Doxil

— THERAPEUTIC DISORDERS TREATED —
  • Gynecologic cancers
  • Kaposi's sarcoma
  • Leukemias, lymphomas, and other hematologic cancers
PAGE CONTENTS
  • Jump to Section
  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Doxil Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Doxorubicin HCl (liposomal) 2mg/mL; dispersion for IV infusion after dilution; preservative-free.

    Pharmacological Class

    Anthracycline.

    How Supplied

    Single-dose vials (10mL, 25mL)—1

    How Supplied

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

    Storage

    Refrigerate unopened vials of Doxil at 2ºC to 8ºC (36ºF to 46ºF). Do not freeze. Discard unused portion. 

    Manufacturer

    Janssen Biotech, Inc.

    Generic Availability

    YES

    Doxil Indications

    Indications

    Ovarian cancer refractory to platinum-based chemotherapy.

    Doxil Dosage and Administration

    Adult

    Give by IV infusion at initial rate of 1mg/min; may increase rate to complete infusion over 1hr if no infusion reactions occur; may premedicate with antiemetics. 50mg/m2 once every 4 weeks until disease progression or unacceptable toxicity. Hepatic dysfunction (serum bilirubin ≥1.2mg/dL), hand-foot syndrome, hematologic toxicity (esp. ANC, platelets), or stomatitis: reduce dose. Consider total anthracycline and anthracenedione doses and irradiation when calculating total cumulative dose. See full labeling.

    Children

    Not established.

    Hepatic Impairment

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

    Other Modifications

    Females and Males of Reproductive Potential

    • Verify the pregnancy status of females of reproductive potential prior to initiation.

    • Advise females of reproductive potential to use effective contraception during and for 6 months after treatment with doxorubicin hydrochloride liposome injection.

    • Males with female sexual partners of reproductive potential should use effective contraception during and for 6 months after treatment with doxorubicin hydrochloride liposome injection.

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

    • Doxorubicin hydrochloride liposome injection 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.

    Doxil Contraindications

    Not Applicable

    Doxil Boxed Warnings

    Boxed Warning

    Cardiomyopathy. Infusion-related reactions.

    Boxed Warning

    Cardiomyopathy 

    • Doxorubicin hydrochloride liposome injection can cause myocardial damage, including acute left ventricular failure. The risk of cardiomyopathy was 11% when the cumulative anthracycline dose was between 450mg/m2 to 550mg/m2.
    • Assess left ventricular cardiac function prior to initiation of doxorubicin hydrochloride liposome injection and during and after treatment.

    Infusion-Related Reactions

    • Serious, life-threatening, and fatal infusion-related reactions can occur with doxorubicin hydrochloride liposome injection. Acute infusion-related reactions occurred in 11% of patients with solid tumors.
    • Withhold doxorubicin hydrochloride liposome injection for infusion-related reactions and resume at a reduced rate. Discontinue doxorubicin hydrochloride liposome injection for serious or life-threatening infusion-related reactions. 

    Doxil Warnings/Precautions

    Warnings/Precautions

    Not substitutable on a mg/mg basis with other doxorubicin products. Risk of cardiomyopathy (including left ventricular failure), acute infusion-related reactions. History of cardiovascular disease. Have medications to treat infusion-related reactions and resuscitative equipment available. Discontinue if serious infusion-related reactions occur. Monitor blood (esp. CBC + platelets), hepatic (esp. SGOT/SGPT, alkaline phosphatase), and cardiac function (eg, MUGA, ECG). Monitor periodically for secondary oral cancers with long-term use. Avoid extravasation. Hepatic impairment. Embryo-fetal toxicity. Advise females and males of reproductive potential to use effective contraception during and for 6 months after last dose. Pregnancy: avoid during 1st trimester. Nursing mothers: not recommended.

    Warnings/Precautions

    Cardiomyopathy

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

    • Assess left ventricular cardiac function (eg, MUGA or echocardiogram) prior to initiation of doxorubicin hydrochloride liposome injection, during treatment to detect acute changes, and after treatment to detect delayed cardiomyopathy. 

    • Administer doxorubicin hydrochloride liposome injection to patients with a history of cardiovascular disease only when the potential benefit of treatment outweighs the risk.

    Infusion-Related Reactions

    • Serious, life-threatening, and fatal infusion-related reactions characterized by one or more of the following symptoms can occur with doxorubicin hydrochloride liposome injection: 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.

    • Ensure that medications to treat infusion-related reactions and cardiopulmonary resuscitative equipment are available for immediate use prior to initiation of doxorubicin hydrochloride liposome injection. 

    • Initiate doxorubicin hydrochloride liposome injection infusions at a rate of 1 mg/min and increase rate as tolerated. Withhold doxorubicin hydrochloride liposome injection for Grade 1, 2, or 3 infusion-related reactions and resume at a reduced infusion rate. Discontinue doxorubicin hydrochloride liposome injection 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 doxorubicin hydrochloride liposome injection arm and 0.9% of patients in the topotecan arm, including 24% Grade 3 or 4 cases of HFS in doxorubicin hydrochloride liposome injection-treated patients and no Grade 3 or 4 cases in topotecan-treated patients. HFS was generally observed after 2 or 3 cycles of treatment but may occur earlier. 

    • Delay doxorubicin hydrochloride liposome injection for the first episode of Grade 2 or greater HFS. Discontinue doxorubicin hydrochloride liposome injection 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 doxorubicin hydrochloride liposome injection. 

    • Examine patients at regular intervals for the presence of oral ulceration or with any oral discomfort that may be indicative of secondary oral cancer.

    Embryo-Fetal Toxicity

    • Based on findings in animals and its mechanism of action, doxorubicin hydrochloride liposome injection can cause fetal harm when administered to a pregnant woman; avoid the use of doxorubicin hydrochloride liposome injection during the 1st trimester. 

    • Available human data do not establish the presence or absence of major birth defects and miscarriage related to the use of doxorubicin hydrochloride during the 2nd and 3rd trimesters. 

    • 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 doxorubicin hydrochloride liposome injection. 

    Pregnancy Considerations

    Based on findings in animals and its mechanism of action, doxorubicin hydrochloride liposome injection can cause fetal harm when administered to a  pregnant woman; avoid use of doxorubicin hydrochloride liposome injection during the 1st trimester. 

    Available human data do not establish the presence or absence of major birth defects and miscarriage related to the use of doxorubicin hydrochloride during the 2nd and 3rd trimesters. Advise pregnant women of the potential risk to a fetus.

    Nursing Mother Considerations

    It is not known whether doxorubicin hydrochloride liposome injection 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 breastfed infants from doxorubicin hydrochloride liposome injection, discontinue breastfeeding during treatment with doxorubicin hydrochloride liposome injection.

    Pediatric Considerations

    Safety and effectiveness of doxorubicin hydrochloride liposome injection in pediatric patients have not been established.

    Geriatric Considerations

    Clinical studies of doxorubicin hydrochloride liposome injection 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 doxorubicin hydrochloride liposome injection in combination with bortezomib for multiple myeloma, 37% were 65 years of age or older and 8% were 75 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients.

    Hepatic Impairment Considerations

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

    Other Considerations for Specific Populations

    Females and Males of Reproductive Potential

    • Verify the pregnancy status of females of reproductive potential prior to initiation.

    • Advise females of reproductive potential to use effective contraception during and for 6 months after treatment with doxorubicin hydrochloride liposome injection.

    • Males with female sexual partners of reproductive potential should use effective contraception during and for 6 months after treatment with doxorubicin hydrochloride liposome injection.

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

    • Doxorubicin hydrochloride liposome injection 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.

    Doxil Pharmacokinetics

    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 doxorubicin hydrochloride liposome injection is largely confined to vascular fluid. Doxorubicin becomes available after the liposomes are extravasated. Plasma protein binding of doxorubicin hydrochloride liposome injection has not been determined; the plasma protein binding of doxorubicin is approximately 70%.

    Elimination

    Hepatic.

    Doxil Interactions

    Interactions

    Caution with cyclosporine, phenobarbital, phenytoin, streptozocin, digoxin, myelosuppressants, others. Previous mediastinal irradiation, cyclophosphamide, other cardiotoxic drugs: monitor for cardiotoxicity and hepatotoxicity.

    Doxil Adverse Reactions

    Adverse Reactions

    Asthenia, fatigue, fever, anorexia, nausea, vomiting, stomatitis, diarrhea, constipation, hand-foot syndrome, rash, neutropenia, thrombocytopenia, anemia; infusion reactions, cardiovascular events (eg, cardiomyopathy, CHF, acute LV failure), recall of skin reaction from prior radiation therapy, toxoplasmosis, urine discoloration (red/orange).

    Doxil Clinical Trials

    Clinical Trials

    Ovarian Cancer

    Doxorubicin hydrochloride liposome injection was evaluated in 3 open-label, single-arm, clinical studies (Trials 1, 2, and 3) in 176 patients with metastatic ovarian cancer, of which 145 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 doxorubicin hydrochloride liposome injection at 50mg/m2 every 3 or 4 weeks for 3-6+ cycles in the absence of dose-limiting toxicity or disease progression.

    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.

    Results showed the following response rates in patients with refractory ovarian cancer: 22.2% (95% CI, 8.6-42.3) in Trial 1 (N=27); 17.1% (95% CI, 9.7-27.0) in Trial 2 (N=82); and 0% (95% CI, 0-9.7) in Trial 3 (N=36).

    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 8.1-19.3). 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.

    Doxorubicin hydrochloride liposome injection was also evaluated in a randomized, multicenter, open-label, trial (Trial 4) in 474 patients with epithelial ovarian cancer after platinum-based chemotherapy. Patients were randomized to receive either doxorubicin hydrochloride liposome injection 50mg/m2 every 4 weeks (n=239) or topotecan 1.5mg/m2 daily for 5 consecutive days every 3 weeks (n=235). The primary outcome measure was time to progression (TTP). Other endpoints included overall survival and objective response rate.

    Results showed that there was no statistically significant difference in TTP between doxorubicin hydrochloride liposome injection and topotecan, 4.1 vs 4.2 months, respectively (hazard ratio [HR], 0.96; 95% CI, 0.76-1.20; P =.62). Patients treated with doxorubicin hydrochloride liposome injection achieved an overall survival of 14.4 months vs 13.7 months for patients treated with topotecan (HR, 0.82; 95% CI, 0.68-1.00; P =.05).

    The overall response rate (ORR) was 19.7% (n=47) for the doxorubicin hydrochloride liposome injection arm, of which 3.8% (n=9) achieved complete response (CR) and 15.9% (38) achieved partial response (PR). The ORR was 17% (n=40) for the topotecan arm, of which 4.7% (n=11) achieved CR and 12.3% (n=29) achieved PR. The median duration of response was 6.9 months for doxorubicin hydrochloride liposome injection and 5.9 months for topotecan.

    Doxil Note

    Not Applicable

    Doxil Patient Counseling

    Patient Counseling

    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).

    Embryo-Fetal Toxicity 

    • Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider with a known or suspected pregnancy.
    • Advise females and males of reproductive potential to use effective contraception during and for 6 months following treatment with doxorubicin hydrochloride liposome injection.

    Doxil Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Doxorubicin HCl (liposomal) 2mg/mL; dispersion for IV infusion after dilution; preservative-free.

    Pharmacological Class

    Anthracycline.

    How Supplied

    Single-dose vials (10mL, 25mL)—1

    How Supplied

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

    Storage

    Refrigerate unopened vials of Doxil at 2ºC to 8ºC (36ºF to 46ºF). Do not freeze. Discard unused portion. 

    Manufacturer

    Janssen Biotech, Inc.

    Generic Availability

    YES

    Doxil Indications

    Indications

    AIDS-related Kaposi's sarcoma refractory or intolerance to prior systemic chemotherapy.

    Doxil Dosage and Administration

    Adult

    Give by IV infusion at initial rate of 1mg/min; may increase rate to complete infusion over 1hr if no infusion reactions occur; may premedicate with antiemetics. 20mg/m2 once every 3 weeks until disease progression or unacceptable toxicity. Hepatic dysfunction (serum bilirubin ≥1.2mg/dL), hand-foot syndrome, hematologic toxicity (esp. ANC, platelets), or stomatitis: reduce dose. Consider total anthracycline and anthracenedione doses and irradiation when calculating total cumulative dose. See full labeling.

    Children

    Not established.

    Hepatic Impairment

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

    Other Modifications

    Females and Males of Reproductive Potential

    • Verify the pregnancy status of females of reproductive potential prior to initiation.

    • Advise females of reproductive potential to use effective contraception during and for 6 months after treatment with doxorubicin hydrochloride liposome injection.

    • Males with female sexual partners of reproductive potential should use effective contraception during and for 6 months after treatment with doxorubicin hydrochloride liposome injection.

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

    • Doxorubicin hydrochloride liposome injection 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.

    Doxil Contraindications

    Not Applicable

    Doxil Boxed Warnings

    Boxed Warning

    Cardiomyopathy. Infusion-related reactions.

    Boxed Warning

    Cardiomyopathy 

    • Doxorubicin hydrochloride liposome injection can cause myocardial damage, including acute left ventricular failure. The risk of cardiomyopathy was 11% when the cumulative anthracycline dose was between 450mg/m2 to 550mg/m2.
    • Assess left ventricular cardiac function prior to initiation of doxorubicin hydrochloride liposome injection and during and after treatment.

    Infusion-Related Reactions

    • Serious, life-threatening, and fatal infusion-related reactions can occur with doxorubicin hydrochloride liposome injection. Acute infusion-related reactions occurred in 11% of patients with solid tumors.
    • Withhold doxorubicin hydrochloride liposome injection for infusion-related reactions and resume at a reduced rate. Discontinue doxorubicin hydrochloride liposome injection for serious or life-threatening infusion-related reactions. 

    Doxil Warnings/Precautions

    Warnings/Precautions

    Not substitutable on a mg/mg basis with other doxorubicin products. Risk of cardiomyopathy (including left ventricular failure), acute infusion-related reactions. History of cardiovascular disease. Have medications to treat infusion-related reactions and resuscitative equipment available. Discontinue if serious infusion-related reactions occur. Monitor blood (esp. CBC + platelets), hepatic (esp. SGOT/SGPT, alkaline phosphatase), and cardiac function (eg, MUGA, ECG). Monitor periodically for secondary oral cancers with long-term use. Avoid extravasation. Hepatic impairment. Embryo-fetal toxicity. Advise females and males of reproductive potential to use effective contraception during and for 6 months after last dose. Pregnancy: avoid during 1st trimester. Nursing mothers: not recommended.

    Warnings/Precautions

    Cardiomyopathy

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

    • Assess left ventricular cardiac function (eg, MUGA or echocardiogram) prior to initiation of doxorubicin hydrochloride liposome injection, during treatment to detect acute changes, and after treatment to detect delayed cardiomyopathy. 

    • Administer doxorubicin hydrochloride liposome injection to patients with a history of cardiovascular disease only when the potential benefit of treatment outweighs the risk.

    Infusion-Related Reactions

    • Serious, life-threatening, and fatal infusion-related reactions characterized by one or more of the following symptoms can occur with doxorubicin hydrochloride liposome injection: 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.

    • Ensure that medications to treat infusion-related reactions and cardiopulmonary resuscitative equipment are available for immediate use prior to initiation of doxorubicin hydrochloride liposome injection. 

    • Initiate doxorubicin hydrochloride liposome injection infusions at a rate of 1 mg/min and increase rate as tolerated. Withhold doxorubicin hydrochloride liposome injection for Grade 1, 2, or 3 infusion-related reactions and resume at a reduced infusion rate. Discontinue doxorubicin hydrochloride liposome injection 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 doxorubicin hydrochloride liposome injection arm and 0.9% of patients in the topotecan arm, including 24% Grade 3 or 4 cases of HFS in doxorubicin hydrochloride liposome injection-treated patients and no Grade 3 or 4 cases in topotecan-treated patients. HFS was generally observed after 2 or 3 cycles of treatment but may occur earlier. 

    • Delay doxorubicin hydrochloride liposome injection for the first episode of Grade 2 or greater HFS. Discontinue doxorubicin hydrochloride liposome injection 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 doxorubicin hydrochloride liposome injection. 

    • Examine patients at regular intervals for the presence of oral ulceration or with any oral discomfort that may be indicative of secondary oral cancer.

    Embryo-Fetal Toxicity

    • Based on findings in animals and its mechanism of action, doxorubicin hydrochloride liposome injection can cause fetal harm when administered to a pregnant woman; avoid the use of doxorubicin hydrochloride liposome injection during the 1st trimester. 

    • Available human data do not establish the presence or absence of major birth defects and miscarriage related to the use of doxorubicin hydrochloride during the 2nd and 3rd trimesters. 

    • 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 doxorubicin hydrochloride liposome injection. 

    Pregnancy Considerations

    Based on findings in animals and its mechanism of action, doxorubicin hydrochloride liposome injection can cause fetal harm when administered to a  pregnant woman; avoid use of doxorubicin hydrochloride liposome injection during the 1st trimester. 

    Available human data do not establish the presence or absence of major birth defects and miscarriage related to the use of doxorubicin hydrochloride during the 2nd and 3rd trimesters. Advise pregnant women of the potential risk to a fetus.

    Nursing Mother Considerations

    It is not known whether doxorubicin hydrochloride liposome injection 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 breastfed infants from doxorubicin hydrochloride liposome injection, discontinue breastfeeding during treatment with doxorubicin hydrochloride liposome injection.

    Pediatric Considerations

    Safety and effectiveness of doxorubicin hydrochloride liposome injection in pediatric patients have not been established.

    Geriatric Considerations

    Clinical studies of doxorubicin hydrochloride liposome injection 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 doxorubicin hydrochloride liposome injection in combination with bortezomib for multiple myeloma, 37% were 65 years of age or older and 8% were 75 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients.

    Hepatic Impairment Considerations

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

    Other Considerations for Specific Populations

    Females and Males of Reproductive Potential

    • Verify the pregnancy status of females of reproductive potential prior to initiation.

    • Advise females of reproductive potential to use effective contraception during and for 6 months after treatment with doxorubicin hydrochloride liposome injection.

    • Males with female sexual partners of reproductive potential should use effective contraception during and for 6 months after treatment with doxorubicin hydrochloride liposome injection.

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

    • Doxorubicin hydrochloride liposome injection 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.

    Doxil Pharmacokinetics

    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 doxorubicin hydrochloride liposome injection is largely confined to vascular fluid. Doxorubicin becomes available after the liposomes are extravasated. Plasma protein binding of doxorubicin hydrochloride liposome injection has not been determined; the plasma protein binding of doxorubicin is approximately 70%.

    Elimination

    Hepatic.

    Doxil Interactions

    Interactions

    Caution with cyclosporine, phenobarbital, phenytoin, streptozocin, digoxin, myelosuppressants, others. Previous mediastinal irradiation, cyclophosphamide, other cardiotoxic drugs: monitor for cardiotoxicity and hepatotoxicity.

    Doxil Adverse Reactions

    Adverse Reactions

    Asthenia, fatigue, fever, anorexia, nausea, vomiting, stomatitis, diarrhea, constipation, hand-foot syndrome, rash, neutropenia, thrombocytopenia, anemia; infusion reactions, cardiovascular events (eg, cardiomyopathy, CHF, acute LV failure), recall of skin reaction from prior radiation therapy, toxoplasmosis, urine discoloration (red/orange).

    Doxil Clinical Trials

    Clinical Trials

    AIDS-Related Kaposi’s Sarcoma

    Doxorubicin hydrochloride liposome injection was studied in an open-label, single-arm, multicenter study at a dose of 20mg/m2 every 3 weeks, until disease progression or unacceptable toxicity.

    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 2 of 3 treatments: bleomycin, vincristine or vinblastine, or doxorubicin) or as being intolerant to such therapy. Forty-nine of the 77 (64%) patients had received prior doxorubicin hydrochloride. 

    Of the 77 patients with refractory AIDS-related Kaposi’s Sarcoma, 34 were evaluable for investigator assessment and 42 were evaluable for indicator lesion assessment. In the investigatory assessment, the following results were observed among all evaluable patients (n=34) and evaluable patients who received prior doxorubicin (n=20), respectively:

    • Response (no complete responses in this population)

      • Partial (PR): 27% vs 30%

      • Stable: 29% vs 40%

      • Progression: 44% vs 30%

    • Duration of PR (Days)

      • Median: 73 vs 89

      • Range: 42+ to 210+ vs 42+ to 210+

    • Time to PR (Days)

      • Median: 43 vs 53

      • Range: 15 – 133 vs 15 – 109

    In the indicator lesion assessment, the following results were observed among all evaluable patients (n=42) and evaluable patients who received prior doxorubicin (n=23), respectively:

    • Response (no complete responses in this population)

      • Partial (PR): 48% vs 52%

      • Stable: 26% vs 30%

      • Progression: 26% vs 17%

    • Duration of PR (Days)

      • Median: 71 vs 79

      • Range: 22+ to 210+ vs 35 to 210+

    • Time to PR (Days)

      • Median: 22 vs 48

      • Range: 15 – 109 vs 15 – 109

    Retrospective efficacy analyses were performed in two trials that had subsets of patients who received single-agent doxorubicin hydrochloride liposome injection 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.

    Doxil Note

    Not Applicable

    Doxil Patient Counseling

    Patient Counseling

    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).

    Embryo-Fetal Toxicity 

    • Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider with a known or suspected pregnancy.
    • Advise females and males of reproductive potential to use effective contraception during and for 6 months following treatment with doxorubicin hydrochloride liposome injection.

    Doxil Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Doxorubicin HCl (liposomal) 2mg/mL; dispersion for IV infusion after dilution; preservative-free.

    Pharmacological Class

    Anthracycline.

    How Supplied

    Single-dose vials (10mL, 25mL)—1

    How Supplied

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

    Storage

    Refrigerate unopened vials of Doxil at 2ºC to 8ºC (36ºF to 46ºF). Do not freeze. Discard unused portion. 

    Manufacturer

    Janssen Biotech, Inc.

    Generic Availability

    YES

    Doxil Indications

    Indications

    Multiple myeloma, in combination with bortezomib, in patients not previously treated with bortezomib and who have received at least one prior therapy.

    Doxil Dosage and Administration

    Adult

    Give by IV infusion at initial rate of 1mg/min; may increase rate to complete infusion over 1hr if no infusion reactions occur; may premedicate with antiemetics. 30mg/m2 on day 4 of each cycle following bortezomib (see full labeling for bortezomib dose) for 8 cycles or until disease progression or unacceptable toxicity. Hepatic dysfunction (serum bilirubin ≥1.2mg/dL), hand-foot syndrome, hematologic toxicity (esp. ANC, platelets), or stomatitis: reduce dose. Consider total anthracycline and anthracenedione doses and irradiation when calculating total cumulative dose. See full labeling.

    Children

    Not established.

    Hepatic Impairment

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

    Other Modifications

    Females and Males of Reproductive Potential

    • Verify the pregnancy status of females of reproductive potential prior to initiation.

    • Advise females of reproductive potential to use effective contraception during and for 6 months after treatment with doxorubicin hydrochloride liposome injection.

    • Males with female sexual partners of reproductive potential should use effective contraception during and for 6 months after treatment with doxorubicin hydrochloride liposome injection.

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

    • Doxorubicin hydrochloride liposome injection 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.

    Doxil Contraindications

    Not Applicable

    Doxil Boxed Warnings

    Boxed Warning

    Cardiomyopathy. Infusion-related reactions.

    Boxed Warning

    Cardiomyopathy 

    • Doxorubicin hydrochloride liposome injection can cause myocardial damage, including acute left ventricular failure. The risk of cardiomyopathy was 11% when the cumulative anthracycline dose was between 450mg/m2 to 550mg/m2.
    • Assess left ventricular cardiac function prior to initiation of doxorubicin hydrochloride liposome injection and during and after treatment.

    Infusion-Related Reactions

    • Serious, life-threatening, and fatal infusion-related reactions can occur with doxorubicin hydrochloride liposome injection. Acute infusion-related reactions occurred in 11% of patients with solid tumors.
    • Withhold doxorubicin hydrochloride liposome injection for infusion-related reactions and resume at a reduced rate. Discontinue doxorubicin hydrochloride liposome injection for serious or life-threatening infusion-related reactions. 

    Doxil Warnings/Precautions

    Warnings/Precautions

    Not substitutable on a mg/mg basis with other doxorubicin products. Risk of cardiomyopathy (including left ventricular failure), acute infusion-related reactions. History of cardiovascular disease. Have medications to treat infusion-related reactions and resuscitative equipment available. Discontinue if serious infusion-related reactions occur. Monitor blood (esp. CBC + platelets), hepatic (esp. SGOT/SGPT, alkaline phosphatase), and cardiac function (eg, MUGA, ECG). Monitor periodically for secondary oral cancers with long-term use. Avoid extravasation. Hepatic impairment. Embryo-fetal toxicity. Advise females and males of reproductive potential to use effective contraception during and for 6 months after last dose. Pregnancy: avoid during 1st trimester. Nursing mothers: not recommended.

    Warnings/Precautions

    Cardiomyopathy

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

    • Assess left ventricular cardiac function (eg, MUGA or echocardiogram) prior to initiation of doxorubicin hydrochloride liposome injection, during treatment to detect acute changes, and after treatment to detect delayed cardiomyopathy. 

    • Administer doxorubicin hydrochloride liposome injection to patients with a history of cardiovascular disease only when the potential benefit of treatment outweighs the risk.

    Infusion-Related Reactions

    • Serious, life-threatening, and fatal infusion-related reactions characterized by one or more of the following symptoms can occur with doxorubicin hydrochloride liposome injection: 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.

    • Ensure that medications to treat infusion-related reactions and cardiopulmonary resuscitative equipment are available for immediate use prior to initiation of doxorubicin hydrochloride liposome injection. 

    • Initiate doxorubicin hydrochloride liposome injection infusions at a rate of 1 mg/min and increase rate as tolerated. Withhold doxorubicin hydrochloride liposome injection for Grade 1, 2, or 3 infusion-related reactions and resume at a reduced infusion rate. Discontinue doxorubicin hydrochloride liposome injection 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 doxorubicin hydrochloride liposome injection arm and 0.9% of patients in the topotecan arm, including 24% Grade 3 or 4 cases of HFS in doxorubicin hydrochloride liposome injection-treated patients and no Grade 3 or 4 cases in topotecan-treated patients. HFS was generally observed after 2 or 3 cycles of treatment but may occur earlier. 

    • Delay doxorubicin hydrochloride liposome injection for the first episode of Grade 2 or greater HFS. Discontinue doxorubicin hydrochloride liposome injection 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 doxorubicin hydrochloride liposome injection. 

    • Examine patients at regular intervals for the presence of oral ulceration or with any oral discomfort that may be indicative of secondary oral cancer.

    Embryo-Fetal Toxicity

    • Based on findings in animals and its mechanism of action, doxorubicin hydrochloride liposome injection can cause fetal harm when administered to a pregnant woman; avoid the use of doxorubicin hydrochloride liposome injection during the 1st trimester. 

    • Available human data do not establish the presence or absence of major birth defects and miscarriage related to the use of doxorubicin hydrochloride during the 2nd and 3rd trimesters. 

    • 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 doxorubicin hydrochloride liposome injection. 

    Pregnancy Considerations

    Based on findings in animals and its mechanism of action, doxorubicin hydrochloride liposome injection can cause fetal harm when administered to a  pregnant woman; avoid use of doxorubicin hydrochloride liposome injection during the 1st trimester. 

    Available human data do not establish the presence or absence of major birth defects and miscarriage related to the use of doxorubicin hydrochloride during the 2nd and 3rd trimesters. Advise pregnant women of the potential risk to a fetus.

    Nursing Mother Considerations

    It is not known whether doxorubicin hydrochloride liposome injection 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 breastfed infants from doxorubicin hydrochloride liposome injection, discontinue breastfeeding during treatment with doxorubicin hydrochloride liposome injection.

    Pediatric Considerations

    Safety and effectiveness of doxorubicin hydrochloride liposome injection in pediatric patients have not been established.

    Geriatric Considerations

    Clinical studies of doxorubicin hydrochloride liposome injection 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 doxorubicin hydrochloride liposome injection in combination with bortezomib for multiple myeloma, 37% were 65 years of age or older and 8% were 75 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients.

    Hepatic Impairment Considerations

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

    Other Considerations for Specific Populations

    Females and Males of Reproductive Potential

    • Verify the pregnancy status of females of reproductive potential prior to initiation.

    • Advise females of reproductive potential to use effective contraception during and for 6 months after treatment with doxorubicin hydrochloride liposome injection.

    • Males with female sexual partners of reproductive potential should use effective contraception during and for 6 months after treatment with doxorubicin hydrochloride liposome injection.

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

    • Doxorubicin hydrochloride liposome injection 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.

    Doxil Pharmacokinetics

    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 doxorubicin hydrochloride liposome injection is largely confined to vascular fluid. Doxorubicin becomes available after the liposomes are extravasated. Plasma protein binding of doxorubicin hydrochloride liposome injection has not been determined; the plasma protein binding of doxorubicin is approximately 70%.

    Elimination

    Hepatic.

    Doxil Interactions

    Interactions

    Caution with cyclosporine, phenobarbital, phenytoin, streptozocin, digoxin, myelosuppressants, others. Previous mediastinal irradiation, cyclophosphamide, other cardiotoxic drugs: monitor for cardiotoxicity and hepatotoxicity.

    Doxil Adverse Reactions

    Adverse Reactions

    Asthenia, fatigue, fever, anorexia, nausea, vomiting, stomatitis, diarrhea, constipation, hand-foot syndrome, rash, neutropenia, thrombocytopenia, anemia; infusion reactions, cardiovascular events (eg, cardiomyopathy, CHF, acute LV failure), recall of skin reaction from prior radiation therapy, toxoplasmosis, urine discoloration (red/orange).

    Doxil Clinical Trials

    Clinical Trials

    Multiple Myeloma

    The efficacy of doxorubicin hydrochloride liposome injection 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 doxorubicin hydrochloride liposome injection (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.

    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.

    Results showed that treatment with doxorubicin hydrochloride liposome injection plus bortezomib achieved a significant improvement in TTP compared with bortezomib alone (HR, 0.55; 95% CI, 0.43-0.71; P <.001). There were 99 patients in the combination arm who had disease progression or death due to progression compared with 150 patients in the bortezomib alone arm. The median duration of response was 10.2 months (95% CI, 10.2-12.9) for the combination arm and 7 months (95% CI, 5.9-8.3) for the bortezomib alone arm.

    At the final analysis of survival, 78% of subjects in the doxorubicin hydrochloride liposome injection and bortezomib combination therapy group and 80% of subjects in the bortezomib monotherapy group had died after a median follow up of 8.6 years. The median survival was 33 months in the doxorubicin hydrochloride liposome injection and bortezomib combination therapy group and 31 months in the bortezomib monotherapy group. There was no difference observed in  overall survival at the final analysis

    Doxil Note

    Not Applicable

    Doxil Patient Counseling

    Patient Counseling

    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).

    Embryo-Fetal Toxicity 

    • Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider with a known or suspected pregnancy.
    • Advise females and males of reproductive potential to use effective contraception during and for 6 months following treatment with doxorubicin hydrochloride liposome injection.

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