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Doxil

Doxil(doxorubicin hcl liposome) – Janssen

BOXED WARNING

May lead to cardiac toxicity. Myocardial damage may lead to congestive heart failure (CHF) when cumulative dose approaches 550mg/m2; include prior use of anthracyclines or anthracenediones in cumulative dose calculations. Cardiac toxicity may occur at lower cumulative doses with prior mediastinal irradiation or concurrent cyclophosphamide therapy. Acute infusion-associated reactions reported. Severe myelosuppression may occur. Reduce dose with impaired hepatic function. Severe side effects reported with accidental substitution for doxorubicin HCl; do not substitute on mg-per-mg basis.

View FDA-Approved Full Prescribing Information for Doxil

THERAPEUTIC CLASS

Anthracycline

INDICATIONS

Treatment of ovarian cancer that has progressed or recurred after platinum-based chemotherapy. Treatment of AIDS-related Kaposi's sarcoma (KS) in patients after failure of/intolerance to prior systemic chemotherapy. In combination with bortezomib for the treatment of multiple myeloma (MM) in patients who have not previously received bortezomib and have received at least 1 prior therapy.

ADULT DOSAGE

Adults: Administer as IV infusion at initial rate of 1mg/min to minimize risk of infusion-related reactions; if no reactions, may increase rate to complete infusion over 1 hr. Ovarian Cancer: 50mg/m2 IV every 4 weeks (for as long as patient tolerates treatment, does not progress, and has no evidence of cardiotoxicity) for a minimum of 4 courses. Consider pretreatment with or concomitant antiemetics. KS: 20mg/m2 IV every 3 weeks for as long as responding satisfactorily and tolerating treatment. MM: Give bortezomib 1.3mg/m2 IV bolus on Days 1, 4, 8, and 11, every 3 weeks. Give doxorubicin 30mg/m2 IV as a 1-hr IV infusion on Day 4 following bortezomib. May treat for up to 8 cycles until disease progression or occurrence of unacceptable toxicity. Hepatic Dysfunction: If serum bilirubin 1.2-3mg/dL, give 50% of normal dose. If serum bilirubin >3mg/dL, give 25% of normal dose. Adjust or delay dose based on toxicities; refer to PI for recommended dose modification guidelines.

HOW SUPPLIED

Inj: 2mg/mL [10mL, 30mL]

WARNINGS/PRECAUTIONS

Monitor cardiac function. Administer only when benefits outweigh the risks in patients with a history of cardiovascular disease (CVD). Potential for myelosuppression; perform hematological monitoring during use, including WBC, neutrophil, platelet counts, and Hgb/Hct. If hematologic toxicity occurs, dose reduction, delay of therapy, or suspension of therapy may be required. Hand-foot syndrome (HFS) reported; may need to modify dose or d/c. Recall reaction reported after radiotherapy. May cause fetal harm. Avoid extravasation.

ADVERSE REACTIONS

Cardiac toxicity, myelosuppression, neutropenia, anemia, thrombocytopenia, stomatitis, fever, fatigue, N/V, asthenia, acute infusion-related reactions, diarrhea, constipation, HFS.

DRUG INTERACTIONS

See Boxed Warning. May potentiate toxicity of other anticancer therapies. May exacerbate cyclophosphamide-induced hemorrhagic cystitis. May enhance hepatotoxicity of 6-mercaptopurine. May increase radiation-induced toxicity of the myocardium, mucosa, skin, and liver. Hematological toxicity may be more severe with agents that cause bone-marrow suppression.

PREGNANCY

Category D, not for use in nursing.

MECHANISM OF ACTION

Anthracycline topoisomerase inhibitor; suspected to bind DNA and inhibit nucleic acid synthesis.

PHARMACOKINETICS

Absorption: (10mg/m2) Cmax=4.12µg/mL, AUC=277µg/mL•h. (20mg/m2) Cmax=8.34µg/mL, AUC=590µg/mL•h. Distribution: (10mg/m2) Vd=2.83L/m2; (20mg/m2) Vd=2.72L/m2. Metabolism: Doxorubicinol (major metabolite). Elimination: 1st Phase: T1/2=4.7 hrs (10mg/m2); 5.2 hrs (20mg/m2). 2nd Phase: T1/2=52.3 hrs (10mg/m2); 55 hrs (20mg/m2).

ASSESSMENT

Assess for history of CVD, hepatic dysfunction, hypersensitivity, pregnancy/nursing status, history of drug/radiotherapy use, and for possible drug interactions. Obtain baseline WBC, neutrophil, platelet counts, Hgb/Hct, and hepatic/cardiac function.

MONITORING

Monitor signs/symptoms of cardiotoxicity, infusion reactions, myelosuppression, radiation recall reaction, extravasation, hand-foot syndrome, and hypersensitivity reactions. Periodically monitor hepatic and cardiac function (endomyocardial biopsy, ECG, multigated radionuclide scan). CBC, including platelet counts, should be frequently obtained; at least once prior to each dose.

PATIENT COUNSELING

Inform that reddish-orange color may appear in urine and other bodily fluids may occur. Advise of pregnancy risks. Instruct to notify physician if symptoms of infusion reaction (eg, flushing, tightness in chest, or throat), HFS (eg, tingling, burning, redness, flaking, bothersome swelling, small blisters), fever of 100.5oF or higher, N/V, tiredness, weakness, rash, mild hair loss, or stomatitis occur.

ADMINISTRATION/STORAGE

Administration: IV route. Refer to PI for instructions on handling, preparation, administration, and disposal. Storage: Diluted/Undiluted Sol: 2-8°C (36-46°F). Administer diluted sol within 24 hrs. Avoid freezing.


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    Doxil

    Doxil

    Generic Name: doxorubicin hydrochloride

    Dosage Form: injection, suspension, liposomal

    For ProfessionalsSide EffectsInteractionsMore…

    WARNING: INFUSION REACTIONS, MYELOSUPPRESSION, CARDIOTOXICITY, LIVER IMPAIRMENT, ACCIDENTAL SUBSTITUTION

    1.
    The use of Doxil (doxorubicin HCl liposome injection) may lead to cardiac toxicity. Myocardial damage may lead to congestive heart failure and may occur as the total cumulative dose of doxorubicin HCl approaches 550 mg/m2. In a clinical study in patients with advanced breast cancer, 250 patients received Doxil at a starting dose of 50 mg/m2 every 4 weeks. At all cumulative anthracycline doses between 450–500 mg/m2 or between 500–550 mg/m2, the risk of cardiac toxicity for patients treated with Doxil was 11%. Prior use of other anthracyclines or anthracenediones should be included in calculations of total cumulative dosage. Cardiac toxicity may also occur at lower cumulative doses in patients with prior mediastinal irradiation or who are receiving concurrent cyclophosphamide therapy [see Warnings and Precautions (5.1)].
    2.
    Acute infusion-related reactions including, but not limited to, flushing, shortness of breath, facial swelling, headache, chills, back pain, tightness in the chest or throat, and/or hypotension have occurred in up to 10% of patients treated with Doxil. In most patients, these reactions resolve over the course of several hours to a day once the infusion is terminated. In some patients, the reaction has resolved with slowing of the infusion rate. Serious and sometimes life-threatening or fatal allergic/anaphylactoid-like infusion reactions have been reported. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use. Doxil should be administered at an initial rate of 1 mg/min to minimize the risk of infusion reactions [see Warnings and Precautions (5.2)].
    3.
    Severe myelosuppression may occur [see Warnings and Precautions (5.3)].
    4.
    Dosage should be reduced in patients with impaired hepatic function [see Dosage and Administration (2.6) and Use in Specific Populations (8.6)].
    5.
    Accidental substitution of Doxil for doxorubicin HCl has resulted in severe side effects. Doxil should not be substituted for doxorubicin HCl on a mg per mg basis [see Dosage and Administration (2.1)].

    Indications and Usage for Doxil

    Ovarian Cancer

    Doxil (doxorubicin HCl liposome injection) 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.

    Doxil Dosage and Administration

    Usage and Administration Precautions

    Liposomal encapsulation can substantially affect a drug’s functional properties relative to those of the unencapsulated drug. Therefore DO NOT SUBSTITUTE one drug for the other.

    Do not administer as a bolus injection or an undiluted solution. Rapid infusion may increase the risk of infusion-related reactions [see Warnings and Precautions (5.2)]. Doxil must not be given by the intramuscular or subcutaneous route.

    Until specific compatibility data are available, it is not recommended that Doxil be mixed with other drugs.

    Doxil should be considered an irritant and precautions should be taken to avoid extravasation. With intravenous administration of Doxil, extravasation may occur with or without an accompanying stinging or burning sensation, even if blood returns well on aspiration of the infusion needle. If any signs or symptoms of extravasation have occurred, the infusion should be immediately terminated and restarted in another vein. The application of ice over the site of extravasation for approximately 30 minutes may be helpful in alleviating the local reaction.

    Patients With Ovarian Cancer

    Doxil (doxorubicin HCl liposome injection) should be administered intravenously at a dose of 50 mg/m2 (doxorubicin HCl equivalent) at an initial rate of 1 mg/min to minimize the risk of infusion reactions. If no infusion-related adverse reactions are observed, the rate of infusion can be increased to complete administration of the drug over one hour. The patient should be dosed once every 4 weeks, for as long as the patient does not progress, shows no evidence of cardiotoxicity [see Warnings and Precautions (5.1)], and continues to tolerate treatment. A minimum of 4 courses is recommended because median time to response in clinical trials was 4 months. To manage adverse reactions such as hand-foot syndrome (HFS), stomatitis, or hematologic toxicity the doses may be delayed or reduced [see Dosage and Administration (2.5)]. Pretreatment with or concomitant use of antiemetics should be considered.

    Patients With AIDS-Related Kaposi’s Sarcoma

    Doxil (doxorubicin HCl liposome injection) should be administered intravenously at a dose of 20 mg/m2 (doxorubicin HCl equivalent). An initial rate of 1 mg/min should be used to minimize the risk of infusion-related reactions. If no infusion-related adverse reactions are observed, the infusion rate should be increased to complete the administration of the drug over one hour. The dose should be repeated once every three weeks, for as long as patients respond satisfactorily and tolerate treatment.

    Patients With Multiple Myeloma

    Bortezomib is administered at a dose of 1.3 mg/m2 as intravenous bolus on days 1, 4 , 8 and 11, every three weeks. Doxil 30 mg/m2 should be administered as a 1-hr intravenous infusion on day 4 following bortezomib. With the first Doxil dose, an initial rate of 1 mg/min should be used to minimize the risk of infusion-related reactions. If no infusion-related adverse reactions are observed, the infusion rate should be increased to complete the administration of the drug over one hour. Patients may be treated for up to 8 cycles until disease progression or the occurrence of unacceptable toxicity.

    Dose Modification Guidelines

    Doxil exhibits nonlinear pharmacokinetics at 50 mg/m2; therefore, dose adjustments may result in a non-proportional greater change in plasma concentration and exposure to the drug [see Clinical Pharmacology (12.3)].

    Patients should be carefully monitored for toxicity. Adverse reactions, such as HFS, hematologic toxicities, and stomatitis may be managed by dose delays and adjustments. Following the first appearance of a Grade 2 or higher adverse reactions, the dosing should be adjusted or delayed as described in the following tables. Once the dose has been reduced, it should not be increased at a later time.

    Recommended Dose Modification Guidelines

    Table 1: Hand-Foot Syndrome (HFS)
    Toxicity Grade Dose Adjustment
    1

    (mild erythema, swelling, or desquamation not interfering with daily activities)

    Redose unless patient has experienced previous Grade 3 or 4 HFS. If so, delay up to 2 weeks and decrease dose by 25%. Return to original dose interval.
       
    2

    (erythema, desquamation, or swelling interfering with, but not precluding normal physical activities; small blisters or ulcerations less than 2 cm in diameter)

    Delay dosing up to 2 weeks or until resolved to Grade 0–1. If after 2 weeks there is no resolution, Doxil should be discontinued. If resolved to Grade 0–1 within 2 weeks, and there are no prior Grade 3–4 HFS, continue treatment at previous dose and return to original dose interval. If patient experienced previous Grade 3–4 toxicity, continue treatment with a 25% dose reduction and return to original dose interval.
       
    3

    (blistering, ulceration, or swelling interfering with walking or normal daily activities; cannot wear regular clothing)

    Delay dosing up to 2 weeks or until resolved to Grade 0–1. Decrease dose by 25% and return to original dose interval. If after 2 weeks there is no resolution, Doxil should be discontinued.
       
    4

    (diffuse or local process causing infectious complications, or a bed ridden state or hospitalization)

    Delay dosing up to 2 weeks or until resolved to Grade 0–1. Decrease dose by 25% and return to original dose interval. If after 2 weeks there is no resolution, Doxil should be discontinued.
    Table 2: Hematological Toxicity
    Grade ANC Platelets Modification
    1 1,500 – 1,900 75,000 – 150,000 Resume treatment with no dose reduction
    2 1,000 – <1,500 50,000 – <75,000 Wait until ANC ≥ 1,500 and platelets ≥ 75,000; redose with no dose reduction
    3 500 – 999 25,000 – <50,000 Wait until ANC ≥ 1,500 and platelets ≥ 75,000; redose with no dose reduction
    4 <500 <25,000 Wait until ANC ≥ 1,500 and platelets ≥ 75,000; redose at 25% dose reduction or continue full dose with cytokine support
    Table 3: Stomatitis
    Toxicity Grade Dose Adjustment
    1

    (painless ulcers, erythema, or mild soreness)

    Redose unless patient has experienced previous Grade 3 or 4 toxicity. If so, delay up to 2 weeks and decrease dose by 25%. Return to original dose interval.
       
    2

    (painful erythema, edema, or ulcers, but can eat)

    Delay dosing up to 2 weeks or until resolved to Grade 0–1. If after 2 weeks there is no resolution, Doxil should be discontinued. If resolved to Grade 0–1 within 2 weeks and there was no prior Grade 3–4 stomatitis, continue treatment at previous dose and return to original dose interval. If patient experienced previous Grade 3–4 toxicity, continue treatment with a 25% dose reduction and return to original dose interval.

       
    3

    (painful erythema, edema, or ulcers, and cannot eat)

    Delay dosing up to 2 weeks or until resolved to Grade 0–1. Decrease dose by 25% and return to original dose interval. If after 2 weeks there is no resolution, Doxil should be discontinued.
       
    4

    (requires parenteral or enteral support)

    Delay dosing up to 2 weeks or until resolved to Grade 0–1. Decrease dose by 25% and return to Doxil original dose interval. If after 2 weeks there is no resolution, Doxil should be discontinued.

    Multiple Myeloma

    For patients treated with Doxil in combination with bortezomib who experience hand-foot syndrome or stomatitis, the Doxil dose should be modified as described in Tables 1 and 3 above. Table 4 describes dosage adjustments for Doxil and bortezomib combination therapy. For bortezomib dosing and dosage adjustments, see manufacturer’s prescribing information.

    Table 4: Dosage adjustments for Doxil + bortezomib combination therapy
    Patient status Doxil bortezomib
    Fever ≥38°C and ANC <1,000/mm3 Do not dose this cycle if before Day 4; if after Day 4, reduce next dose by 25%. Reduce next dose by 25%
         
    On any day of drug administration after Day 1 of each cycle:

    Platelet count <25,000/mm3 Hemoglobin <8g/dL

    ANC <500/mm3

    Do not dose this cycle if before Day 4; if after Day 4 reduce next dose by 25% in the following cycles if bortezomib is reduced for hematologic toxicity. Do not dose; if 2 or more doses are not given in a cycle, reduce dose by 25% in following cycles.
         
    Grade 3 or 4 non-hematologic drug related toxicity Do not dose until recovered to Grade <2 and reduce dose by 25% for all subsequent doses. Do not dose until recovered to Grade <2 and reduce dose by 25% for all subsequent doses.
         
    Neuropathic pain or peripheral neuropathy No dosage adjustments. See bortezomib manufacturer’s prescribing information for dosage adjustments in patients with neuropathic pain.

    Patients With Impaired Hepatic Function

    Limited clinical experience exists in treating patients with hepatic impairment with Doxil. Based on experience with doxorubicin HCl, it is recommended that the Doxil dosage be reduced if the bilirubin is elevated as follows: serum bilirubin 1.2 to 3.0 mg/dL – give ½ normal dose; serum bilirubin > 3 mg/dL – give ¼ normal dose.

    No information, including dosage adjustments, is available for patients with multiple myeloma with hepatic impairment.

    Preparation for Intravenous Administration

    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.

    Doxil doses up to 90 mg must be diluted in 250 mL of 5% Dextrose Injection, USP prior to administration. Doses exceeding 90 mg should be diluted in 500 mL of 5% Dextrose Injection, USP prior to administration. Aseptic technique must be strictly observed since no preservative or bacteriostatic agent is present in Doxil. Diluted Doxil should be refrigerated at 2°C to 8°C (36°F to 46°F) and administered within 24 hours.

    Do not use with in-line filters.

    Do not mix with other drugs.

    Do not use with any diluent other than 5% Dextrose Injection.

    Do not use any bacteriostatic agent, such as benzyl alcohol.

    Doxil is not a clear solution but a translucent, red liposomal dispersion.

    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.

    Rapid flushing of the infusion line should be avoided.

    Procedure for Proper Handling and Disposal

    Caution should be exercised in the handling and preparation of Doxil.

    The use of gloves is required.

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

    Doxil should be considered an irritant and precautions should be taken to avoid extravasation. With intravenous administration of Doxil, extravasation may occur with or without an accompanying stinging or burning sensation, even if blood returns well on aspiration of the infusion needle. If any signs or symptoms of extravasation have occurred, the infusion should be immediately terminated and restarted in another vein. Doxil must not be given by the intramuscular or subcutaneous route.

    Doxil should be handled and disposed of in a manner consistent with other anticancer drugs. Several guidelines on this subject exist [see References (15)].

    Dosage Forms and Strengths

    • Single use vial: 20 mg/10 mL
    • Single use vial: 50 mg/25 mL

    Contraindications

    Doxil (doxorubicin HCl liposome injection) is contraindicated in patients who have a history of hypersensitivity reactions to a conventional formulation of doxorubicin HCl or the components of Doxil [see Warnings and Precautions (5.2)].

    Warnings and Precautions

    Cardiac Toxicity

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

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

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

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

    Table 5: Number of Patients With Advanced Breast Cancer
    Doxil (n=250)
    Patients who Developed Cardiotoxicity (LVEF Defined) 10
      Cardiotoxicity (With Signs & Symptoms of CHF) 0
      Cardiotoxicity (no Signs & Symptoms of CHF) 10
    Patients With Signs and Symptoms of CHF Only 2

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

    Infusion Reactions

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

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

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

    The initial rate of infusion should be 1 mg/min to help minimize the risk of infusion reactions [see Dosage and Administration (2)].

    Myelosuppression

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

    Doxil may potentiate the toxicity of other anticancer therapies. In particular, hematologic toxicity may be more severe when Doxil is administered in combination with other agents that cause bone marrow suppression.

    In patients with relapsed ovarian cancer, myelosuppression was generally moderate and reversible. In the three single-arm studies, anemia was the most common hematologic adverse reaction (52.6%), followed by leukopenia (WBC< 4,000 mm3; 42.2%), thrombocytopenia (24.2%), and neutropenia (ANC <1,000; 19.0%). In the randomized study, anemia was the most common hematologic adverse reaction (40.2%), followed by leukopenia (WBC <4,000 mm3; 36.8%), neutropenia (ANC <1,000; 35.1%), and thrombocytopenia (13.0%) [see Adverse Reactions (6.2)].

    In patients with relapsed ovarian cancer, 4.6% received G-CSF (or GM-CSF) to support their blood counts [see Dosage and Administrations (2.5)].

    For patients with AIDS-related Kaposi’s sarcoma who often present with baseline myelosuppression due to such factors as their HIV disease or concomitant medications, myelosuppression appears to be the dose-limiting adverse reaction at the recommended dose of 20 mg/m2 [see Adverse Reactions (6.2)]. Leukopenia is the most common adverse reaction experienced in this population; anemia and thrombocytopenia can also be expected. Sepsis occurred in 5% of patients; for 0.7% of patients the event was considered possibly or probably related to Doxil. Eleven patients (1.6%) discontinued study because of bone marrow suppression or neutropenia.

    Table 10 presents data on myelosuppression in patients with multiple myeloma receiving Doxil and bortezomib in combination [see Adverse Reactions (6.2)].

    Hand-Foot Syndrome (HFS)

    In the randomized ovarian cancer study, 50.6% of patients treated with Doxil at 50 mg/m2 every 4 weeks experienced HFS (developed palmar-plantar skin eruptions characterized by swelling, pain, erythema and, for some patients, desquamation of the skin on the hands and the feet), with 23.8% of the patients reporting HFS Grade 3 or 4 events. Ten subjects (4.2%) discontinued treatment due to HFS or other skin toxicity. HFS toxicity grades are described above [see definitions of HFS grades in Dosage and Administration (2.5)].

    Among 705 patients with AIDS-related Kaposi’s sarcoma treated with Doxil at 20 mg/m2 every 2 weeks, 24 (3.4%) developed HFS, with 3 (0.9%) discontinuing.

    In the randomized multiple myeloma study, 19% of patients treated with Doxil at 30 mg/m2 every three weeks experienced HFS.

    HFS was generally observed after 2 or 3 cycles of treatment but may occur earlier. In most patients the reaction is mild and resolves in one to two weeks so that prolonged delay of therapy need not occur. However, dose modification may be required to manage HFS [see Dosage and Administration (2.5)]. The reaction can be severe and debilitating in some patients and may require discontinuation of treatment.

    Radiation Recall Reaction

    Recall reaction has occurred with Doxil administration after radiotherapy.

    Fetal Mortality

    Pregnancy Category D

    Doxil can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies in pregnant women. If Doxil is to be used during pregnancy, or if the patient becomes pregnant during therapy, the patient should be apprised of the potential hazard to the fetus. If pregnancy occurs in the first few months following treatment with Doxil, the prolonged half-life of the drug must be considered. Women of childbearing potential should be advised to avoid pregnancy during treatment with Doxil. [see Use in Specific Populations (8.1)].

    Toxicity Potentiation

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

    Monitoring: Laboratory Tests

    Complete blood counts, including platelet counts, should be obtained frequently and at a minimum prior to each dose of Doxil [see Warnings and Precautions (5.3)].

    Adverse Reactions

    Overall Adverse Reactions Profile

    The following adverse reactions are discussed in more detail in other sections of the labeling.

    • Cardiac Toxicity [see Warnings and Precautions (5.1)]
    • Infusion reactions [see Warnings and Precautions (5.2)]
    • Myelosuppression [see Warnings and Precautions (5.3)]
    • Hand-Foot syndrome [see Warnings and Precautions (5.4)]

    The most common adverse reactions observed with Doxil are asthenia, fatigue, fever, nausea, stomatitis, vomiting, diarrhea, constipation, anorexia, hand-foot syndrome, rash and neutropenia, thrombocytopenia and anemia.

    The most common serious adverse reactions observed with Doxil are described in Section 6.2.

    The safety data described below 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 [see Adverse Reactions in Clinical Trials (6.2)].

    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 following tables present adverse reactions from clinical trials of Doxil in ovarian cancer and AIDS-Related Kaposi’s sarcoma.

    Patients With Ovarian Cancer

    The safety data described below are from 239 patients with ovarian cancer treated with Doxil (doxorubicin HCl liposome injection) at 50 mg/m2 once every 4 weeks for a minimum of 4 courses in a randomized, multicenter, open-label study. In this study, patients received Doxil for a median number of 98.0 days (range 1–785 days). The population studied was 27–87 years of age, 91% Caucasian, 6% Black and 3% Hispanic and other.

    Table 6 presents the hematologic adverse reactions from the randomized study of Doxil compared to topotecan.

    Table 6: Ovarian Cancer Randomized Study Hematology Data Reported in Patients With Ovarian Cancer
    Doxil Patients

    (n = 239)

    Topotecan Patients

    (n = 235)

    Neutropenia
      500 – <1000/mm3 19 (7.9%) 33 (14.0%)
      <500/mm3 10 (4.2%) 146 (62.1%)
    Anemia
      6.5 – <8 g/dL 13 (5.4%) 59 (25.1%)
      < 6.5 g/dL 1 (0.4%) 10 (4.3%)
    Thrombocytopenia
      10,000 – <50,000/mm3 3 (1.3%) 40 (17.0%)
      <10,000/mm3 0 (0.0%) 40 (17.0%)

    Table 7 presents a comparative profile of the non-hematologic adverse reactions from the randomized study of Doxil compared to topotecan.

    Table 7: Ovarian Cancer Randomized Study
    Non-Hematologic

    Adverse Reaction

    10% or Greater

    Doxil (%)

    treated

    (n = 239)

    Topotecan (%)

    treated

    (n =235)

    All grades Grades 3–4 All grades Grades 3–4
    Body as a Whole
      Asthenia 40.2 7.1 51.5 8.1
      Fever 21.3 0.8 30.6 5.5
      Mucous Membrane Disorder 14.2 3.8 3.4 0
      Back Pain 11.7 1.7 10.2 0.9
      Infection 11.7 2.1 6.4 0.9
      Headache 10.5 0.8 14.9 0
    Digestive
      Nausea 46.0 5.4 63.0 8.1
      Stomatitis 41.4 8.3 15.3 0.4
      Vomiting 32.6 7.9 43.8 9.8
      Diarrhea 20.9 2.5 34.9 4.2
      Anorexia 20.1 2.5 21.7 1.3
      Dyspepsia 12.1 0.8 14.0 0
    Nervous
      Dizziness 4.2 0 10.2 0
    Respiratory
      Pharyngitis 15.9 0 17.9 0.4
      Dyspnea 15.1 4.1 23.4 4.3
      Cough increased 9.6 0 11.5 0
    Skin and Appendages
      Hand-foot syndrome 50.6 23.8 0.9 0
      Rash 28.5 4.2 12.3 0.4
      Alopecia 19.2 N/A 52.3 N/A

    The following additional adverse reactions (not in table) were observed in patients with ovarian cancer with doses administered every four weeks.

    Incidence 1% to 10%

    Cardiovascular: vasodilation, tachycardia, deep thrombophlebitis, hypotension, cardiac arrest.

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

    Hemic 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 below is based on the experience reported in 753 patients with AIDS-related Kaposi’s sarcoma enrolled in four studies. The median age of the population was 38.7 years (range 24–70 years), which was 99% male, 1% female, 88% Caucasian, 6% Hispanic, 4% Black, and 2% Asian/other/unknown. The majority of patients were treated with 20 mg/m2 of Doxil every two to three weeks. The median time on study was 127 days and ranged from 1 to 811 days. The median cumulative dose was 120 mg/m2 and ranged from 3.3 to 798.6 mg/m2. Twenty-six patients (3.0%) received cumulative doses of greater than 450 mg/m2.

    Of these 753 patients, 61.2% were considered poor risk for KS tumor burden, 91.5% poor for immune system, and 46.9% for systemic illness; 36.2% were poor risk for all three categories. Patients’ median CD4 count was 21.0 cells/mm3, with 50.8% of patients having less than 50 cells/mm3. The mean absolute neutrophil count at study entry was approximately 3,000 cells/mm3.

    Patients received a variety of potentially myelotoxic drugs in combination with Doxil. Of the 693 patients with concomitant medication information, 58.7% were on one or more antiretroviral medications; 34.9% patients were on zidovudine (AZT), 20.8% on didanosine (ddI), 16.5% on zalcitabine (ddC), and 9.5% on stavudine (D4T). A total of 85.1% patients were on PCP prophylaxis, most (54.4%) on sulfamethoxazole/trimethoprim. Eighty-five percent of patients were receiving antifungal medications, primarily fluconazole (75.8%). Seventy-two percent of patients were receiving antivirals, 56.3% acyclovir, 29% ganciclovir, and 16% foscarnet. In addition, 47.8% patients received colony-stimulating factors (sargramostim/filgrastim) sometime during their course of treatment.

    Adverse reactions led to discontinuation of treatment in 5% of patients with AIDS related Kaposi’s sarcoma. Those that did so included bone marrow suppression, 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.

    Table 8: Hematology Data Reported in Patients With AIDS-Related Kaposi’s Sarcoma
    Patients With Refractory or Intolerant AIDS-Related Kaposi’s Sarcoma

    (n = 74)

    Total Patients With AIDS-Related

    Kaposi’s Sarcoma

    (n = 720)

    Neutropenia
    < 1000/mm3 34 (45.9%) 352 (48.9%)
    < 500/mm3 8 (10.8%) 96 (13.3%)
    Anemia
    < 10 g/dL 43 (58.1%) 399 (55.4%)
    < 8 g/dL 12 (16.2%) 131 (18.2%)
    Thrombocytopenia
    < 150,000/mm3 45 (60.8%) 439 (60.9%)
    < 25,000/mm3 1 (1.4%) 30 (4.2%)
    Table 9: Probably and Possibly Drug-Related Non-Hematologic Adverse Reactions Reported in ≥ 5% of Patients With AIDS-Related Kaposi’s Sarcoma
    Adverse Reactions Patients With Refractory or Intolerant AIDS-Related Kaposi’s Sarcoma

    (n = 77)

    Total Patients With AIDS-Related

    Kaposi’s Sarcoma

    (n = 705)

    Nausea 14 (18.2%) 119 (16.9%)
    Asthenia 5 (6.5%) 70 (9.9%)
    Fever 6 (7.8%) 64 (9.1%)
    Alopecia 7 (9.1%) 63 (8.9%)
    Alkaline Phosphatase Increase 1 (1.3%) 55 (7.8%)
    Vomiting 6 (7.8%) 55 (7.8%)
    Diarrhea 4 (5.2%) 55 (7.8%)
    Stomatitis 4 (5.2%) 48 (6.8%)
    Oral Moniliasis 1 (1.3%) 39 (5.5%)

    The following additional (not in table) adverse reactions were observed in patients with AIDS-related Kaposi’s sarcoma.

    Incidence 1% to 5%

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

    Cardiovascular: chest pain, hypotension, tachycardia.

    Cutaneous: herpes simplex, rash, itching.

    Digestive: mouth ulceration, anorexia, dysphagia.

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

    Other: dyspnea, pneumonia, dizziness, somnolence.

    Incidence Less Than 1%

    Body As A Whole: sepsis, moniliasis, cryptococcosis.

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

    Digestive: hepatitis.

    Metabolic and Nutritional Disorders: dehydration

    Respiratory: cough increase, pharyngitis.

    Skin and Appendages: maculopapular rash, herpes zoster.

    Special Senses: taste perversion, conjunctivitis.

    Patients With Multiple Myeloma

    The safety data below are from 318 patients treated with Doxil (30 mg/m2 as a 1-hr i.v. infusion) administered on day 4 following bortezomib (1.3 mg/m2 i.v. bolus on days 1, 4 , 8 and 11) every three weeks, in a randomized, open-label, multicenter study. In this study, patients in the Doxil + bortezomib combination group were treated for a median number of 138 days (range 21–410 days). The population was 28–85 years of age, 58% male, 42% female, 90% Caucasian, 6% Black, and 4% Asian and other. Table 10 lists adverse reactions reported in 10% or more of patients treated with Doxil in combination with bortezomib for multiple myeloma.

    Table 10. Frequency of treatment emergent adverse reactions reported in ≥10% patients treated for multiple myeloma with Doxil in combination with bortezomib, by Severity, Body System, and MedDRA Terminology.
    Adverse Reaction Doxil + bortezomib

    (n=318)

    Bortezomib

    (n=318)

    Any (%) Grade 3 Grade 4 Any (%) Grade 3 Grade 4
    *
    Peripheral neuropathy includes the following adverse reactions: peripheral sensory neuropathy, neuropathy peripheral, polyneuropathy, peripheral motor neuropathy, and neuropathy NOS.
    Rash includes the following adverse reactions: rash, rash erythematous, rash macular, rash maculo-papular, rash pruritic, exfoliative rash, and rash generalized.
    Blood and lymphatic system disorders
    Neutropenia 36 22 10 22 11 5
    Thrombocytopenia 33 11 13 28 9 8
    Anemia 25 7 2 21 8 2
    General disorders and administration site conditions
    Fatigue 36 6 1 28 3 0
    Pyrexia 31 1 0 22 1 0
    Asthenia 22 6 0 18 4 0
    Gastrointestinal disorders
    Nausea 48 3 0 40 1 0
    Diarrhea 46 7 0 39 5 0
    Vomiting 32 4 0 22 1 0
    Constipation 31 1 0 31 1 0
    Mucositis/Stomatitis 20 2 0 5 <1 0
    Abdominal pain 11 1 0 8 1 0
    Infections and infestations
    Herpes zoster 11 2 0 9 2 0
    Herpes simplex 10 0 0 6 1 0
    Investigations
    Weight decreased 12 0 0 4 0 0
    Metabolism and Nutritional disorders
    Anorexia 19 2 0 14 <1 0
    Nervous system disorders
    Peripheral Neuropathy* 42 7 <1 45 10 1
    Neuralgia 17 3 0 20 4 1
    Paresthesia/dysesthesia 13 <1 0 10 0 0
    Respiratory, thoracic and mediastinal disorders
    Cough 18 0 0 12 0 0
    Skin and subcutaneous tissue disorders
    Rash† 22 1 0 18 1 0
    Hand-foot syndrome 19 6 0 <1 0 0

    Post Marketing 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: rare cases of muscle spasms.

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

    Hematologic disorders: Secondary acute myelogenous leukemia with and without fatal outcome has been reported in patients whose treatment included Doxil.

    Skin and subcutaneous tissue disorders: rare cases of erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported.

    Drug Interactions

    No formal drug interaction studies have been conducted with Doxil. Doxil may interact with drugs known to interact with the conventional formulation of doxorubicin HCl.

    USE IN SPECIFIC POPULATIONS

    Pregnancy

    Pregnancy Category D [see Warnings and Precautions (5.6)].

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

    Nursing Mothers

    It is not known whether this drug is excreted in human milk. Because many drugs, including anthracyclines, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Doxil, discontinue nursing during treatment with Doxil.

    Pediatric Use

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

    Geriatric Use

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

    Hepatic Impairment

    The pharmacokinetics of Doxil has not been adequately evaluated in patients with hepatic impairment. Doxorubicin is eliminated in large part by the liver. Thus, Doxil dosage should be reduced in patients with impaired hepatic function [see Dosage and Administration (2.6)].

    Prior to Doxil administration, evaluation of hepatic function is recommended using conventional clinical laboratory tests such as SGOT, SGPT, alkaline phosphatase, and bilirubin [see Dosage and Administration (2.6)].

    Overdosage

    Acute overdosage with doxorubicin HCl causes increases in mucositis, leucopenia, and thrombocytopenia.

    Treatment of acute overdosage consists of treatment of the severely myelosuppressed patient with hospitalization, antibiotics, platelet and granulocyte transfusions, and symptomatic treatment of mucositis.

    Doxil Description

    Doxil (doxorubicin HCl liposome injection) is doxorubicin hydrochloride (HCl) encapsulated in STEALTH® liposomes for intravenous administration.

    Doxorubicin is an anthracycline topoisomerase inhibitor isolated from Streptomyces peucetius var. caesius.

    Doxorubicin HCl, which is the established name for (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, has the following structure:

    The molecular formula of the drug is C27 H29 NO11•HCl; its molecular weight is 579.99.

    Doxil is provided as 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:

    n = ca. 45

    HSPC has the following structural formula:

    m, n = 14 or 16

    Doxil – Clinical Pharmacology

    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.

    Doxil is doxorubicin HCl encapsulated in long-circulating STEALTH® liposomes. Liposomes are microscopic vesicles composed of a phospholipid bilayer that are capable of encapsulating active drugs. The STEALTH® liposomes of Doxil are formulated with surface-bound methoxypolyethylene glycol (MPEG), a process often referred to as pegylation, to protect liposomes from detection by the mononuclear phagocyte system (MPS) and to increase blood circulation time.

    Representation of a STEALTH® liposome:

    STEALTH® liposomes have a half-life of approximately 55 hours in humans. They are stable in blood, and 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.

    It is hypothesized that because of their small size (ca. 100 nm) and persistence in the circulation, the pegylated Doxil liposomes are able to penetrate the altered and often compromised vasculature of tumors. This hypothesis is supported by studies using colloidal gold-containing STEALTH® liposomes, which can be visualized microscopically. Evidence of penetration of STEALTH® liposomes from blood vessels and their entry and accumulation in tumors has been seen in mice with C-26 colon carcinoma tumors and in transgenic mice with Kaposi’s sarcoma-like lesions. Once the STEALTH® liposomes distribute to the tissue compartment, the encapsulated doxorubicin HCl becomes available. The exact mechanism of release is not understood.

    Pharmacokinetics

    The plasma pharmacokinetics of Doxil were evaluated in 42 patients with AIDS-related Kaposi’s sarcoma (KS) who received single doses of 10 or 20 mg/m2 administered by a 30-minute infusion. Twenty-three of these patients received single doses of both 10 and 20 mg/m2 with a 3-week wash-out period between doses. The pharmacokinetic parameter values of Doxil, given for total doxorubicin (mostly liposomally bound), are presented in Table 11.

    Table 11: Pharmacokinetic Parameters of Doxil in Patients With AIDS-Related Kaposi’s Sarcoma
    Dose
    Parameter (units) 10 mg/m2 20 mg/m2
    N = 23

    Mean ± Standard Error

    Peak Plasma Concentration (µg/mL) 4.12 ± 0.215 8.34 ± 0.49
    Plasma Clearance (L/h/m2) 0.056 ± 0.01 0.041 ± 0.004
    Steady State Volume of Distribution (L/m2) 2.83 ± 0.145 2.72 ± 0.120
    AUC (µg/mL∙h) 277 ± 32.9 590 ± 58.7
    First Phase (λ1) Half-Life (h) 4.7 ± 1.1 5.2 ± 1.4
    Second Phase (λ1) Half-Life (h) 52.3 ± 5.6 55.0 ± 4.8

    Doxil displayed linear pharmacokinetics over the range of 10 to 20 mg/m2. Disposition occurred in two phases after Doxil administration, with a relatively short first phase (≈ 5 hours) and a prolonged second phase (≈ 55 hours) that accounted for the majority of the area under the curve (AUC).

    The pharmacokinetics of Doxil at a 50 mg/m2 dose is reported to be nonlinear. At this dose, the elimination half-life of Doxil is expected to be longer and the clearance lower compared to a 20 mg/m2 dose. The exposure (AUC) is thus expected to be more than proportional at a 50 mg/m2 dose when compared with the lower doses.

    Distribution:

    In contrast to the pharmacokinetics of doxorubicin, which displays a large volume of distribution, ranging from 700 to 1100 L/m2, the small steady state volume of distribution of Doxil shows that Doxil is confined mostly to the vascular fluid volume. 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 very low levels (range: of 0.8 to 26.2 ng/mL) in the plasma of patients who received 10 or 20 mg/m2 Doxil.

    Excretion:

    The plasma clearance of Doxil was slow, with a mean clearance value of 0.041 L/h/m2 at a dose of 20 mg/m2. This is in contrast to doxorubicin, which displays a plasma clearance value ranging from 24 to 35 L/h/m2.

    Because of its slower clearance, the AUC of Doxil, primarily representing the circulation of liposome-encapsulated doxorubicin, is approximately two to three orders of magnitude larger than the AUC for a similar dose of conventional doxorubicin HCl as reported in the literature.

    Special Populations:

    The pharmacokinetics of Doxil have not been separately evaluated in women, in members of different ethnic groups, or in individuals with renal or hepatic insufficiency.

    Drug-Drug Interactions:

    Drug-drug interactions between Doxil and other drugs, including antiviral agents, have not been adequately evaluated in patients with ovarian cancer, AIDS-related Kaposi’s sarcoma or multiple myeloma.

    Tissue Distribution in Patients with Kaposi’s Sarcoma:

    Kaposi’s sarcoma lesions and normal skin biopsies were obtained at 48 and 96 hours post infusion of 20 mg/m2 Doxil in 11 patients. The concentration of Doxil in KS lesions was a median of 19 (range, 3–53) times higher than in normal skin at 48 hours post treatment; however, this was not corrected for likely differences in blood content between KS lesions and normal skin. The corrected ratio may lie between 1 and 22 times. Thus, higher concentrations of Doxil are delivered to KS lesions than to normal skin.

    NON-CLINICAL TOXICOLOGY

    Carcinogenesis, Mutagenesis, and Impairment of Fertility

    Although no studies have been conducted with Doxil, doxorubicin HCl and related compounds have been shown to have mutagenic and carcinogenic properties when tested in experimental models.

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

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

    Clinical Studies

    Ovarian Cancer

    Doxil (doxorubicin HCl liposome injection) was studied in three open-label, single-arm, clinical studies of 176 patients with metastatic ovarian cancer. One hundred forty-five (145) of these patients were refractory to both paclitaxel- and platinum-based chemotherapy regimens. Refractory ovarian cancer is defined as disease progression while on treatment, or relapse within 6 months of completing treatment. Patients in these studies received Doxil at 50 mg/m2 infused over one hour every 3 or 4 weeks for 3–6 cycles or longer in the absence of dose-limiting toxicity or progression of disease.

    The baseline demographics and clinical characteristics of the patients with refractory ovarian cancer are provided in Table 12 below.

    Table 12: Patient Demographics for Patients With Refractory Ovarian Cancer From Single Arm Ovarian Cancer Studies
    Study 1 (U.S.)

    (n = 27)

    Study 2 (U.S.)

    (n = 82)

    Study 3 (non-U.S.)

    (n = 36)

    Age at Diagnosis (Years)
      Median 64 61.5 51.5
      Range 46 – 75 34 – 85 22 – 80
    Drug-Free Interval (Months)
      Median 1.8 1.7 2.6
      Range 0.5 – 15.6 0.6 – 7.0 0.7 – 15.2
    Sum of Lesions at

    Baseline (cm2)

      Median 25 18.3 32.4
      Range 1.2 – 230.0 1.3 – 285.0 0.3 – 114.0
    FIGO Staging
      I 1 (3.7%) 3 (3.7%) 4 (11.1%)
      II 3 (11.1%) 3 (3.7%) 1 (2.8%)
      III 15 (55.6%) 60 (73.2%) 24 (66.7%)
      IV 8 (29.6%) 16 (19.5%) 6 (16.7%)
      Not Specified 1 (2.8%)
    CA-125 at Baseline
      Median 123.5 199.0 1004.5
      Range 20 – 14,012 7 – 46,594 20 – 12,089
    Number of Prior Chemotherapy Regimens
      1 7 (25.9%) 13 (15.9%) 9 (25.0%)
      2 11 (40.7%) 44 (53.7%) 19 (52.8%)
      3 6 (22.2%) 25 (30.5%) 8 (22.8%)
      4 3 (11.1%)

    The primary efficacy parameter was response rate for the population of patients refractory to both paclitaxel- and a platinum-containing regimen. Assessment of response was based on Southwest Oncology Group (SWOG) criteria, and required confirmation four weeks after the initial observation. Secondary efficacy parameters were time to response, duration of response, and time to progression.

    The response rates for the individual single arm studies are given in Table 13 below.

    Table 13: Response Rates in Patients With Refractory Ovarian Cancer From Single Arm Ovarian Cancer Studies
    Study 1 (U.S.) Study 2 (U.S.) Study 3 (non-U.S.)
    Response Rate 22.2% (6/27) 17.1% (14/82) 0% (0/36)
    95% Confidence Interval 8.6% – 42.3% 9.7% – 27.0% 0.0% – 9.7%

    When the data from the single arm studies are combined, the response rate for all patients refractory to paclitaxel and platinum agents was 13.8% (20/145) (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.

    Doxil (doxorubicin HCl liposome injection) was also studied in a randomized, multicenter, open-label, study in 474 patients with epithelial ovarian cancer after platinum-based chemotherapy. Patients in this study received an initial dose of either Doxil 50 mg/m2 infused over one hour every 4 weeks or topotecan 1.5 mg/m2 infused daily for 5 consecutive days every 3 weeks. Patients were stratified according to platinum sensitivity and the presence of bulky disease (presence of tumor mass greater than 5 cm in size). Platinum sensitivity is defined by response to initial platinum-based therapy and a progression-free interval of greater than 6 months off treatment. The primary efficacy endpoint for this study was time to progression (TTP). Other efficacy endpoints included overall survival and objective response rate.

    The baseline patient demographic and clinical characteristics are provided in Table 14 below.

    Table 14: Ovarian Cancer Randomized Study Baseline Demographic and Clinical Characteristics
    Doxil

    (n = 239)

    Topotecan

    (n = 235)

    Age at Diagnosis (Years)
      Median 60.0 60.0
      Range 27 – 87 25 – 85
    Drug-Free Interval (Months)
      Median 7.0 6.7
      Range 0.9 – 82.1 0.5 – 109.6
    FIGO Staging
      I 11 (4.6%) 15 (6.4%)
      II 13 (5.4%) 8 (3.4%)
      III 175 (73.2%) 164 (69.8%)
      IV 40 (16.7%) 48 (20.4%)
    Platinum Sensitivity
      Sensitive 109 (45.6%) 110 (46.8%)
      Refractory 130 (54.4%) 125 (53.2%)
    Bulky Disease
      Present 108 (45.2%) 105 (44.7%)
      Absent 131 (54.8%) 130 (55.3%)

    Study results are provided in Table 15.

    There was no statistically significant difference in TTP between the two treatment arms.

    Table 15: Results of Efficacy Analyses*
    Protocol Defined ITT Population
    Doxil

    (n = 239)

    Topotecan

    (n = 235)

    *
    Analysis based on investigators’ strata for protocol defined ITT population.
    Kaplan-Meier estimates.
    p-value is based on the stratified log-rank test.
    §
    Hazard ratio is based on Cox proportional-hazard model with the treatment as single independent variable. A hazard ratio less than 1 indicates an advantage for Doxil.
    p-value not adjusted for multiple comparisons.
    TTP (Protocol Specified Primary Endpoint)
    Median (Months)† 4.1 4.2
    p-value‡ 0.617
    Hazard Ratio§

    95% CI for Hazard Ratio

    0.955

    (0.762, 1.196)

    Overall Survival
    Median (Months)† 14.4 13.7
    p-value¶

    Hazard Ratio§

    0.05

    0.822

    95% CI for Hazard Ratio (0.676, 1.000)
    Response Rate
    Overall Response n (%) 47 (19.7) 40 (17.0)
    Complete Response n (%) 9 (3.8) 11 (4.7)
    Partial Response n (%) 38 (15.9) 29 (12.3)
    Median Duration of Response (Months)† 6.9 5.9

    AIDS-Related Kaposi’s Sarcoma

    Doxil was studied in an open-label, single-arm, multicenter study utilizing Doxil at 20 mg/m2 by intravenous infusion every three weeks, generally until progression or intolerance occurred. In an interim analysis, the treatment history of 383 patients was reviewed, and a cohort of 77 patients was retrospectively identified as having disease progression on prior systemic combination chemotherapy (at least 2 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.

    These 77 patients were predominantly Caucasian, homosexual males with a median CD4 count of 10 cells/mm3. Their age ranged from 24 to 54 years, with a mean age of 38 years. Using the ACTG staging criteria, 78% of the patients were at poor risk for tumor burden, 96% at poor risk for immune system, and 58% at poor risk for systemic illness at baseline. Their mean Karnofsky status score was 74%. All 77 patients had cutaneous or subcutaneous lesions, 40% also had oral lesions, 26% pulmonary lesions, and 14% of patients had lesions of the stomach/intestine.

    The majority of these patients had disease progression on prior systemic combination chemotherapy.

    The median time on study for these 77 patients was 155 days and ranged from 1 to 456 days. The median cumulative dose was 154 mg/m2 and ranged from 20 to 620 mg/m2.

    Two analyses of tumor response were used to evaluate the effectiveness of Doxil: one analysis based on investigator assessment of changes in lesions over the entire body, and one analysis based on changes in indicator lesions.

    Investigator Assessment

    Investigator response was based on modified ACTG criteria. Partial response was 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.

    Indicator Lesion Assessment

    A retrospectively defined analysis was conducted based on assessment of the response of up to five prospectively identified representative indicator lesions. A partial response was 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.

    Only patients with adequate documentation of baseline status and follow-up assessments were considered evaluable for response. Patients who received concomitant KS treatment during study, who completed local radiotherapy to sites encompassing one or more of the indicator lesions within two months of study entry, who had less than four indicator lesions, or who had less than three raised indicator lesions at baseline (the latter applies solely to indicator lesion assessment) were considered nonevaluable for response. Of the 77 patients who had disease progression on prior systemic combination chemotherapy or who were intolerant to such therapy, 34 were evaluable for investigator assessment and 42 were evaluable for indicator lesion assessment.

    Table 16: Response in Patients with Refractory* AIDS-related Kaposi’s Sarcoma
    *
    Patients with disease that progressed on prior combination chemotherapy or who were intolerant to such therapy.
    There were no complete responses in this population.
    Investigator Assessment All Evaluable Patients

    (n = 34)

    Evaluable Patients Who Received Prior Doxorubicin

    (n = 20)

    Response†
      Partial (PR) 27% 30%
      Stable 29% 40%
      Progression 44% 30%
    Duration of PR (Days)
      Median 73 89
      Range 42+ – 210+ 42+ – 210+
    Time to PR (Days)
      Median 43 53
      Range 15 – 133 15 – 109
    Indicator Lesion Assessment All Evaluable Patients

    (n = 42)

    Evaluable Patients Who Received Prior Doxorubicin

    (n = 23)

    Response†
      Partial (PR) 48% 52%
      Stable 26% 30%
      Progression 26% 17%
    Duration of PR (Days)
      Median 71 79
      Range 22+ – 210+ 35 – 210+
    Time to PR (Days)
      Median 22 48
      Range 15 – 109 15 – 109

    Retrospective efficacy analyses were performed on two studies 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 at least until a response was demonstrated. In one cooperative group trial that was closed early due to slow accrual, 7 of 17 patients (40%) on stable antiretroviral therapy had a durable response. The median duration was not reached but was longer than 11.6 months. In another trial, 4 of 11 patients (40%) on stable antiretroviral therapy demonstrated durable responses.

    Multiple Myeloma

    The safety and efficacy of Doxil in combination with bortezomib in the treatment of multiple myeloma were evaluated in a randomized, open label, international multicenter study. This study included 646 patients who have not previously received bortezomib and whose disease progressed during or after at least one prior therapy. Patients were randomized (1:1 ratio) to receive either Doxil (30 mg/m2 as a 1-hr i.v. infusion) administered on day 4 following bortezomib (1.3 mg/m2 i.v. bolus on days 1, 4 , 8 and 11) or bortezomib alone (1.3 mg/m2 i.v. bolus on days 1, 4 , 8 and 11). Treatment was administered every 3 weeks. Patients were treated for up to 8 cycles until disease progression or the occurrence of 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 are provided in Table 17 below.

    Table 17 Summary of Baseline Patient and Disease Characteristics
    Patient Characteristics Doxil + bortezomib

    n=324

    bortezomib

    n=322

      Median age in years (range) 61 (28, 85) 62 (34, 88)
      % Male/female 58 / 42 54 / 46
      % Caucasian/Black/other 90 / 6/ 4 94 / 4 / 2%
    Disease Characteristics
      % with IgG/IgA/Light chain 57 / 27 / 12 62 / 24 /11
      % β2-microglobulin group
        ≤2.5 mg/L 14 14
        >2.5 mg/L and ≤5.5 mg/L 56 55
        >5.5 mg/L 30 31
    Serum M-protein (g/dL): Median (Range) 2.5 (0–10.0) 2.7 (0–10.0)
    Urine M-protein (mg/24 hours): Median (Range) 107 (0–24883) 66 (0–39657)
    Median Months Since Diagnosis 35.2 37.5
    % Prior Therapy
      One 34 34
      More than one 66 66
    Prior Systemic Therapies for Multiple Myeloma
      Corticosteroid (%) 99 >99
      Anthracyclines 68 67
      Alkylating agent (%) 92 90
      Thalidomide/lenalidomide (%) 40 43
      Stem cell transplantation (%) 57 54

    The primary endpoint in this study 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 18 and Figure 1.

    Table 18 Efficacy of Doxil in combination with bortezomib in the treatment of patients with multiple myeloma
    Endpoint Doxil + bortezomib

    n=324

    Bortezomib

    n=322

    *
    Kaplan Meier estimate.
    Hazard ratio based on stratified Cox proportional hazards regression. A hazard ratio < 1 indicates an advantage for Doxil+bortezomib.
    Stratified log-rank test.
    §
    RR as per EBMT criteria.
    Cochran-Mantel-Haenszel test adjusted for the stratification factors.
    Time to Progression*
    Progression or death due to progression (n) 99 150
      Censored (n) 225 172
      Median in days (months) 282 (9.3) 197 (6.5)
      95% CI 250;338 170;217
      Hazard ratio† 0.55
      (95% CI) (0.43, 0.71)
      p-value‡ <0.0001
    Response (n)§ 303 310
      % Complete Response (CR) 5 3
      %Partial Response (PR) 43 40
      %CR + PR 48 43
      p-value¶ 0.251
    Median Duration of Response (months) 10.2 7.0
    (95% CI) (10.2;12.9) (5.9;8.3)

    Time to progression outcomes were consistent with the overall result across most subgroups defined by patient demographic and baseline characteristics. There were too few Blacks or Asian patients to adequately assess differences in effects for the race subgroup.

    Figure 1- Time to Progression Kaplan-Meier Curve

    REFERENCES

    1. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165.
    2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html
    3. NIH [2002]. 1999 recommendations for the safe handling of cytotoxic drugs. U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, NIH Publication No. 92-2621.
    4. American Society of Health-System Pharmacists. (2006) ASHP Guidelines on Handling Hazardous Drugs.
    5. Polovich, M., White, J. M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd. ed.) Pittsburgh, PA: Oncology Nursing Society.

    How Supplied/Storage and Handling

    Doxil (doxorubicin HCl liposome injection) is supplied as 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.

    Refrigerate unopened vials of Doxil at 2°–8°C (36°–46°F). Avoid freezing. Prolonged freezing may adversely affect liposomal drug products; however, short-term freezing (less than 1 month) does not appear to have a deleterious effect on Doxil.

    The following individually cartoned vials are available:

    Table 19
    mg in vial fill volume vial size NDC #s
    20 mg vial 10-mL 10-mL 59676-960-01
    50 mg vial 25-mL 30-mL 59676-960-02

    Patient Counseling Information

    Patients and patients’ caregivers should be informed of the expected adverse effects of Doxil, particularly hand-foot syndrome, stomatitis, and neutropenia and related complications of neutropenic fever, infection, and sepsis.

    Hand-Foot Syndrome (HFS): Patients who 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) should notify their physician.

    Stomatitis: Patients who experience painful redness, swelling, or sores in the mouth (symptoms of stomatitis) should notify their physician.

    Fever and Neutropenia: Patients who develop a fever of 100.5°F or higher should notify their physician.

    Nausea, vomiting, tiredness, weakness, rash, or mild hair loss: Patients who develop any of these symptoms should notify their physician.

    Following its administration, Doxil may impart a reddish-orange color to the urine and other body fluids. This nontoxic reaction is due to the color of the product and will dissipate as the drug is eliminated from the body.

    Manufactured by:

    Ben Venue Laboratories, Inc.

    Bedford, OH 44146

    Manufactured for:

    Janssen Products, LP

    Horsham, PA 19044

    © Janssen Products, LP 2010

    Revised September 2012

    An ALZA STEALTH®

    Technology Product

    STEALTH® and Doxil® are registered trademarks of ALZA Corporation.

    PRINCIPAL DISPLAY PANEL – 20 mg Vial Carton

    NDC 59676-960-01

    Doxil®

    (doxorubicin HCl

    liposome injection)

    20 mg in 10 mL (2 mg/mL)

    sterile, single use vial

    LIPOSOMAL FORMULATION

    DO NOT SUBSTITUTE

    FOR INTRAVENOUS

    INFUSION ONLY

    Refrigerate, 2°-8°C

    (36°-46°F). Avoid freezing.

    Janssen

    alza

    An ALZA STEALTH®

    Technology Product

    Doxil 

    doxorubicin hydrochloride injection, suspension, liposomal

    Product Information
    Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:59676-960
    Route of Administration INTRAVENOUS DEA Schedule     
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    doxorubicin hydrochloride (doxorubicin) doxorubicin hydrochloride 2 mg  in 1 mL
    Inactive Ingredients
    Ingredient Name Strength
    N-(CARBONYL-METHOXYPOLYETHYLENE GLYCOL 2000)-1,2-DISTEAROYL-SN-GLYCERO-3-PHOSPHOETHANOLAMINE, SODIUM SALT 3.19 mg  in 1 mL
    hydrogenated soybean lecithin 9.58 mg  in 1 mL
    cholesterol 3.19 mg  in 1 mL
    ammonium sulfate 2 mg  in 1 mL
    histidine  
    hydrochloric acid  
    sodium hydroxide  
    sucrose  
    Packaging
    # Item Code Package Description
    1 NDC:59676-960-01 1 VIAL, SINGLE-USE in 1 CARTON
    1 10 mL in 1 VIAL, SINGLE-USE
    2 NDC:59676-960-02 1 VIAL, SINGLE-USE in 1 CARTON
    2 25 mL in 1 VIAL, SINGLE-USE
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    NDA NDA050718 11/17/1995
    Labeler - Janssen Products, LP (804684207)
    Establishment
    Name Address ID/FEI Operations
    Ben Venue Laboratories Inc. 004327953 MANUFACTURE(59676-960)
    Establishment
    Name Address ID/FEI Operations
    Meiji Seika Pharma Co., Ltd. 695400580 API MANUFACTURE(59676-960)

    Revised: 09/2012   Janssen Products, LP

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    Doxil

    Doxil

    Generic Name: doxorubicin hydrochloride liposome (Intravenous route)

    dox-oh-ROO-bi-sin hye-droe-KLOR-ide LYE-poh-some

    Intravenous route(Solution) Myocardial damage may lead to congestive heart failure and may be encountered as the total cumulative dose of doxorubicin hydrochloride (HCl) approaches 550 mg/m(2). Cardiac toxicity may also occur at lower cumulative doses with mediastinal irradiation or concurrent cardiotoxic agents. Serious and sometimes life-threatening or fatal allergic/anaphylactoid-like infusion reactions have been reported. Administer at an initial rate of 1 mg/min to minimize the risk of infusion reactions. Severe myelosuppression may occur with therapy. Reduce dosage in patients with impaired hepatic function. Doxorubicin HCl liposome should not be substituted for doxorubicin HCl on a mg per mg basis .

    OverviewSide EffectsInteractionsMore…

    Commonly used brand name(s)

    In the U.S.

    • Doxil

    Available Dosage Forms:

    • Solution

    Therapeutic Class: Antineoplastic Agent

    Chemical Class: Anthracycline

    Uses For Doxil

    Liposomal doxorubicin belongs to the general group of medicines known as antineoplastics. It is used to treat patients with ovarian cancer, and Kaposi’s Sarcoma in patients with human immunodeficiency virus (HIV). Liposomal doxorubicin is also used together with bortezomib to treat multiple myeloma in patients who have not yet received bortezomib in the past and have received at least one prior treatment .

    Liposomal doxorubicin seems to interfere with the growth of cancer cells, which are eventually destroyed. Since the growth of normal body cells may also be affected by liposomal doxorubicin, other effects will also occur. Some of these may be serious and must be reported to your doctor. Other effects, like hair loss, may not be serious but may cause concern. Some effects may not occur for months or years after the medicine is used.

    Before you begin treatment with liposomal doxorubicin, you and your doctor should talk about the good this medicine will do as well as the risks of using it.

    Liposomal doxorubicin is to be administered only by or under the immediate supervision of your doctor.

    Once a medicine has been approved for marketing for a certain use, experience may show that it is also useful for other medical problems. Although these uses are not included in product labeling, liposomal doxorubicin is used in certain patients with the following medical conditions:

    • Cancer of the breast
    • Multiple myeloma, in combination with vincristine and dexamethasone

    Before Using Doxil

    In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

    Allergies

    Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

    Pediatric

    There is no specific information comparing the use of liposomal doxorubicin in children with use in any other age group. Safety and efficacy of liposomal doxorubicin in children have not been established. However, problems are more likely to occur in children younger than 2 years of age, who are usually more sensitive to the effects of the active ingredient, doxorubicin.

    Geriatric

    This medicine has been tested in a limited number of patients 60 years of age or older and has not been shown to cause different side effects in older people than it does in younger adults. However, problems are more likely to occur in the elderly, who are usually more sensitive to the effects of the active ingredient, doxorubicin. The elderly are also more likely to have blood problems.

    Interactions with Medicines

    Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are receiving this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

    Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

    • Rotavirus Vaccine, Live

    Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

    • Adenovirus Vaccine Type 4, Live
    • Adenovirus Vaccine Type 7, Live
    • Bacillus of Calmette and Guerin Vaccine, Live
    • Cisplatin
    • Influenza Virus Vaccine, Live
    • Measles Virus Vaccine, Live
    • Mumps Virus Vaccine, Live
    • Rotavirus Vaccine, Live
    • Rubella Virus Vaccine, Live
    • Smallpox Vaccine
    • Trastuzumab
    • Typhoid Vaccine
    • Varicella Virus Vaccine
    • Yellow Fever Vaccine

    Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

    • Paclitaxel

    Interactions with Food/Tobacco/Alcohol

    Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

    Other Medical Problems

    The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

    • Chickenpox (including recent exposure) or
    • Herpes zoster (shingles)—Risk of severe disease affecting other parts of the body.
    • Heart disease—Risk of heart problems caused by liposomal doxorubicin may be increased.
    • Infection—Liposomal doxorubicin can decrease your body’s ability to fight infection.
    • Liver disease—Effects of liposomal doxorubicin may be increased because of slower removal from the body.

    Proper Use of Doxil

    Liposomal doxorubicin is sometimes given together with certain other medicines. If you are using a combination of medicines, it is important that you receive each one at the proper time. If you are taking some of these medicines by mouth, ask your health care professional to help you plan a way to take them at the right times.

    While you are receiving liposomal doxorubicin, your doctor may want you to drink extra fluids so that you will pass more urine. This will help prevent kidney problems and keep your kidneys working well.

    This medicine often causes nausea and vomiting. However, it is very important that you continue to receive it, even if you begin to feel ill. Ask your health care professional for ways to lessen these effects.

    Dosing

    The dose of this medicine will be different for different patients. Follow your doctor’s orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

    The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

    Precautions While Using Doxil

    It is very important that your doctor check your progress at regular visits to make sure that this medicine is working properly. Your doctor will need to check your blood for unwanted effects .

    Check with your doctor immediately if you are having chest pain or discomfort, fast or irregular heartbeat, shortness of breath, swelling of the feet and lower legs, or troubled breathing. These could be symptoms of a serious heart problem .

    Acute infusion-related reactions can occur during treatment with this medicine. Symptoms of this reaction include: flushing; shortness of breath; swelling of the face; headache; chills; chest pain; back pain; tightness in chest and throat; fever; itching skin; rash; bluish color of fingernails, lips, skin, palms, or nail beds; difficulty breathing; wheezing; fainting; lightheadedness; or fast, pounding, or irregular heartbeat or pulse .

    This medicine may cause hand-foot syndrome. Check with your doctor right away if you experience tingling or burning, redness, swelling, blistering, or small sores on the palms of your hands or soles of your feet.

    You should not receive this medicine if you are pregnant or breastfeeding. Using this medicine while you are pregnant can harm your unborn baby. Use an effective form of birth control to keep from getting pregnant. If you think you have become pregnant while using the medicine, tell your doctor right away .

    While you are being treated with liposomal doxorubicin, and after you stop treatment with it, do not have any immunizations (vaccinations) without your doctor’s approval. Liposomal doxorubicin may lower your body’s resistance and there is a chance you might get the infection the immunization is meant to prevent. In addition, other persons living in your household should not take oral poliovirus vaccine since there is a chance they could pass the poliovirus on to you. Also, avoid persons who have taken oral poliovirus vaccine. Do not get close to them, and do not stay in the same room with them for very long. If you cannot take these precautions, you should consider wearing a protective face mask that covers the nose and the mouth.

    Liposomal doxorubicin can temporarily lower the number of white blood cells in your blood, increasing the chance of getting an infection. It can also lower the number of platelets, which are necessary for proper blood clotting. If this occurs, there are certain precautions you can take, especially when your blood count is low, to reduce the risk of infection or bleeding:

    • If you can, avoid people with infections. Check with your doctor immediately if you think you are getting an infection or if you get a fever or chills, cough or hoarseness, lower back or side pain, or painful or difficult urination.
    • Check with your doctor immediately if you notice any unusual bleeding or bruising; black, tarry stools; blood in urine or stools; or pinpoint red spots on your skin.
    • Do not touch your eyes or the inside of your nose unless you have just washed your hands and have not touched anything else in the meantime.
    • Be careful not to cut yourself when you are using sharp objects such as a safety razor or fingernail or toenail cutters.
    • Avoid contact sports or other situations where bruising or injury can occur.

    If liposomal doxorubicin accidentally seeps out of the vein into which it is injected, it may damage some tissues and cause scarring. Tell the doctor or nurse right away if you notice redness, pain, or swelling at the place of injection.

    Be careful when using a regular toothbrush, dental floss, or toothpick. Your medical doctor, dentist, or nurse may recommend other ways to clean your teeth and gums. Check with your medical doctor before having any dental work done.

    Doxil Side Effects

    Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

    Check with your doctor as soon as possible if any of the following side effects occur:

    More common–in any treatment group

    • Black, tarry stools
    • blistering, peeling, redness, and/or swelling of palms of hands or bottoms of feet
    • blood in urine or stools
    • chills
    • cough or hoarseness
    • facial swelling
    • fever
    • headache
    • loss of strength and energy
    • low blood pressure
    • lower back or side pain
    • numbness, pain, tingling, or unusual sensations in palms of hands or bottoms of feet
    • painful or difficult urination
    • pinpoint red spots on skin
    • shortness of breath
    • sore throat
    • sores in mouth and on lips
    • unusual bleeding or bruising
    • unusual tiredness or weakness

    Less common–in any treatment group

    • Skin rash or itching

    Rare–in any treatment group

    • Chest pain
    • decreased urine output
    • dilated neck veins
    • extreme fatigue
    • irregular breathing
    • irregular heartbeat
    • shortness of breath
    • swelling of face, fingers, feet, or lower legs
    • tightness in chest
    • troubled breathing
    • weight gain
    • wheezing
    • yellowing of the eyes and skin

    Less common—for patients being treated for Kaposi’s sarcoma

    • Cough
    • fever
    • pain at place of injection
    • troubled breathing
    • wheezing

    Rare—for patients being treated for Kaposi’s sarcoma

    • Blurred or loss of vision
    • eye pain
    • flushed, dry skin
    • frequent urination
    • fruit-like breath odor
    • unusual thirst

    Less common—for patients being treated for ovarian cancer

    • Bloating or swelling of face, hands, lower legs, and/or feet
    • chest pain
    • cough or hoarseness
    • decreased urination
    • fever or chills
    • lower back or side pain
    • painful or difficult urination
    • rapid weight gain

    Rare—for patients being treated for ovarian cancer

    • Cough
    • difficulty swallowing
    • hives
    • pain at place of injection
    • puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
    • shortness of breath
    • tightness in chest
    • wheezing

    Symptoms of overdose

    • Black, tarry stools
    • blood in urine or stools
    • cough or hoarseness accompanied by fever or chills
    • fever or chills
    • lower back or side pain accompanied by fever or chills
    • painful or difficult urination accompanied by fever or chills
    • pinpoint red spots on skin
    • sores in mouth and on lips
    • unusual bleeding or bruising

    Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

    More common–in any treatment group

    • Diarrhea
    • nausea
    • vomiting

    Less common–in any treatment group

    • Back pain
    • difficulty swallowing
    • dizziness

    More common—for patients being treated for Kaposi’s sarcoma

    • Creamy white, curd-like patches in mouth or throat
    • pain when eating or swallowing

    Less common—for patients being treated for Kaposi’s sarcoma

    • Constipation
    • headache

    More common—for patients being treated for ovarian cancer

    • Abdominal or stomach pain
    • changes in the lining of the mouth or nose
    • constipation
    • headache
    • loss of appetite
    • pain
    • rash
    • sore throat
    • tingling, burning, or prickly sensations

    Less common—for patients being treated for ovarian cancer

    • Anxiety
    • bad, unusual, or unpleasant (after)taste
    • burning, dry, or itching eyes
    • change in taste
    • difficulty swallowing
    • excessive tearing
    • itching skin
    • muscle aches
    • redness, pain, swelling of eye, eyelid, or inner lining of eyelid
    • trouble sleeping

    Rare—for patients being treated for ovarian cancer

    • Change in sense of smell
    • chills
    • clumsiness, unsteadiness, trembling, or other problems with muscle control or coordination
    • cough
    • fever
    • general feeling of discomfort or illness
    • increased white vaginal discharge
    • joint pain
    • nausea
    • shakiness and unsteady walk
    • shivering
    • sore throat
    • sweating
    • thinking abnormal
    • vomiting

    Liposomal doxorubicin causes the urine to turn reddish in color, which may stain clothes. This is not blood. It is to be expected and only lasts for 1 or 2 days after each dose is given.

    Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

    More common—for patients being treated for ovarian cancer

    • Dry skin

    Less common—for patients being treated for ovarian cancer

    • Change in skin color

    This medicine often causes a temporary and total loss of hair. After treatment with liposomal doxorubicin has ended, normal hair growth should return.

    After you stop using this medicine, it may still produce some side effects that need attention. During this period of time, check with your doctor immediately if you notice the following side effects:

    • Fast or irregular heartbeat
    • shortness of breath
    • swelling of feet and lower legs

    Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

    Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

    See also: Doxil side effects (in more detail)

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    Doxil

    Doxil

    Generic Name: doxorubicin liposomal (DOZ oh ROO bi sin LYE poe SOE mal)

    Brand Name: Doxil, Lipodox, Lipodox 50

    OverviewSide EffectsInteractionsMore…

    What is Doxil (doxorubicin liposomal)?

    Doxorubicin liposomal is a cancer medication that interferes with the growth and spread of cancer cells in the body.

    Doxorubicin liposomal is used to treat ovarian cancer, AIDS-related Kaposi’s sarcoma, and multiple myeloma.

    Doxorubicin liposomal may also be used for purposes not listed in this medication guide.

    What is the most important information I should know about Doxil (doxorubicin liposomal)?

    Doxorubicin liposomal is a cancer medication.

    Doxorubicin liposomal may increase the risk of heart or liver problems. Before you receive doxorubicin liposomal, tell your doctor if you have heart or liver disease.

    Doxorubicin liposomal can lower blood cells that help your body fight infections and help your blood to clot. You may get an infection or bleed more easily. Call your doctor if you have unusual bruising or bleeding, or signs of infection (fever, chills, body aches).

    Some side effects may occur during the injection. Tell your caregiver right away if you feel dizzy, nauseated, light-headed, sweaty, or have a headache, chest tightness, back pain, trouble breathing, or swelling in your face.

    What should I discuss with my healthcare provider before receiving Doxil (doxorubicin liposomal)?

    You should not use this medication if you are allergic to doxorubicin.

    To make sure doxorubicin liposomal is safe for you, tell your doctor if you have:

    • kidney or liver disease;

    • heart disease; or
    • bone marrow suppression.

    Tell your doctor about all other cancer medicines or radiation treatments you have received in the past.

    FDA pregnancy category D. Do not use doxorubicin liposomal if you are pregnant. It could harm the unborn baby. Use effective birth control while you are using this medication and for at least a few months after your treatment ends.

    It is not known whether doxorubicin liposomal passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.

    How is doxorubicin liposomal given?

    Doxorubicin liposomal is injected into a vein through an IV. A healthcare provider will give you this injection.

    Tell your caregivers if you feel any burning, pain, or swelling around the IV needle when doxorubicin liposomal is injected.

    If this medicine accidentally gets on your skin, wash it thoroughly with soap and warm water.

    Doxorubicin liposomal can lower blood cells that help your body fight infections and help your blood to clot. Your blood will need to be tested often. Your cancer treatments may be delayed based on the results of these tests.

    Chemotherapy can pass into body fluids (including urine, feces, vomit, semen, vaginal fluid). Patients or caregivers should wear rubber gloves while cleaning up body fluids, handling contaminated trash or laundry or changing diapers. Wash hands before and after removing gloves. Wash soiled clothing and linens separately from other laundry.

    Body fluids should not be handled by a woman who is pregnant or who may become pregnant. Use condoms during sexual activity to avoid exposure to body fluids.

    What happens if I miss a dose?

    Call your doctor for instructions if you miss an appointment for your doxorubicin liposomal injection.

    What happens if I overdose?

    Since this medication is given by a healthcare professional in a medical setting, an overdose is unlikely to occur.

    What should I avoid while using Doxil (doxorubicin liposomal)?

    Do not receive a “live” vaccine while using doxorubicin liposomal. The vaccine may not work as well during this time, and may not fully protect you from disease. Live vaccines include measles, mumps, rubella (MMR), rotavirus, typhoid, yellow fever, varicella (chickenpox), zoster (shingles), and nasal flu (influenza) vaccine.

    Avoid activities that may increase your risk of bleeding or injury. Use extra care to prevent bleeding while shaving or brushing your teeth.

    Doxil (doxorubicin liposomal) side effects

    Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

    Some side effects may occur during the injection. Tell your caregiver right away if you feel dizzy, nauseated, light-headed, sweaty, or have a headache, chest tightness, back pain, trouble breathing, or swelling in your face.

    Call your doctor at once if you have:

    • pain, redness, swelling, blistering, or peeling skin on your hands or feet;

    • feeling short of breath (even with mild exertion), swelling, rapid weight gain;
    • fever, chills, body aches, flu symptoms;
    • white patches or sores inside your mouth or on your lips;
    • easy bruising, unusual bleeding (nose, mouth, vagina, or rectum), purple or red pinpoint spots under your skin; or
    • pale skin, feeling light-headed or short of breath, rapid heart rate, trouble concentrating.

    Doxorubicin liposomal may cause your urine to turn a reddish-orange color. This side effect by itself is usually not harmful. However, call your doctor if you also have upper stomach pain, clay-colored stools, or jaundice (yellowing of your skin or the whites of your eyes).

    Common side effects may include:

    • tired feeling;

    • loss of appetite, nausea, vomiting;
    • constipation, diarrhea; or
    • temporary hair loss.

    This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

    See also: Doxil side effects (in more detail)

    What other drugs will affect Doxil (doxorubicin liposomal)?

    Tell your doctor about all medicines you use, and those you start or stop using during your treatment with doxorubicin liposomal, especially:

    • cyclophosphamide; or

    • mercaptopurine.

    This list is not complete. Other drugs may interact with doxorubicin liposomal, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

    Next Page → Side Effects

    More Doxil resources

    • Side Effects
    • Pregnancy Warnings
    • Drug Interactions
    • Support Group
    • 0 Reviews - Add your own review/rating
    • Doxil Prescribing Information (FDA)
    • Doxil Advanced Consumer (Micromedex) – Includes Dosage Information
    • Doxil MedFacts Consumer Leaflet (Wolters Kluwer)
    • Lipodox Prescribing Information (FDA)

    Compare Doxil with other medications

    • Kaposi’s Sarcoma
    • Multiple Myeloma
    • Ovarian Cancer

    Where can I get more information?

    • Your doctor or pharmacist can provide more information about doxorubicin liposomal.

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    Doxil

    Doxil

    Generic Name: doxorubicin liposomal (DOX-oh-ROO-bi-sin)

    Brand Name: Doxil

    Doxil is for intravenous (IV) use only and should only be given under the supervision of a doctor experienced in the use of cancer chemotherapy agents. If Doxil accidentally leaks into surrounding tissue, the skin and/or muscle may be severely damaged. Notify your doctor immediately if redness, pain, or swelling at or around the injection site occurs.

    Doxil may cause severe and possibly life-threatening heart problems (eg, heart failure). These problems may occur during therapy or sometimes months to years after receiving Doxil. In some cases heart problems are irreversible. The risk may be increased if you are using certain medicines that may affect heart function (eg, trastuzumab), or have a history of heart problems, radiation treatment to the chest area, or previous therapy with other anthracyclines (eg, epirubicin). The risk of developing heart problems varies depending on your dose and condition, although it can occur at any dose whether or not you are at risk. Notify your doctor right away if you develop cough; fast, slow, or irregular heartbeat; shortness of breath; sudden, unexplained weight gain; or swelling of the hands, ankles, or feet.

    Serious and sometimes life threatening infusion-related reactions have occurred with the use of Doxil. Contact your doctor right away if you experience back pain, chills, fainting, flushing, headache, severe dizziness or light-headedness, shortness of breath, swelling of the face, or tightness in the chest or throat.

    Another type of cancer (acute myelogenous leukemia [AML]) and a certain blood problem (myelodysplastic syndrome [MDS]) have been reported in patients treated with anthracyclines, including Doxil. The risk varies depending on your dose, and other medicines and/or radiation therapy. Discuss any questions or concerns with your doctor.

    Doxil may cause bone marrow suppression. Notify your doctor immediately if you develop easy bruising or bleeding, unusual tiredness or weakness, or signs of an infection (eg, fever, chills, persistent sore throat).

    Tell your doctor if you have liver problems because your dose will have to be decreased. Your doctor will closely monitor you while you are using Doxil.

    OverviewSide EffectsInteractionsMore…

    Doxil is used for:

    Treating advanced ovarian cancer and AIDS-related Kaposi sarcoma in certain patients. It is also used with another medicine to treat a type of bone marrow cancer (multiple myeloma) in certain patients.

    Doxil is an antineoplastic antibiotic. It works by killing cancer cells.

    Do NOT use Doxil if:

    • you are allergic to any ingredient in Doxil or to similar medicines (eg, epirubicin)
    • you have certain bone marrow problems (eg, low blood platelet levels, low red blood cell levels, low white blood cell levels)
    • you have taken or will be taking palifermin within 24 hours before or after using Doxil

    Contact your doctor or health care provider right away if any of these apply to you.

    Before using Doxil:

    Some medical conditions may interact with Doxil. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

    • if you are pregnant, planning to become pregnant, or are breast-feeding
    • if you are able to become pregnant
    • if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement
    • if you have allergies to medicines, foods, or other substances
    • if you have swelling or soreness of the mouth or tongue, blood vessel disease, an infection, or liver problems
    • if you plan to receive any vaccines
    • if you are older than 50 years old
    • if you have a history of heart problems, radiation treatment (or are currently receiving radiation treatment), or if you have previously received Doxil or similar medicines (eg, epirubicin, daunorubicin)
    • if you are taking medicines that may affect heart function (eg, calcium channel blockers, trastuzumab). Ask your doctor if you are unsure if any of your medicines may affect heart function

    Some MEDICINES MAY INTERACT with Doxil. Tell your health care provider if you are taking any other medicines, especially any of the following:

    • Calcium channel blockers (eg, diltiazem, verapamil), cyclophosphamide, or trastuzumab because the risk of heart problems (eg, heart failure) may be increased
    • Cyclosporine, cytarabine, paclitaxel, progesterone, or streptozocin because they may increase the risk of Doxil’s side effects
    • Phenobarbital because it may decrease Doxil’s effectiveness
    • Anticoagulants (eg, warfarin) because the risk of their side effects may be increased by Doxil
    • Palifermin because if mouth or tongue sores develop, they may be more severe or last longer
    • Hydantoins (eg, phenytoin) because their effectiveness may be decreased by Doxil
    • Medicines that may harm the liver (eg, acetaminophen, methotrexate, ketoconazole, isoniazid, certain medicines for HIV infection) because the risk of Doxil’s side effects may be increased. Ask your doctor if you are unsure if any of your medicines might harm the liver

    This may not be a complete list of all interactions that may occur. Ask your health care provider if Doxil may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

    How to use Doxil:

    Use Doxil as directed by your doctor. Check the label on the medicine for exact dosing instructions.

    • Doxil is usually given as an injection at your doctor’s office, hospital, or clinic. Ask your doctor any questions that you may have about Doxil.
    • Do not use Doxil if it contains particles, is cloudy or discolored, or if the vial is cracked or damaged.
    • Drinking extra fluids while you are taking Doxil is recommended. Check with your doctor for instructions.
    • Your doctor may prescribe another medicine to lessen nausea and vomiting that can occur when taking Doxil. Discuss any questions with your doctor.
    • If you spill Doxil on your skin, wash it off right away with soap and water.
    • Keep this product, as well as syringes and needles, out of the reach of children and pets. Do not reuse needles, syringes, or other materials. Ask your health care provider how to dispose of these materials after use. Follow all local rules for disposal.
    • If you miss a dose of Doxil, contact your doctor right away.

    Ask your health care provider any questions you may have about how to use Doxil.

    Important safety information:

    • Doxil may reduce the number of clot-forming cells (platelets) in your blood. Avoid activities that may cause bruising or injury. Tell your doctor if you have unusual bruising or bleeding. Tell your doctor if you have dark, tarry, or bloody stools.
    • Doxil may lower the ability of your body to fight infection. Avoid contact with people who have colds or infections. Tell your doctor if you notice signs of infection like fever, sore throat, rash, or chills.
    • Do not receive a live vaccine (eg, measles, mumps) while you are taking Doxil. Talk with your doctor before you receive any vaccine.
    • Doxil may cause the urine to turn red. This is harmless and usually goes away 1 to 2 days after receiving a dose of Doxil.
    • Doxil may cause you to become sunburned more easily. Avoid the sun, sunlamps, or tanning booths until you know how you react to Doxil. Use a sunscreen or wear protective clothing if you must be outside for more than a short time.
    • Lab tests, including liver function, complete blood cell counts, blood uric acid and electrolyte levels, and heart function, may be performed while you use Doxil. These tests may be used to monitor your condition or check for side effects. Be sure to keep all doctor and lab appointments.
    • Tell your doctor or dentist that you take Doxil before you receive any medical or dental care, emergency care, or surgery.
    • Doxil should be used with extreme caution in CHILDREN; safety and effectiveness in children have not been confirmed.
    • Caution is advised when using Doxil in CHILDREN; they may be more sensitive to its effects.
    • Doxil may damage sperm. Use effective birth control methods (eg, condoms) while using Doxil. Discuss any questions or concerns with your doctor.
    • PREGNANCY and BREAST-FEEDING: Doxil has been shown to cause harm to the fetus. Avoid becoming pregnant while you are taking it. If you are able to become pregnant, talk with your doctor about using an effective form of birth control. If you think you may be pregnant, contact your doctor. You will need to discuss the benefits and risks of using Doxil while you are pregnant. It is not known if Doxil is found in breast milk. Do not breast-feed while taking Doxil.

    Possible side effects of Doxil:

    All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

    Constipation; diarrhea; hair loss; indigestion; loss of appetite; nausea; tiredness; weakness; weight changes.

    Seek medical attention right away if any of these SEVERE side effects occur:

    Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest or throat; swelling of the mouth, face, lips, or tongue); absence of menstrual cycle or menstrual changes; back pain; black, tarry stools; bluish skin or nails; calf or leg pain, swelling, redness, or tenderness; chest pain; dizziness or light-headedness; fainting; fast, slow, or irregular heartbeat; flushing; headache; loose or bloody stools; pain, redness, burning, stinging, swelling, or open sores at the injection site; rectal bleeding or irritation; redness or discharge of the eyes; redness, pain, swelling, peeling, tingling, or blistering of the palms of the hands and the soles of the feet; severe or persistent nausea; shortness of breath; sudden, unexplained weight gain; swelling of the hands, ankles, or feet; swelling or soreness of the mouth or tongue; symptoms of dehydration (eg, dry mouth or eyes, decreased urination, fast heartbeat, sluggishness, unusual thirst); symptoms of infection (eg, fever, chills, cough, sore throat, burning or painful urination); unusual bruising or bleeding; unusual tiredness or weakness; vomiting.

    This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

    If OVERDOSE is suspected:

    Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include swelling or soreness of the mouth or tongue; unusual bruising or bleeding.

    Proper storage of Doxil: Doxil is usually handled and stored by a health care provider. If you are using Doxil at home, store Doxil as directed by your pharmacist or health care provider. Keep Doxil out of the reach of children and away from pets.

    General information:

    • If you have any questions about Doxil, please talk with your doctor, pharmacist, or other health care provider.
    • Doxil is to be used only by the patient for whom it is prescribed. Do not share it with other people.
    • If your symptoms do not improve or if they become worse, check with your doctor.
    • Check with your pharmacist about how to dispose of unused medicine.

    This information should not be used to decide whether or not to take Doxil or any other medicine. Only your health care provider has the knowledge and training to decide which medicines are right for you. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about Doxil. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to Doxil. This information is not specific medical advice and does not replace information you receive from your health care provider. You must talk with your healthcare provider for complete information about the risks and benefits of using Doxil.

    Issue Date: March 6, 2013 Database Edition 13.1.1.003 Copyright © 2013 Wolters Kluwer Health, Inc.

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