemical name of doxorubicin HCl is (8S,10S)-10-[(3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl)oxy]-8-glycolyl-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12-naphthacenedione hydrochloride. The molecular formula is C27-H29 -NO11∙HCl; its molecular weight is 579.99.
+[[File:Doxil image01.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
+Doxil is a sterile, translucent, red liposomal dispersion in 10-mL or 30-mL glass, single use vials. Each vial contains 20 mg or 50 mg doxorubicin HCl at a concentration of 2 mg/mL and a pH of 6.5. The STEALTH liposome carriers are composed of cholesterol, 3.19 mg/mL; fully hydrogenated soy phosphatidylcholine (HSPC), 9.58 mg/mL; and N-(carbonyl-methoxypolyethylene glycol 2000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine sodium salt (MPEG-DSPE), 3.19 mg/mL. Each mL also contains ammonium sulfate, approximately 2 mg; histidine as a buffer; hydrochloric acid and/or sodium hydroxide for pH control; and sucrose to maintain isotonicity. Greater than 90% of the drug is encapsulated in the STEALTH liposomes.
+MPEG-DSPE has the following structural formula:
+[[File:Doxil image02.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
+HSPC has the following structural formula:
+[[File:Doxil image03.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
+Representation of a STEALTH liposome:
+[[File:Doxil image04.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
+<!--Pharmacodynamics-->
+|PD=<SMALL>There is limited information regarding <i>Pharmacodynamics</i> of {{PAGENAME}} in the drug label.</SMALL>
+<!--Pharmacokinetics-->
+|PK=The pharmacokinetic parameters for total doxorubicin following a single dose of Doxil infused over 30 minutes are presented in Table 8.
+[[File:Doxil table08.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
+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.
+Distribution:
+Direct measurement of liposomal doxorubicin shows that at least 90% of the drug (the assay used cannot quantify less than 5–10% free doxorubicin) remains liposome-encapsulated during circulation.
+In contrast to doxorubicin, which displays a large volume of distribution (range 700 to 1100 L/m2), the small steady state volume of distribution of liposomal doxorubicin suggests that Doxil is largely confined to vascular fluid. Doxorubicin becomes available after the liposomes are extravasated. Plasma protein binding of Doxil has not been determined; the plasma protein binding of doxorubicin is approximately 70%.
+Metabolism:
+Doxorubicinol, the major metabolite of doxorubicin, was detected at concentrations of 0.8 to 26.2 ng/mL in the plasma of patients who received 10 or 20 mg/m2 Doxil.
+Elimination:
+The plasma clearance of total doxorubicin from Doxil was 0.041 L/h/m2 at a dose of 20 mg/m2. Following administration of doxorubicin HCl, the plasma clearance of doxorubicin is 24 to 35 L/h/m2.`
+<!--Nonclinical Toxicology-->
+|nonClinToxic======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).
+<!--Clinical Studies-->
+|clinicalStudies======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.
+[[File:Doxil table09.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
+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.
+[[File:Doxil table10.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
+=====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 HCl.
+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.
+[[File:Doxil table11.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
+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.
+=====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).
+[[File:Doxil table12.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
+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. Survival continued to be followed after the interim analysis and survival data are not mature at this time. Efficacy results are as shown in Table 13 and Figure 1.
+[[File:Doxil table13.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
+[[File:Doxil image05.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
+<!--How Supplied-->
+|howSupplied=Doxil is a sterile, translucent, red liposomal dispersion in 10-mL or 30-mL glass, single use vials.
+Each 10-mL vial contains 20 mg doxorubicin HCl at a concentration of 2 mg/mL.
+Each 30-mL vial contains 50 mg doxorubicin HCl at a concentration of 2 mg/mL.
+The following individually cartoned vials are available:
+[[File:Doxil table14.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
+<!--Package Label-->
+|fdaPatientInfo======Cardiomyopathy=====
+Advise patients to contact their healthcare provider if they develop symptoms of heart failure.
+=====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.
+=====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).
+=====Stomatitis=====
+Advise patients to notify their healthcare provider if they develop painful redness, swelling, or sores in the mouth (symptoms of stomatitis).
+=====Embryofetal 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.
+Advise females and males of reproductive potential to use effective contraception during and for 6 months following treatment with Doxil.
+=====Lactation=====
+Advise females not to breastfeed during treatment with Doxil.
+=====Infertility=====
+Advise females and males of reproductive potential that Doxil may cause temporary or permanent infertility.
+=====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.
+<!--Precautions with Alcohol-->
+|alcohol=<SMALL>Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.</SMALL>
+<!--Brand Names-->
+|brandNames=*Doxil ®<ref>{{Cite web | title = DOXIL- doxorubicin hydrochloride injection, suspension, liposomal  | url =http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=21d9c619-7e94-49e2-ac41-31e9ea96554a }}</ref>
+*Lipodox
+<!--Look-Alike Drug Names-->
+|lookAlike=<!--Drug Shortage Status-->
+|packLabel=[[File:Doxil image06.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
+[[File:Doxil image07.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
+[[File:Doxil image08.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
+<!--Patient Counseling Information-->
+|useInPregnancyAUS=* '''Australian Drug Evaluation Committee (ADEC) Pregnancy Category'''
+<SMALL>There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of {{PAGENAME}} in women who are pregnant.</SMALL>
+|IVCompat=<SMALL>There is limited information regarding <i>IV Compatibility</i> of {{PAGENAME}} in the drug label.</SMALL>
+<!--Overdosage-->
+|drugShortage=
 }}
+<!--Category-->
+[[Category:Drug]]
+[[Category:Chemotherapy]]
+[[Category:Chemotherapeutic agents]]
+[[Category:Natural products]]
+[[Category:Anthracyclines]]