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All about: Doxil

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Generic Name: doxorubicin hydrochloride
Dosage Form: Liposome injection

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)].

1 INDICATIONS AND USAGE

1.1 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.

1.2 AIDS-related Kaposi's Sarcoma

Doxil is indicated for the treatment of AIDS-related Kaposi's sarcoma in patients with disease that has progressed on prior combination chemotherapy or in patients who are intolerant to such therapy.

The treatment of patients with AIDS-related Kaposi's sarcoma is based on objective tumor response rates. No results are available from controlled trials that demonstrate a clinical benefit resulting from this treatment, such as improvement in disease-related symptoms or increased survival.

1.3 Multiple myeloma

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

2 DOSAGE AND ADMINISTRATION

2.1 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 (5.1)]. 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.

2.2 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.

2.3 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.

2.4 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.

2.5 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.

2.6 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 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.

2.7 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.

2.8 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)].

3 DOSAGE FORMS AND STRENGTHS

  • 20 mg/10 mL single use vial
  • 50 mg/30 mL single use vial

4 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)].

Doxil is contraindiacated in nursing mothers [see Use in Specific Populations (8.3)].

5 WARNINGS AND PRECAUTIONS

5.1 Cardiac Toxicity

Special attention must be given to the 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.

5.2 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 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)].

5.3 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 event (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 event (40.2%), followed by leukopenia (WBC <4,000 mm3; 36.8%), neutropenia (ANC <1,000; 35.1%), and thrombocytopenia (13.0%) [see Hematology Data table in 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)].

5.4 Hand-Foot Syndrome (HFS)

In the randomized 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.

5.5 Radiation Recall Reaction

Recall reaction has occurred with Doxil administration after radiotherapy.

5.6 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)].

5.7 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.

5.8 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)].

6 ADVERSE REACTIONS

6.1 Overall Adverse Reactions Profile

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

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)].

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% white, 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% white, 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% white, 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

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