Lipo-Dox

Doxorubicin hydrochloride (pegylated liposomal doxorubicin).

Lipo-Dox, a liposome formulation, is doxorubicin hydrochloride encapsulated in liposomes with surface-bound methoxypolyethylene glycol (MPEG). This process is known as pegylation and protects liposomes from detection by the mononuclear phagocyte system (MPS), which increases blood circulation time.
Each Lipo-Dox vial contains pegylated liposomal doxorubicin HCl 2 mg/mL and delivers 10 ml (20 mg) in a concentrate for infusion for single intravenous use and is presented as a sterile, translucent, red suspension. The active ingredient of Lipo-Dox is doxorubicin HCl, a cytotoxic anthracycline antibiotic obtained from Streptomyces peucetius var. caesius.
Excipients/Inactive Ingredients: Each vial of product contains the following excipients: Cholesterol, Sucrose, Water for Injection.

The exact mechanism of the antitumor activity of doxorubicin is not known. It is generally believed that inhibition of DNA, RNA and protein synthesis is responsible for the majority of the cytotoxic effect. This is probably the result of intercalation of the doxorubicin between adjacent base pairs of the DNA double helix, thus preventing their unwinding for replication.
Pharmacology: Lipo-Dox is a long-circulating pegylated liposomal formulation of doxorubicin HCl that provides greater concentration of doxorubicin in Karposi's sarcoma tumors than in normal skin.
Hydrophilic polymer methoxy-polyethylene glycol (MPEG) is bound to the surface of pegylated liposomes. These linear MPEG groups extend from the liposome surface forming a protective coating that reduces interactions between the liposomal lipid bilayer membrane and the plasma components, so the circulation time of pegylated liposomal doxorubicin is prolonged in the blood stream.
Pegylated liposomes are small enough (average diameter of approximately 100 nm) to pass intact (extravasate) through defective blood vessels supplying tumors. Evidence of penetration of pegylated 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. The doxorubicin HCl could been capsulated during liposome residence time in circulation, because of low permeability lipid matrix and internal liquid buffer system of the pegylated liposomes.
Clinical Efficacy: A phase III randomized study of pegylated liposomal doxorubicin versus doxorubicin HCl in patients with metastatic breast cancer was completed in 509 patients. The protocol-specified objective of demonstrating non-inferiority between pegylated liposomal doxorubicin and doxorubicin was met: the hazard ratio (HR) for progression-free survival (PFS) was 1.00 (95% Cl for HR=0.82-1.22). The treatment HR for PFS when adjusted for prognostic variables was consistent with PFS for the ITT population.
301 patients with advanced breast cancer who had failed a taxane-containing regimen were randomized in a phase III comparative study to pegylated liposomal doxorubicin versus an approved salvage regimen (vinorelbine or mitomycin C + vinblastine). Both PFS were the same.
In a 474 patients, phase III clinical study, compared the protocol-specified primary endpoint of time to progression between pegylated liposomal doxorubicin and topotecan in the evaluated patients with epithelial ovarian cancer, who were failed to first-line, platinum based chemotherapy. The results indicated that pegylated liposomal doxorubicin HCl was better than topotecan (hazard ratio of 1.262, 90% CI 1.062-1.500, p=0.026) Supported by a hazard ratio of 1.121 (90% CI 0.920-1.367, P=0.34), for the entire ITT population, the overall survival of pegylated liposomal doxorubicin HCl was at least equivalent to topotecan.
In the protocol-defined platinum-sensitive subgroup in the ITT population, both time to progression and overall survival were significantly in favor of pegylated liposomal doxorubicin (time to progression: hazard ratio of 1.349, p=0.037, 90% CI 1.065-1.709, median=202 days vs. 163 days; overall survival: hazard ratio 1.720, 90% CI 1.222-2.422, p<0.01, median: 756 days vs. 498 days).
When the quality of life, such as toxicity and progression are considered, pegylated liposomal doxorubicin is always preferred over topotecan as demonstrated in the quality-adjusted survival analysis. Although patients treated with pegylated liposomal doxorubicin experience palmar-plantar erythrodysesthesia (PPE) caused pain more frequently, but rarely resulted in study discontinuation.
No matter the efficacy endpoint or different prognostic population, pegylated liposomal doxorubicin showed consistent advantage in clinical studies.
Pharmacokinetics: The plasma pharmacokinetics in humans are significant different between pegylated liposomal doxorubicin and conventional doxorubicin HCl preparations. At lower doses (10 mg/m²-20 mg/m²), pegylated liposomal doxorubicin displayed linear pharmacokinetics. However, the pharmacokinetics are displayed to be non-linear over the dose range of 10 mg/ m² to 60 mg/m².
In contrast to the pharmacokinetic of conventional doxorubicin HCl, which displays extensive tissue distribution (volume of distribution, 700 to 1100 L/m²) and a rapid elimination clearance (24-73 L/h/m²). The pharmacokinetic profile of Lipo-Dox indicates that Lipo-Dox is confined mostly to the vascular fluid volume and that the clearance of doxorubicin from the blood is dependent upon the liposomal carrier. After the liposomes are extravasated and enter the tissue compartment, doxorubicin becomes available.
At equivalent doses, the plasma concentration and AUC values of pegylated liposomal doxorubicin which mostly exist as encapsulated in liposomes (containing 90% to 95% of the measured doxorubicin) are significant higher than conventional doxorubicin HCl.
Population Pharmacokinetics: The population pharmacokinetics of pegylated liposomal doxorubicin were evaluated in 120 patients from 10 different clinical trials. The pharmacokinetics of pegylated liposomal doxorubicin over the dose range of 10 mg/m² to 60 mg/m² was best described by a two compartment non-linear model with zero order input and Michaelis-Menten elimination. The mean intrinsic clearance of pegylated liposomal doxorubicin was 0.030 L/h/m² (0.008-0.152 L/h/m²) and the central volume of distribution was 1.93 L/m² (0.96-3.85 L/m²), approximating the volume of human plasma, and the half-life ranged from 24 to 231 hours with a mean of 73.9 hours.
Breast Cancer Patients: The pharmacokinetics of Lipo-Dox determined in 18 patients with breast cancer were similar to the pharmacokinetics determined in the large population of 120 patients with various cancers. The mean intrinsic clearance was 0.016 L/h/m² (range 0.009-0.027 L/h/m²), the mean central volume of distribution was 1.46 L/m² (range 1.10-1.64 L/m²). The mean half-life was 71.5 hours (range 45.2-98.5 hours).
Ovarian Cancer Patients: The pharmacokinetics data from 11 ovarian cancer patients were similar with the pharmacokinetics data from the other 120 patients with various cancers. The mean intrinsic clearance was 0.021 L/h/m² (0.009-0.041 L/h/m²), the mean central volume of distribution was 1.95 L/m² (1.67 -2.40 L/m²), and the mean half-life was 75.0 hours (36.1-125 hours).
AIDS-KS Patients: The pharmacokinetics of pegylated liposomal doxorubicin HCl were evaluated in 23 patients with Kaposi's sarcoma who received single doses of 20 mg/m² administered by a 30-minute infusion. The pharmacokinetic parameters of pegylated liposomal doxorubicin (primarily representing liposome-encapsulated doxorubicin HCl and low levels of unencapsulated doxorubicin HCl), are presented in the Table 1. (See Table 1.)

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Toxicology: Pre-clinical Toxicological Study: In repeat dose studies conducted in animals, the toxicity profile of pegylated liposomal doxorubicin appears very similar to that reported in humans who receive long-term infusions of conventional doxorubicin HCl. However, the pegylated liposomal doxorubicin HCl and conventional doxorubicin HCl have different toxicity strength, as follows: Cardiotoxicity: In rabbits studies, the cardiotoxicity of pegylated liposomal doxorubicin was reduced compared with conventional formulation of doxorubicin HCl preparations.
(Skin) Dermal Toxicity: After the repeated administration of pegylated liposomal doxorubicin, which at clinically relevant dosages to rats and dogs, severe dermatitis and ulcer were observed. In the study in dogs, lowering the dose or prolonging the intervals between doses could reduce the incidence and severity of skin lesions. Similar dermal lesions, which are described as palmar-plantar erythrodysesthesia were also observed in patients after long-term intravenous infusion. (See Adverse Reactions).
Anaphylactoid response: During repeated-dose toxicity studies in dogs, the acute response characterized by hypotension, ashen mucosa, salivation, emesis and periods of hyperactivity followed by hypoactivity and lethargy was observed following administration of pegylated liposomes (placebo). Similar but less severe reactions were also noted in dogs treated with pegylated liposomal doxorubicin or conventional doxorubicin. Pretreatment with antihistamines could reduce hypotension magnitude. However, the dogs recovered quickly upon discontinuation of treatment and the responses were not life-threatening.
Local Toxicity: In subcutaneous tolerance studies, the local irritation or damage to the tissue that were caused by extravasations of pegylated liposomal doxorubicin were slighter than conventional doxorubicin HCl.
Mutagenicity and Carcinogenicity: Although no studies have been conducted with pegylated liposomal doxorubicin, doxorubicin HCl, the pharmacologically active ingredient of Lipo-Dox, is mutagenic and carcinogenic. Pegylated placebo liposomes are neither mutagenic nor genotoxic.
Reproductive Toxicity: Pegylated liposomal doxorubicin resulted in mild to moderate ovarian and testicular atrophy in mice after a single dose of 36 mg/kg. Decreased testicular weights and hypospermia were present in rats after repeat doses ≧0.25 mg/kg/day. Diffuse degeneration of the seminiferous tubules and a marked decrease in spermatogenesis were observed in dogs after repeat doses of 1 mg/kg/day.

The treatment of AIDS-related Kaposi's sarcoma in patients with low CD₄ counts (<200 CD₄ lymphocytes/mm³) and diseases in mucosa, skin and internal organs.
The treatment of metastasis carcinoma of the ovary in patients with disease that is recurrent to both first-line platinum- and paclitaxel-based chemotherapy regimens.
As monotherapy for patients with metastatic breast carcer, where there is an increased cardiac risk.

Pegylated liposomal doxorubicin exhibits unique pharmacokinetic properties and must not be used interchangeably with other formulations of doxorubicin HCl.
Lipo-dox should only be administered under the supervision of a qualified oncologist specialized in the administration of cytotoxic agents.
Breast/Ovarian Cancer: Lipo-Dox should be administered intravenously at a dose of 50 mg/m² once every 4 weeks for as long as the disease does not progress and the patient continues to tolerate treatment.
For dose <90 mg: dilute Lipo-Dox in 250 mL Dextrose 5% in Water.
For dose >90 mg: dilute Lipo-Dox in 500 mL Dextrose 5% in Water.
To minimize the risk of infusion reactions, the initial dose is administered at a rate no greater than 1 mg/min. If no infusion reaction is observed, subsequent Lipo-Dox infusions can be increased to complete administration over 60 minute period. In the breast cancer trial program, modification of the infusion was permitted for those patients experiencing an infusion reaction as follows: 5% of the total dose was infused slowly over the 15 minutes. If tolerated without reaction, the infusion rate was doubled for the next 15 minutes. If tolerated, the infusion was completed over the next hour for total infusion time of 90 minutes.
Subsequent pegylated liposomal doxorubicin infusions may be administered over a 60 minute period.
AIDS-KS Patients: Lipo-Dox should be administered intravenously at 20 mg/m² every two to three weeks. The intervals should not be shorter than 10 days to avoid drug accumulation and increased toxicity. Patients should be treated for 2 to 3 months to achieve a therapeutic response. If necessary, keep on treatment to maintain a therapeutic response.
Dilute Lipo-Dox in 250 ml Dextrose 5% in Water and complete administration by intravenous infusion over 30 minutes.
All patients: If any signs or early symptoms of infusion reaction occur, the infusion should be immediately discontinued, give appropriate premedications (antihistamine and/or short acting corticosteroid) and restart at a slower rate.
Do not administer as a bolus injection or an undiluted solution. It is recommended that the pegylated liposomal doxorubicin infusion line be connected through the side port of an intravenous infusion of Dextrose 5% in Water to achieve further dilution and minimize the risk of thrombosis and extravasation. The infusion may given through a peripheral vein. Pegylated liposomal doxorubicin must not be given by the intramuscular or subcutaneous route. Do not use with in-line filters.
Adverse events, such as palmar-plantar erythrodysesthesia (PPE), hematologic toxicity or stomatitis, may be managed by dose reducing or delay. Guidelines for dose modification secondary to these adverse effects are provided in the table as follows. The toxicity grading is based on the National Cancer Institute Common Toxicity Criteria (NCI-CTC). (See Tables 2, 3 and 4.)

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Patients with Impaired Hepatic Function: Base on reports, in the small number of patients with elevated total bilirubin levels, the pharmacokinetics are similar with patients with normal total bilirubin. However, until further experience is gained, the pegylated liposomal doxorubicin dosage in patients with impaired hepatic function should be reduced based on the experience from the breast and ovarian cancer clinical trial programs as follows: at initiation of therapy, if the bilirubin 1.2 to 3.0 mg/dL, the initial dose is reduced by 25%. If the bilirubin >3.0 mg/dL, the initial dose is reduced by 50%. If the patient tolerates the initial dose without an increase in serum bilirubin or liver enzymes, the dose of cycle 2 can be increased to the next dose level, i.e., if reduced by 25% for the initial dose, increase to full dose for cycle 2; if reduced by 50% for the initial dose, increase to 75% of full dose for cycle 2. Then, if the patient well tolerates, the dosage can be increased to full dose for subsequent cycles. In the liver metastases patients with concurrent elevation of bilirubin and liver enzymes up to 4x the upper limit of the normal range, pegylated liposomal doxorubicin could be administered. Before pegylated liposomal doxorubicin administration, evaluate hepatic function using conventional clinical laboratory tests such as ALT/AST, alkaline phosphatase, and bilirubin.
Patients with Impaired Renal Function: Doxorubicin is metabolized by the liver and excreted in the bile, so no need to adjust the dose. From the pharmacokinetic analysis of special population, it is confirmed that the pharmacokinetic properties are not changed in the patients with the creatinine clearance between 30-156 mL/min. No pharmacokinetic data are available patients with the creatinine clearance of less than 30 mL/min.
AIDS-KS Patients with Splenectomy: No experience with pegylated liposomal doxorubicin in patients with splenectomy the bladder-excision AIDS-KS patients. Not recommended to use.
Pediatric Patients: Limited Phase Ⅰ safety clinical data indicated that doses up to 60 mg/m² pegylated liposomal doxorubicin every 4 weeks are well tolerated in pediatric patients; however the efficacy in patients under 18 years old has not been established.
Geriatric Patients: Base on population analysis, the pharmacokinetics of pegylated liposomal doxorubicin in 21-75 year-old patients are not changed.

Acute overdosage with doxorubicin HCl worsens the toxic effects of mucositis, leukopenia and thrombocytopenia. Treatment of acute overdosage of the severely myelosuppressed patient consists of hospitalization, antibiotics, platelet and granulocyte transfusions and symptomatic treatment of mucositis.

Lipo-Dox is contraindicated in patients who have hypersensitivity reactions to doxorubicin HCl or to its components.
Lipo-Dox should not be administered while breast-feeding.
Lipo-Dox should not be used to treat AIDS-KS that may be effectively treated with local therapy or systemic alfa-interferon.

Cardiac Toxicity: All patients treating with Lipo-Dox should routinely undergo EKG monitoring. When T-wave flattening, S-T segment depression and benign arrhythmias occur, no need to discontinue therapy immediately. However, reduction of the QRS complex is considered more indicative of, it usually shows the cardiac toxicity. Endomyocardial biopsy should be considered to define for anthracycline myocardial injury (see Adverse Reactions).
Besides ECG, there are many specific methods for monitoring cardiac functions, such as a measurement of LVEF by echocardiography or preferably by Multigated Angiography (MUGA). These methods should be applied routinely before or during the Lipo-Dox treatment. In a phase III clinical trial comparing pegylated liposomal doxorubicin (50 mg/m²/every 4 weeks) versus conventional doxorubicin (60 mg/m²/every 3 weeks), the risk of developing a cardiac toxicity as a function of cumulative anthracycline dose was significant lower with pegylated liposomal doxorubicin than with conventional doxorubicin (HR=3.16, p<0.001). At cumulative doses between 450 mg/m² and 600 mg/m² there was no increased risk of cardiac toxicity with pegylated liposomal doxorubicin. The evaluation of left ventricular function is considered to be mandatory before each addition administration of pegylated liposomal doxorubicin which exceeds a lifetime cumulative anthracycline dose of 600 mg/m² in patients without prior anthracycline exposure. For patients who have received prior adjuvant anthracyclines (epirubicin or doxorubicin), LVEF assessments should be performed before each additional administration of pegylated liposomal doxorubicin that exceeds a lifetime, doxorubicin-equivalent, cumulative anthracycline dose of 450 mg/m².
The evaluation tests and monitoring of cardiac performance during anthracycline therapy should be employed in the following order: ECG monitoring, measurement of left ventricular ejection fraction, endomyocardial biopsy. If the test result indicates possible cardiac injury associated with pegylated liposomal doxorubicin therapy, the benefit of continued therapy must be carefully evaluated.
In patients with cardiovascular disease requiring treatment, administer Lipo-Dox only when the benefit outweighs the risk to the patient.
Caution should be exercised in patients with impaired cardiac function who receive pegylated liposomal doxorubicin.
If the test results indicate possible cardiac injure, such as the left ventricular ejection fraction lower than pre-treatment baseline and/or LVEF is lower than a prognostically relevant values (<45%), endomyocardial biopsy may be considered. The benefit of continued therapy must be carefully weighed against the risk of developing irreversible myocardial injury.
Moreover, congestive heart failure due to cardiomyopathy may occur suddenly, without prior ECG changes and may also be encountered several weeks after discontinuation of therapy.
Caution should be carefully monitored in patients who have received other anthracyclines, and the total dose of doxorubicin HCl should take into account any previous or concomitant therapy with cardiotoxic compounds such as other anthracyclines/anthraquinones or 5-fluorouracil. The cardiac toxicity also may occur at cumulative anthracycline doses lower than 450 mg/m² in patients with prior mediastinal irradiation or in those treating concurrent cyclophosphamide therapy.
The cardiac safety profile for the recommended dose for both breast and ovarian caner (50 mg/m²/every 4 weeks) is similar to the 20 mg/m²/every 2 weeks profile in AIDS-KS patients. (See Adverse Reactions.)
Myelosuppression: Many patients treated with pegylated liposomal doxorubicin have baseline myelosuppression due to such factors as their pre-existing HIV disease or concomitant or previous medications, or tumors involving bone marrow. In the ovarian cancer clinical trial, patients who treated with 50 mg/m² of pegylated liposomal doxorubicin, myelosuppression was generally mild to moderate, reversible, and was not related to the neutropenic infection or sepsis.
Besides these, the clinical results of ovarian cancer using topotecan as control group proved that the incidence of therapy-related sepsis was lower in pegylated liposomal doxorubicin group than in topotecan group. A similar low incidence of myelosuppression was seen in metastatic breast cancer patients receiving pegylated liposomal doxorubicin in a first-line clinical trial. In contrast to the experience in breast cancer and ovarian cancer patients, the myelosuppression appears to be the dose-limiting adverse event in AIDS-KS patients. Because of the potential for bone marrow suppression, periodic blood counts must be performed during the course of pegylated liposomal doxorubicin, and at least before each dose of pegylated liposomal doxorubicin.
Persistent severe bone marrow suppression is not seen in breast or ovarian cancer patients, but it may result in superinfection or hemorrhage.
Due to the different pharmacokinetic properties and dosing schedules, Lipo-Dox should not be used interchangeably with other doxorubicin HCl formulations. Combination chemotherapy with pegylated liposomal doxorubicin has been studied in solid tumor populations. Pegylated liposomal doxorubicin has been safely co-administered with standard doses of chemotherapeutic agents that are frequently used in the treatment of advanced breast cancer or ovarian cancer, however the efficacy of such combination regimens has not been established.
Diabetic Patients: Each vial of Lipo-Dox contains sucrose and is administered in Dextrose 5% in Water for intravenous infusion, so precaution should be exercised.
Infusion-related Adverse Reactions: Serious and sometimes life-threatening infusion reactions which are characterized by allergic-like or anaphylactoid-like reactions, with symptoms including asthma, flushing, urticarial rash, chest pain, fever, hypertension, tachycardia, pruritus, sweating, shortness of breath, facial edema, chills, back pain, tightness in the chest and throat and/or hypotension may occur within minutes of starting the infusion of pegylated liposomal doxorubicin. Temporarily stopping the infusion usually resolved these symptoms without further therapy. However, medications to treat these symptoms (e.g., antihistamines, corticosteroids, and adrenaline), as well as emergency equipment should be available for immediate use. In most patients can be resumed after all symptoms have resolved, without recurrence. Infusion reactions rarely recur after the first treatment cycle. To minimize the risk of infusion reactions, the initial dose should be administered at a rate no greater than 1 mg/minute. (See Adverse Reactions.)
Driving and Machine Operations: As reported, pegylated liposomal doxorubicin does not affect on patient's driving, but few people (<5%) occur dizziness and somnolence. Patients who suffer from these effects should avoid driving and machine operations.

Pegylated liposomal doxorubicin is embryotoxic in rats and embryotoxic and abortifacient in rabbits. Teratogenicity cannot be excluded. There is no experience in pregnant women with pegylated liposomal doxorubicin, therefore administration to pregnant women is not recommended. Avoiding pregnancy in women of childbearing potential while they or their male partner are in the treatment and in the 6 months following discontinuation of Lipo-Dox therapy.
It is not known whether Lipo-Dox is excreted in human milk and because of the potential for serious adverse reactions in nursing infants, mothers should discontinue nursing. Medical experts recommend that HIV-infected women should not nurse infants under any circumstances in order to avoid transmission of HIV.

Breast Cancer Patients: 254 patients with advanced breast cancer who had not received prior chemotherapy for metastatic disease were treated with pegylated liposomal doxorubicin at a dose of 50 mg/m² every 4 weeks in a phase III clinical trial (I 97-328). The most frequently reported treatment related adverse reactions included palmar-plantar erythrodysesthesia (PPE) (48.0%) and nausea (37.0%) (see Table 5). These effects were mostly mild and reversible, with severe (Grade 3) cases reported in 17.0% and 3.0% respectively, and no reported incidences of life threatening (Grade 4) cases for either PPE or nausea. Infrequently, these effects resulted in permanent treatment discontinuation (7.0% and 0% respectively). Pronounced alopecia (or total hair loss) was seen in only 7.0% of pegylated liposomal doxorubicin-treated patients as compared with 54.0% of patients treated with conventional doxorubicin.
Hematologic adverse reactions were infrequently reported and were mostly mild or moderate in severity and manageable. Anemia, neutropenia, leucopenia and thrombocytopenia were infrequently reported at incidences of 5.0%, 4.0%, 2.0% and 1.0%, respectively. Life threatening (Grade 4) hematologic effects were reported at incidences of <1.0%. The need for either growth factor support or transfusion support was minimal (5.1% and 5.5% of patients, respectively) (see Dose and Administration).
Clinically significant laboratory abnormalities (Grade 3 and 4) in this breast cancer group included increases in total bilirubin (2.4%) and AST (1.6%). Increases in ALT were less frequent (<1%). Clinically significant hematologic measurements were infrequent as measured by leukopenia (4.3%), anemia (3.9%), neutropenia (1.6%) and thrombocytopenia (1.2%). Sepsis was reported at an incidence of 1%. No clinically significant increases in serum creatinine were reported.
In 150 patients with advanced breast cancer who had failed a prior first or second line taxane-containing chemotherapy regimen and were subsequently treated with pegylated liposomal doxorubicin at a dose of 50 mg/m² every 4 weeks in phase III clinical trial (C/I 96-352), the safety profile was consistent with that reported in previous studies using the same dosage regimen (see Table 5). The proportion of patients experiencing clinically significant laboratory abnormalities was low and comparable numerically to the 254 breast cancer patients receiving pegylated liposomal doxorubicin as first-line therapy, with exception of leukopenia (20%). (See Table 5.)

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Undesirable effects reported between 1% and 5% in 404 pegylated liposomal doxorubicin-treated breast cancer patients, not previously reported (≥1%) were breast pain, leg cramps, edema, leg edema, peripheral neuropathy, oral pain, ventricular arrhythmia, folliculitis, bone pain, musculo-skeletal pain, thrombocythemia, cold sores (non-herpetic), fungal infection, epistaxis, upper respiratory tract infection, bullous eruption, dermatitis, erythematous rash, nail disorder, scaly skin, lacrimation and blurred vision.
Ovarian Cancer Patients: In clinical trials, safety data are available from 512 ovarian cancer patients (a subset of 876 solid tumor patients) treated with 50 mg/m² pegylated liposomal doxorubicin.
The most frequently reported therapeutic-related adverse reactions included palmar-plantar erythrodysesthesia (PPE) (46.1%) and stomatitis (38.9%) (see table 6). These reactions were mainly mild. The incidence of severe cases (Grade 3) were 19.5% and 8.0% respectively, and the life-threatening cases (Grade 4) were 0.6% and 0.8% respectively. These reactions infrequently resulted in permanent therapy discontinuation. (<5% and <1% respectively). (See Table 6.)

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The myelosuppression was mostly mild to moderate and treatable. Most frequently reported hematologic adverse reaction was leukopenia, followed by anemia, neutropenia, and thrombocytopenia. Very few happened life-threatening (Grade 4) hematological adverse event, at incidences of; leukopenia (1.6%), anemia (0.4%), neutropenia (2.9%) and thrombocytopenia (0.2%). Less than 5% patients need the growth factor support and less than 15% patients need the blood infusion support. (See Dosage & Administration.)
Other less frequently (1-5%) reported included peripheral edema, mouth moniliasis, vasodilatation, mouth ulceration, pruritus, allergic reaction, dehydration, dyspnea, vesiculobullous rash, chills, infection, weight loss, esophagitis, skin disorder, exfoliative dermatitis, cardiovascular disorder, chest pain, dizziness, maculopapular rash, gastritis, myalgia, back pain, depression, insomnia, dysphagia, increased cough, sweating, nausea and vomiting, malaise, taste perversion, urinary tract infection, conjunctivitis, acne, gingivitis, herpes zoster, hypochromic anemia, anxiety, vaginitis, headache, flatulence, dry mouth, cachexia, neuropathy, hypertension, skin ulcer and dysuria.
In the analysis of the data from 410 ovarian cancer patients, the clinically significant abnormal laboratory values included total bilirubin value elevating (usually in patients with liver metastases) (5%), and serum creatinine clearance levels elevating (5%). Clinically significant measurements, measured by Grade 3 and 4 neutropenia (11.4%), anemia (5.7%) and thrombocytopenia (1.2%) were low. Very few cases (<1%) happened AST elevating. Sepsis related to leukopenia was also not frequently observed. The similar results could be found in solid tumor patients.
AIDS-KS Patients: Open-label and controlled clinical studies on AIDS-KS patients treated with pegylated liposomal doxorubicin at a dose of 20 mg/m² show that, the most frequent adverse reaction is bone marrow suppression. About half of the patients have bone marrow suppression.
Within these patients, the most frequent adverse reaction is leukopenia; then neutropenia, anemia and thrombocytopenia have been observed. These reactions may happen in the early stage of the therapy. Dose reduction or suspension or delay of therapy may be required when the hematological toxicities happen. Temporarily suspend Lipo-Dox when the absolute neutrophil count (ANC) is less than 1000/mm³ or/and the platelet count is less than 50,000/mm³. When the ANC <1000/mm³, may add G-CSF (or GM-CSF) in subsequent cycles to support the blood count. The hematological toxicity is milder in breast cancer or ovarian cancer patients than in the AIDS-KS patients with pegylated liposomal doxorubicin treatment. (See Ovarian Cancer Patients as previously mentioned.)
Other frequently (≧5%) adverse reactions include nausea, asthenia, alopecia, fever, diarrhea, infusion-associated acute reactions, and stomatitis.
Respiratory adverse reactions are frequent (≧5%). It may be related to opportunistic infections in the AIDS patients. Opportunistic infections are observed in KS patients with pegylated liposomal doxorubicin treatment, and are frequently seen in patients with HIV-induced immunodeficiency. The most frequent opportunistic infections are candidiasis, cytomegalovirus, herpes simplex, Pneumocystis carinii pneumonia, and Mycobacterium avium complex.
Other less frequent adverse events (<5%) are palmar-plantar erythrodysesthesia, mouth moniliasis, nausea and vomiting, weight loss, rash, mouth ulceration, dyspnea, abdominal pain and hypersensitivity reaction including: anaphylactic reactions, dizziness, vasodilatation, insomnia, glossitis, constipation, paresthesia, retinitis, and confusion.
In pegylated liposomal doxorubicin HCl clinical studies, the frequently (≧5%) significant laboratory abnormalities included alkaline phosphatase increases, AST increases, and bilirubin value increases which are related to the underlying disease and not pegylated liposomal doxorubicin. Reduction in hemoglobin and platelets are less frequently (<5%). Sepsis caused by leukopenia is rarely observed (<1%). These abnormalities may have been related to the underlying HIV infection and not pegylated liposomal doxorubicin.
For Solid Tumor Patients: In a large study containing 929 solid tumor, including breast and ovarian cancer, patients, 50 mg/m² of Pegylated liposomal doxorubicin/4 weeks was prescribed. The safety properties and the incidence of adverse reactions are similar to the results in the breast and ovarian cancer clinical trial as previously mentioned.
For All Patients: The following reactions, defined with Costart, were occurred within the Pegylated liposomal doxorubicin treatment period among 100 of 928 (10.8%) solid tumor patients: allergic reaction, anaphylactoid reaction, asthma, face edema, hypotension, vasodilatation, urticaria, back pain, chest pain, chills, fever, hypertension, tachycardia, dyspepsia, dizziness, dyspnea, pharyngitis, rash, nausea, pruritus, sweating, injection site reaction and drug interactions. Permanent treatment discontinuation rates were infrequently reported at 2%. A similar incidence of infusion reactions (12.4%) was observed in the pivotal breast cancer trials. The rate of permanent treatment discontinuation was also similar at 1.5%. In the AIDS-KS patients, the infusion related reactions are flushing, shortness of breath, facial edema, headache, chills, back pain, tightness in the chest and throat, and/or hypotension. Those reactions primarily appear during the first treatment and can be expected at the rate of 5-10%.
Usually, temporarily stopping the infusion or reduce infusion rate could resolve these symptom without further therapy. In nearly all patients could resume pegylated liposomal doxorubicin treatment after all symptoms have resolved without recurrence. After the first cycle of pegylated liposomal doxorubicin treatment, the infusion reactions rarely recur.
There was stomatitis reported in patients receiving continuous infusions of conventional doxorubicin HCl and was frequently reported in patients receiving pegylated liposomal doxorubicin. It did not interrupt the treatment and no need to adjust dosage, unless it affects a patient's eating ability. When it occurs, prolong the dose interval by 1 to 2 weeks or reduce dose.
Palmar-Plantar erythrodysesthesia (PPE), characterized by painful, macular reddening skin eruptions, is generally seen after 2 or 3 cycles of treatment. No matter whether treated with corticosteroid or not, it usually disappears in 1-2 weeks. Pyridoxine at a dose of 50-150 mg per day had been used for the prophylaxis and treatment of PPE. Other strategies to prevent and treat PPE may be initiated 4-7 days after pegylated liposomal doxorubicin treatment. Immerse hands and feet in cold water (soaks, baths or swimming) to keep them cool. Avoiding to contact heat or hot water and keeping hands and feet unrestricted (no socks, gloves or shoes that are tight fitting). This reaction is related to dose and schedule. Prolonging dose interval 1 to 2 weeks or reducing dose could improve it. The reaction can be severe and debilitating in some patients and may require discontinuation of treatment.
Treatment of conventional doxorubicin HCl, at cumulative lifetime doses >450 mg/m² or at lower doses for patients with cardiac risk factors, may increase the incidence of congestive heart failure. However, in 10 AIDS-KS patients receiving pegylated liposomal doxorubicin treatment and cumulative doses exceeding 460 mg/m², Endomyocardial biopsies on 9 patients did not show anthracycline-induced cardiomyopathy. The recommended dose of pegylated liposomal doxorubicin for AIDS-KS patients is 20 mg/m² every 2 to 3 weeks. Therefore, to cumulative doses at which cardiotoxicity would become a concern for these patients (>400 mg/m²) would required more than 20 courses over 40 to 60 weeks.
In addition, endomyocardial biopsies were performed in 8 solid tumor patients with cumulative anthracycline doses of 509 mg/m²-1680 mg/m². The range of Billingham cardiotoxicity scores was grades 0-1.5. These grading scores are consistent with no or mild cardiac toxicity.
In the pivotal phase III trial versus conventional doxorubicin, 10/254 patients randomized to receive pegylated liposomal doxorubicin (at a dose of 50 mg/m²/every 4 weeks) versus 48/255 patients randomized to receive conventional doxorubicin met the protocol-defined criteria for cardiac toxicity during treatment and/or follow-up. Cardiac toxicity was defined as a decrease of 20 points or greater from baseline if the resting LVEF remained in the normal range or a decrease of 10 points or greater if the LVEF became abnormal (less than the lower limit for normal). Patients were also assessed for signs and symptoms of congestive heart failure (CHF). None of the 10 pegylated liposomal doxorubicin patients developed CHF. In contract, 10 of 48 conventional doxorubicin patients developed signs and symptoms of CHF.
The incidence of clinically significant cardiac injure was very low in the solid tumor patients (including breast and ovarian cancers) receiving dosage of 50 mg/m² at every cycle with lifetime cumulative anthracycline doses up to 1532 mg/m². Within 929 patients treated with 50 mg/m² of pegylated liposomal doxorubicin every cycle, 418 patients received the baseline measurement of left ventricular ejection fraction (LVEF) and at least once follow-up measurement by MUGA scan as evaluation method. 88 out of these 418 patients had a cumulative anthracycline dosage exceeding 400 mg/m². Under the conventional doxorubicin HCl formulation therapy, such high dosage is enough to increase risk of cardiac toxicity. Only 13 of these 88 patients (15%) occurred at least once clinically significant change in their LVEF, defined as an LVEF value less than 45% or a decrease of at least 20 points from baseline. Only one patient with cumulative dosage of 944 mg/m² discontinued the clinical study due to clinical symptoms of congestive heart failure. Although local tissue necrosis following extravasation of pegylated liposomal doxorubicin has been reported very rarely, but an irritant should be considered. Animal studies indicate that the liposomal doxorubicin HCl could reduce the potential for extravasation injury. If any symptoms of extravasation occur (e.g., stinging, erythema), 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. Pegylated liposomal doxorubicin must not be given by the intramuscular or subcutaneous route.
The recall of skin reaction due to prior radiotherapy is very rarely seen in pegylated liposomal doxorubicin HCl administration.

Although phase II combination trials with conventional chemotherapy agents have been conducted in patients with gynecological malignancies, there is no formal drug interaction studies. Caution should be exercised in the concomitant use of drugs known to interact with conventional doxorubicin HCl. Like other doxorubicin HCl preparations, pegylated liposomal doxorubicin may increase the toxicity of other anti-cancer drugs.
Pegylated liposomal doxorubicin HCl has been administered to 230 cancer patients with solid tumors (including ovarian cancer or breast cancer) as part of combination therapy regimen (combined with either cyclophosphamide, taxanes or vinorelbine). In AIDS-KS patients, it has been reported that conventional doxorubicin HCl exacerbates the cyclophosphamide-induced hemorrhagic cystitis and enhances the hepatotoxicity of 6-mercaptopurine. With caution when use with other anti-cancer drugs, especially those may induce bone marrow suppression.

Instructions for use/handling: Do not use material if precipitation or any other particulate matter are present. Caution should be exercised in handling pegylated liposomal doxorubicin. The use of gloves is required. If pegylated liposomal doxorubicin comes into contact with skin or mucosa, immediately wash thoroughly with soap and water. Pegylated liposomal doxorubicin should be handled and disposed of in a manner consistent with that of other anticancer drugs.
Determine the dose of pegylated liposomal doxorubicin to be administered based on the recommended dose and the patient's body surface area. Take the appropriate volume of pegylated liposomal doxorubicin up into a sterile syringe. Aseptic technique must be strictly observed since no preservation or bacteriostatic agent is present in pegylated liposomal doxorubicin HCl.
The appropriate dose of pegylated liposomal doxorubicin must be diluted in Dextrose 5% in Water prior to administration. For doses <90 mg, dilute in 250 ml of Dextrose 5% in Water, and for doses ≥90 mg, dilute in 500 ml of Dextrose 5% in Water.
Do not use other diluents or solution containing any bacteriostatic agent, such as benzyl alcohol, which will cause precipitation.
It is recommended that the pegylated liposomal doxorubicin infusion line be connected through the side port of an intravenous infusion of Dextrose 5% in Water. The infusion may be given through a peripheral vein. Do not use with in-line filters.
Incompatibilities: Do not mix with other drugs.

Refrigerate unopened vials at 2°C to 8°C. Avoid freezing. After dilution with Dextrose 5% in Water, the diluted Lipo-Dox solution should be used immediately or stored at 2°C to 8°C for no longer than 24 hours.
Discard the partially used vials.
Ask the physicians or pharmacists for further information.

Cytotoxic Chemotherapy

L01DB01 - doxorubicin ; Belongs to the class of cytotoxic antibiotics, anthracyclines and related substances. Used in the treatment of cancer.

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