Lipo-Dox

Lipo-Dox

doxorubicin

Manufacturer:

TTY Biopharm

Distributor:

Onco Care Pharma

Marketer:

American Taiwan Biopharma
Full Prescribing Info
Contents
Doxorubicin hydrochloride.
Description
Each ml contains: Liposomal Doxorubicin Hydrochloride 2 mg/ml.
Doxorubicin HCl (Lipo-Dox), a liposome formulation, is doxorubicin hydrochloride encapsulated in liposomes with surface-bound methoxypolyethylene glycol (MPEG). This process is known pegylation and it protects liposomes from detection by the mononuclear phagocyte system (MPS) and increases circulation time in blood.
Each Doxorubicin HCl (Lipo-Dox) vial contains pegylated liposomal doxorubicin HCl 2 mg/mL and delivers 10 mL (20 mg) in a concentrate for single dose intravenous infusion and is presented as a sterile, translucent, and red suspension. The active ingredient of Lipo-Dox is doxorubicin HCl, a cytotoxic anthracycline antibiotic obtained from Streptomyces peuticus var. caesius.
Excipients/Inactive Ingredients: Each vial of products contains the following excipients: Cholesterol, Sucrose, Water for Injection.
Action
Pharmacology: Doxorubicin HCl (Lipo-Dox) is a long-circulating pegylated liposomal formulation of doxorubicin HCl that provides greater concentration of doxorubicin in Kaposi'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 tumor. 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 lesions. The doxorubicin HCl could be encapsulated during liposome residence time in circulation, because of low permeability lipid matrix and internal liquid buffer system of the pegylated liposomes.
The plasma pharmacokinetics in humans is significantly 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 is displayed to be non-linear over the dose range of 10 mg/m2 to 60 mg/m2.
In contrast to the pharmacokinetics 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 and enter the tissue compartment, doxorubicin becomes available.
At equivalent doses, the plasma concentration and AUC values of pegylated liposomal doxorubicin which mostly exists as encapsulated in liposomes (containing 90% to 95% of the measured doxorubicin) are significantly higher than conventional doxorubicin HCl.
Pharmacodynamics: Mechanism of Action: The exact mechanism of the antitumor activity of doxorubicin is not clear. 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 the inter-chelation of the doxorubicin between the adjacent base pairs of the DNA double helix, thus preventing their unwinding for replication.
Clinical Efficacy: A Phase III randomized study of pegylated liposomal doxorubicin versus doxorubicin HCl in metastatic breast cancer was completed in 509 patients. The protocol-specified objective of demonstrating non-inferiority between pegylated liposomal doxorubicin and doxorubicin has met the hazard ratio (HR) for progression-free survival (PFS) was 1.00 (95% CI for HR=0.8201.22). 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). PFS of both were the same.
In 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 failed to first-line platinum-based chemotherapy. The results indicated that the effect of 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 0.0920-1.367, 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: Population Pharmacokinetics: The population pharmacokinetics of pegylated liposomal doxorubicin was evaluated in 120 patients from 10 different clinical trials. The pharmacokinetics over the dose range from 10 mg/m2 was the 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 (0.96-3.83 L/m2), approximating the volume of a 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 Doxorubicin HCl (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 0.16 L/h/m2 (0.009-0.027 L/h/m2), the mean central volume of distribution was 1.46 L/m2 (1.10-1.64 L/m2). The mean half-life was 75.1 hours (45.2-98.5 hours).
Ovarian Cancer Patients: The pharmacokinetic data from the 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 Table 1. (See Table 1.)

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Toxicology: Pre-clinical Toxicological Study: In multiple doses 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 has different toxicity strength, as follows: Cardiotoxicity: In rabbit studies, the cardiotoxicity of pegylated liposomal doxorubicin was less than the 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, which are described as palmar-plantar erythrodysesthesia were also observed in patient's long-term intravenous infusion. (See Adverse Reactions).
Anaphylactoid response: During the multiple 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 extraversations of pegylated liposomal doxorubicin were slighter than the conventional doxorubicin HCl.
Mutagenicity and Carcinogenicity: Although no studies have been conducted with pegylated liposomal 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 multiple doses 0.25 mg/kg/day. Diffuse degeneration of the seminiferous tubules and a marked decreased in spermatogenesis were observed in dogs after multiple doses of 1 mg/kg/day.
Indications/Uses
For the treatment of AIDS-related Kaposi's sarcoma in patients with low CD4 (<200 CD4 lymphocytes/mm3) and disease in mucosa, skin and internal organs.
For the treatment of metastasis carcinoma of the ovary in patients with disease that is recurrent to both first-line platinum and paclitaxel-based chemotherapy regiments.
As monotherapy for patients with metastatic breast cancer, where there is an increased cardiac risk.
Dosage/Direction for Use
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: Doxorubicin HCl (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 Doxorubicin HCl (Lipo-Dox) in 250 mL Dextrose 5% in Water.
For dose ≥90 mg: dilute Doxorubicin HCl (Lipo-Dox) in 500 mL Dextrose 5% in Water.
To minimize the risk of infusion reactions, the initial dose should be administered at a rate no more than 1 mg/min. If no infusion reaction was observed, subsequent Doxorubicin HCl (Lipo-Dox) infusions can be increased to complete administration over a 60-minute period. In the breast cancer trial program, modification of the infusion was permitted for those patients experiencing an illusion reaction as follows: 5% of the total dose should be administered slowly over 15 minutes. If tolerated without reactions, the infusion rate could be 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 infusion might be administered over a 60-minute period.
AIDS-KS Patients: Doxorubicin HCl (Lipo-Dox) should be administered intravenously at 20 mg/m2 every 2 to 3 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.
Dilute Doxorubicin HCl (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 discontinued immediately. Appropriate premedications (antihistamine and/or short-acting corticosteroid) should be given when restarting the infusion 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 should 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 might be given through a peripheral vein. Pegylated liposomal doxorubicin must not be given by 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 secondary to these adverse effects are provided in the following table. The toxicity grading is based on the National Cancer Institute Common Toxicity Criteria (NCI-CTC).
Guidelines for Lipo-Dox Dose Modification: See Tables 2, 3 and 4.

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Patients with Impaired Hepatic Function: Based on reports, in the small amount of patients with elevated total bilirubin levels, the pharmacokinetics is similar to patients with normal total bilirubin levels. 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 ranges from 1.2 to 3.0 mg/dL, the initial dose should be reduced by 50%. If the patient tolerates the initial dose without an increase in serum bilirubin or liver enzymes, the dosage in cycle 2 can be increased to the next dose level, i.e. when reduced by 25% for the initial dose, increase to 75% of full dose for cycle 2. Then, if the patient tolerates well, the dosage can be increased to full dose for the 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, evaluation of hepatic function using conventional clinical laboratory tests such as ALT/AST, alkaline phosphatase, and bilirubin is necessary.
Patients with Impaired Renal Function: Since doxorubicin is metabolized by the liver and excreted in bile, dosage adjustment is not necessary. From the pharmacokinetic analysis of special population, it is confirmed that the pharmacokinetic properties are not different in the patients with the creatinine clearance between 30-156 mL/min. No pharmacokinetic data are available in patients with the creatinine less than 30 mL/min.
AIDS-KS Patients with Splenectomy: There is no experience with pegylated liposomal doxorubicin in patients with splenectomy. Lipo-Dox is not recommended.
Pediatric Patients: Limited Phase I safety clinical data indicated that doses up to 60 mg/m2 pegylated liposomal doxorubicin every 4 weeks is well-tolerated in pediatric patients; however the efficacy in patients under 18 years old has not been established.
Geriatric Patients: Based on the population analysis, the pharmacokinetics of pegylated liposomal doxorubicin in 21-75 year old patients is not changed.
Overdosage
Acute reaction of overdosage with doxorubicin HCl worsens the effects of mucositis, leucopenia and thrombocytopenia. Treatments of acute reaction of overdosage in the severely myelosuppressed patient include hospitalization, antibiotic, platelet and granulocyte transfusions and symptom relief of mucositis.
Contraindications
Lipo-Dox is contraindicated in patients who have a history of hypersensitivity to doxorubicin HCl or the excipient of Lipo-Dox.
Lipo-Dox should not be administered while breastfeeding.
Lipo-Dox should not be used in AIDS-KS patients when they were effectively treated by local therapy or systemic alfa-interferon.
Special Precautions
Cardiac Toxicity: All patients treating with Lipo-Dox should routinely undergo ECG monitoring. When T-wave flattening, S-T segment depression and arrhythmia occur, therapy discontinuance immediately is not necessary. However, when the reduction of the QRS complex occurs, it usually shows the cardiac toxicity. Endomyocardial biopsy should be considered to define for anthracycline-induced myocardial injury. (See Adverse Reaction).
Besides ECG, there are many specific methods for monitoring cardiac functions, such as a measurement of LVEF by cardiac echo 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 ) with conventional doxorubicin (60 mg/m2 every 3 weeks), the risk of cardiac toxicity development as a function of cumulative anthracycline dose was significantly lower with pegylated liposomal doxorubicin than with conventional doxorubicin (HR=3.16, p<0.001). At cumulative doses between 450 mg/m2 to 600 mg/m, 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 and each time when the accumulated dosage increment of pegylated liposomal doxorubicin is 100 mg/m2, the patients must receive the evaluation of LVEF.
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 indicated possible cardiac injury associated with pegylated liposomal doxorubicin therapy, the benefit of continuance of therapy or not must be carefully evaluated.
In patients with cardiovascular disease requiring treatment, administer Lipo-Dox only when the benefit outweighs the risk to the patients.
Caution should be exercised in patients with impaired cardiac function who receive pegylated liposomal doxorubicin.
If the test results indicate possible cardiac injury, such as the left ventricular ejection fraction lower than pre-treatment baseline and/or LVEF is lower that a prognostically relevant values (<45%), endomyocardial biopsy might be considered. The benefit of continuance of 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 be taken 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 that 450 mg/m2 in patients with prior mediastinal irradiation or in those with concurrent cyclophosphamide therapy.
The cardiac safety profile for the recommended dose for both breast and ovarian cancer (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 preexisting HIV disease or concomitant or previous medications or tumors involving bone marrow. In the ovarian cancer clinical trial, patients who were treated with 50 mg/m2 of 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 ach dose of pegylated liposomal doxorubicin.
Persistent severe bone marrow suppression is not seen in breast or ovarian cancer patients, but it may result in recurrent infection hemorrhage.
Due to the different pharmacokinetic properties and dosing schedule, Lipo-Dox should not be interchanged with other doxorubicin HCl formulations. Combination chemotherapy with 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 regiments 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: Severe and sometimes life-threatening infusion reactions which are characterized by allergic-like or anaphylactoid-like reactions with symptoms including asthma, flushing, urticaria 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. Discontinuance of infusion temporarily usually resolved 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. The initial rate of infusion should not be over 1 mg/min to help minimize the risk of infusion reactions. (See Adverse Reactions.)
Driving and Machine Operations: As reported, pegylated liposomal doxorubicin does not affect patient's driving but dizziness occur and somnolence occur in a few people (<5%). Driving and machine operations should be avoided in patients who suffer from these effects.
Use in Pregnancy & Lactation: 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. Avoid pregnancy in women of child-bearing potential and their male partner within 6 months after discontinuation of Lipo-Dox therapy.
It is not known whether Lipo-Dox is excreted in human milk and because of the potential for severe 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.
Use In Pregnancy & Lactation
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. Avoid pregnancy in women of child-bearing potential and their male partner within 6 months after discontinuation of Lipo-Dox therapy.
It is not known whether Lipo-Dox is excreted in human milk and because of the potential for severe 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.
Adverse Reactions
Although Phase II clinical trials, combined with conventional chemotherapy agents have been conducted n 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 induce the toxicity of other anti-cancer drugs.
Pegylated liposomal doxorubicin HCl has been administered to 230 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 hemorrhage cystitis and enhances the hepatotoxicity of 6-mercaptopurine. With caution when use with other anti-cancer drugs, especially those may induce bone marrow suppression.
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 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 Dosage & 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 leucopenia (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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The incidence of adverse reactions have been reported between 1% and 5% in 404 pegylated liposomal doxorubicin-treated breast cancer patients and the adverse reactions which had been reported previously (≥1%) were breast pain, leg cramps, 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 incidences 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 leucopenia, followed by anemia, neutropenia, and thrombocytopenia. Life-threatening (Grade 4) hematological adverse events occurred at incidences of leucopenia (1.6%), anemia (0.4%), neutropenia (2.9%) and thrombocytopenia (0.2%). Less than 5% of the patients need the growth factor support and less than 15% of the patients need the blood infusion support. (See Dosage & Administration.)
Other less frequently (1-5%) reported adverse events 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 data analysis of the data from 410 ovarian cancer patients, the clinically significant abnormal laboratory result included total bilirubin elevating (usually in patients with liver metastases) (5%), and serum creatinine clearance elevating (5%). Clinically significant measurements, measured by Grade 3 and 4 neutropenia (11.4%), anemia (5.7%) and thrombocytopenia (1.2%) were low. AST elevating occurred in very few cases (<1%). Leukopenia-related sepsis was also observed frequently. The similar results could be found in solid tumor patients.
For Solid Tumor Patients: In a large study containing 929 patients with solid tumor, inducing breast and ovarian cancer, 50 mg/m2 of pegylated liposomal doxorubicin every 4 weeks was prescribed. The safely properties and the incidence of adverse reactions are similar to the results in the breast and ovarian cancer clinical trial described previously.
AIDS-KS Patients: In open-labeled and active controlled clinical studies, it was shown that the most frequent adverse reaction in AIDS-KS patients treated with pegylated liposomal doxorubicin at a dose of 20 mg/m2 was bone marrow suppression. It happened on half of these patients.
Within these patients, the most frequent adverse reaction was leukopenia, then neutropenia, anemia, and thrombocytopenia were observed. These reactions might happen in the early stage of the therapy. Dose reduction, suspension or delay of therapy might be required when the hematological toxicities happened. 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) might be added in subsequent cycles to keep the blood cell count. The hematological toxicity is minor in breast cancer or ovarian cancer patients than in AIDS-KS patients with pegylated liposomal doxorubicin treatment. (See Ovarian Cancer Patients previously.)
Other frequently (%) 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 leucopenia is rarely observed (1%). These abnormalities may have been related the underlying HIV infection and not pegylated liposomal doxorubicin.
For All Patients: The following reactions, defined with Costart 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 and were reported about 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 appeared during the first treatment and can be expected at the rate of 5-10%.
Usually, temporarily stopping the infusion or reducing infusion rate could resolve these symptoms 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 recurred.
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. Otherwise, prolong the dose interval by 1 or 2 weeks or reduce the dosage.
Palmar-Plantar erythrodysesthesia (PPE), characterized by painful, macular reddening skin eruptions, is generally seen after 2 or 3 cycles of treatment. No matter whether treater with corticosteroid or not, it usually disappears within 1-2 weeks. Pyridoxine at a dose of 50-150 mg per day has 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. Avoid to contact heat or hot water and keep hands and feet unrestricted (no socks, gloves or shoes that are tight fitting). This reaction is related to dose regimen. Prolonging dose interval 1 to 2 weeks or reducing dose could improve it. If the reaction was severe or patients feel very then the treatment may be required to be discontinued.
Treatment of conventional doxorubicin HCl at cumulative doses of lifetime was above 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 do not show anthracycline-induced cardiomyopathy. The recommended dosage of pegylated liposomal doxorubicin for AIDS-KS patients is 20 mg/m2 every 2 to 3 weeks. Cumulative doses (>400 mg/m2) which may cause cardiotoxicity, a main concern in AIDS-KS patients, will require more than 20 courses within 40 to 60 weeks.
In addition, endomyocardial biopsies were performed in 8 solid tumor patients with cumulative anthracycline doses of 509-1680 mg/m2. These range of Billingham cardiotoxicity scores were grades 0-1.5. These grading scores are consistent with no or minor cardiac toxicity.
In the pivotal Phase III trial (pegylated liposomal doxorubicin 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-treated patients developed signs and symptoms of CHF.
The recurrence of skin reaction due to prior radiotherapy is very rarely seen in pegylated liposomal doxorubicin HCl administration.
Caution For Usage
Instructions for use/handling: Do not use material if precipitation or any other particulate matter is 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 off 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 there is no preservation or bacteriostatic agent 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 should be connected through the side of port of an intravenous infusion of Dextrose 5% in Water. The infusion might be given through a peripheral vein. Do not use with in-lin filters.
Incompatibilities: Do not mix with other drugs.
Storage
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 not longer than 24 hours.
Discard the partially used vials.
Ask the physicians or pharmacists for further information.
ATC Classification
L01DB01 - doxorubicin ; Belongs to the class of cytotoxic antibiotics, anthracyclines and related substances. Used in the treatment of cancer.
Presentation/Packing
Soln for inj (vial) 2 mg/mL x 10 mL x 10's.
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