Caelyx

Caelyx

doxorubicin

Manufacturer:

Janssen

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Doxorubicin HCl.
Description
Each vial contains doxorubicin HCl 2 mg/mL in a pegylated liposomal formulation and delivers 10 mL (20 mg) or 25 mL (50 mg) in a concentrate for infusion for single IV use.
It also contains the following excipients: α-(2-[1.2-distearoyl-sn-glycero(3)phosphooxy]ethylcarbamoyl)-ω-methoxypoly(oxyethylen)-40 sodium salt (MPEG-DSPE), fully hydrogenated soy phosphatidylcholine (HSPC), cholesterol, ammonium sulphate ACS, sucrose, histidine, water for injection, hydrochloric acid and sodium hydroxide.
Caelyx, a liposome formulation, is doxorubicin HCl 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.
Doxorubicin HCl is a cytotoxic anthracycline antibiotic obtained from Streptomyces peucetius var. caesius.
Action
The exact mechanism of the antitumour 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 anthracycline between adjacent base pairs of the DNA double helix, thus preventing their unwinding for replication.
Pharmacology: Caelyx is a long-circulating pegylated liposomal formulation of doxorubicin HCl that provides greater concentration of doxorubicin in Kaposi's sarcoma (KS) tumours than in normal skin. Pegylated liposomes contain surface-grafted segments of the hydrophilic polymer methoxypolyethylene glycol (MPEG). These linear MPEG groups extend from the liposome surface creating a protective-coating that reduces interactions between the lipid bilayer membrane and the plasma components. This allows the Caelyx liposomes to circulate for prolonged periods in the blood stream. Pegylated liposomes are small enough (average diameter of approximately 100 nm) to pass intact (extravasate) through defective blood vessels supplying tumours. Evidence of penetration of pegylated liposomes from blood vessels, and the entry and accumulation in tumours has been seen in mice with C-26 colon carcinoma tumours and in transgenic mice with KS-like lesions. The pegylated liposomes also have a low permeability lipid matrix and internal aqueous buffer system that combine to keep doxorubicin HCl encapsulated during liposome residence time in circulation.
Pharmacokinetics: The plasma pharmacokinetics of Caelyx in humans differ significantly from those reported in the literature for standard doxorubicin HCl preparations. At lower doses (10-20 mg/m2), Caelyx displayed linear pharmacokinetics. Over the dose range of 10-60 mg/m2, Caelyx displayed nonlinear pharmacokinetics. Standard doxorubicin HCl displays extensive tissue distribution (volume of distribution, 700-1100 L/m2) and a rapid elimination clearance (24-73 L/hr/m2). In contrast, the pharmacokinetic profile of Caelyx indicates that it is confined mostly to the vascular fluid volume and that the clearance of doxorubicin from the blood is dependent upon the liposomal carrier. Doxorubicin becomes available after the liposomes are extravasated and enter the tissue compartment.
At equivalent doses, the plasma concentration and AUC values of Caelyx which represent mostly pegylated liposomal doxorubicin HCl (containing measured doxorubicin 90-95%) are significantly higher than those achieved with standard doxorubicin HCl preparations.
Population Pharmacokinetics: The pharmacokinetics of Caelyx was evaluated in 120 patients from 10 different clinical trials using the population pharmacokinetic approach. The pharmacokinetics of Caelyx over the dose range of 10-60 mg/m2 was best described by a 2-compartment nonlinear model with zero order input and Michaelis-Menten elimination. The mean intrinsic clearance of Caelyx was 0.03 L/hr/m2 (range 0.008-0.152 L/hr/m2) and the mean central volume of distribution was 1.93 L/m2 (range 0.96-3.85 L/m2) approximating the plasma volume. The apparent half-life (t½) ranged from 24-231 hrs, with a mean of 73.9 hrs.
Breast Cancer Patients: The pharmacokinetics of Caelyx determined in 18 patients with breast carcinoma were similar to the pharmacokinetics determined in the larger population of 120 patients with various cancers. The mean intrinsic clearance was 0.016 L/hr/m2 (range 0.009-0.027 L/hr/m2), the mean central volume of distribution was 1.46 L/m2 (range 1.1-1.64 L/m2). The mean apparent t½ was 71.5 hrs (range 45.2-98.5 hrs).
Ovarian Cancer Patients: The pharmacokinetics of Caelyx determined in 11 patients with ovarian carcinoma were similar to the pharmacokinetics determined in the larger population of 120 patients with various cancers. The mean intrinsic clearance was 0.021 L/hr/m2 (range 0.009-0.041 L/hr/m2), the mean central volume of distribution was 1.95 L/m2 (range 1.67-2.4 L/m2). The mean apparent t½ was 75 hrs (range 36.1-125 hrs).
Acquired Immunodeficiency Syndrome (AIDS)-KS Patients: The plasma pharmacokinetics of Caelyx were evaluated in 23 patients with KS who received single doses of 20 mg/m2 administered by a 30-min infusion. The pharmacokinetic parameters of Caelyx (primarily representing liposome-encapsulated doxorubicin HCl and low levels of unencapsulated doxorubicin HCl) observed after the 20-mg/m2 doses are presented as follows (see Table 1).

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Kaposi's sarcoma lesion and normal skin biopsies were obtained 48 hrs and 96 hrs post-infusion. In patients receiving Caelyx 20 mg/m2, the concentration of total (liposome encapsulated and unencapsulated) doxorubicin in the KS lesions was a median of 19 (range 3-53) times higher than in normal skin at 48 hrs post-treatment.
Clinical Efficacy: A phase III randomized study of Caelyx versus doxorubicin HCl in patients with metastatic breast cancer was completed in 509 patients. The protocol-specified objective of demonstrating noninferiority between Caelyx and doxorubicin was met: The hazard ratio (HR) for progression-free survival (PFS) was 1 (95% CI for HR=0.82-1.22). The treatment HR for PFS when adjusted for prognostic variables was consistent with PFS for the ITT population. (See Table 2.)

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About 301 patients with advanced breast cancer who had failed a taxane-containing regimen were randomized in a phase III comparative study to Caelyx versus an approved salvage regimen (vinorelbine or mitomycin C + vinblastine). PFS was similar for Caelyx and the active comparator, with a strong trend favoring Caelyx (HR=1.26, 95% CI 0.98-1.62, p=0.11). In all subgroups analysed, including those patients ≥55 years (n=166), there was a consistent treatment effect with PFS favouring Caelyx over the active comparator (all hazard ratio were >1). (See Table 3.)

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A phase III comparative study of Caelyx versus topotecan in patients with epithelial ovarian cancer following failure of 1st-line, platinum-based chemotherapy was completed in 474 patients. The results of the study for evaluable patients demonstrate superiority of Caelyx over topotecan (hazard ratio* of 1.262, 90% CI 1.062-1.5, p=0.026) for the protocol-specified primary endpoint of time to progression. For the entire ITT population, overall survival for Caelyx was at least equivalent to topotecan with a hazard ratio of 1.121 (90% CI 0.92-1.367, p=0.34) in favour of Caelyx.
Both time to progression and overall survival were significantly in favor of Caelyx (time to progression: Hazard ratio of 1.349, p=0.037, 90% CI 1.065-1.709, median 202 days versus 163 days; overall survival: Hazard ratio of 1.72, 90% CI 1.222-2.422, p<0.01, median 756 days versus 498 days) in the protocol-defined platinum-sensitive subgroups in the ITT population.
When quality of life outcomes eg, toxicity and progression are considered, Caelyx is always preferred over topotecan as demonstrated in the quality-adjusted survival analysis. Although pain secondary to palmar-plantar erythrodysesthesia (PPE) is more common in Caelyx-treated patients, this rarely resulted in study discontinuation.
A consistent trend favouring Caelyx was demonstrated across efficacy endpoints and prognostic subgroups.
Toxicology: Preclinical Toxicology: In repeat-dose studies conducted in animals, the toxicity profile of Caelyx appears very similar to that reported in humans who received long-term infusions of standard doxorubicin HCl. With Caelyx, the encapsulation of doxorubicin HCl in pegylated liposomes results in these effects having a differing strength, as follows.
Cardiotoxicity: Studies in rabbits have shown that the cardiotoxicity of Caelyx is reduced compared with conventional doxorubicin HCl preparations.
Dermal Toxicity: In studies performed after the repeated administration of Caelyx to rats and dogs, serious dermal inflammations and ulcer formations were observed at clinically relevant dosages. In the study in dogs, the occurrence and severity of these lesions was reduced by lowering the dose or prolonging the intervals between doses. Similar dermal lesions, which are described as PPE were also observed in patients after long-term IV infusion (see Adverse Reactions).
Anaphylactoid Response: During repeat-dose toxicology studies in dogs, an acute response characterised by hypotension, pale mucous membranes, salivation, emesis and periods of hyperactivity followed by hypoactivity and lethargy was observed following administration of pegylated liposomes (placebo). A similar, but less severe response was also noted in dogs treated with Caelyx or standard doxorubicin. The hypotensive response was reduced in magnitude by pre-treatment with antihistamines. However, the response was not life-threatening and the dogs recovered quickly upon discontinuation of treatment.
Local Toxicity: Subcutaneous tolerance studies indicate that Caelyx, as against standard doxorubicin HCl, causes slighter local irritation or damage to the tissue after a possible extravasation.
Carcinogenicity and Mutagenicity: Although no studies have been conducted with Caelyx, doxorubicin HCl, the pharmacologically active ingredient of Caelyx, is mutagenic and carcinogenic. Pegylated placebo liposomes are neither mutagenic nor genotoxic.
Reproductive Toxicity: Caelyx 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, and diffuse degeneration of the seminiferous tubules and a marked decrease in spermatogenesis were observed in dogs after repeat doses of 1 mg/kg/day.
Indications/Uses
For monotherapy treatment of metastatic breast cancer.
Treatment of advanced ovarian cancer in women who have failed a 1st-line platinum-based chemotherapy regimen.
Acquired immunodeficiency syndrome (AIDS)-related Kaposi's sarcoma (KS) in patients with low CD4 counts (<200 CD4 lymphocytes/mm3) and extensive mucocutaneous or visceral disease.
May be used as 1st-line systemic chemotherapy or as 2nd-line chemotherapy in AIDS-KS patients with disease that has progressed with, or in patients intolerant to, prior combination systemic chemotherapy comprising at least 2 of the following agents: A vinca alkaloid, bleomycin and standard doxorubicin (or other anthracyclines).
In combination with bortezomib, for the treatment of progressive multiple myeloma in patients who have received at least 1 prior therapy and have not previously received bortezomib. Patients should have already undergone or are unsuitable for bone marrow transplant.
Dosage/Direction for Use
Caelyx exhibits unique pharmacokinetic properties and must not be used interchangeably with other formulations of doxorubicin HCl.
Caelyx should only be administered under the supervision of a qualified oncologist specialized in the administration of cytotoxic agents.
Caelyx is for single-use IV administration only.
Breast/Ovarian Cancer: 50 mg/m2 IV once every 4 weeks for as long as the disease does not progress and the patient continues to tolerate treatment.
For doses <90 mg and >90 mg, dilute Caelyx in Dextrose 5% in Water 250 mL and 500 mL, respectively.
To minimize the risk of infusion reactions, the initial dose is administered at a rate not greater than 1 mg/min. If no infusion reaction is observed, subsequent Caelyx infusions may be administered over a 60-min 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 first 15 min. If tolerated without reaction, the infusion rate was doubled for the next 15 min. If tolerated, the infusion was completed over the next hour for a total infusion time of 90 min.
Subsequent Caelyx infusions may be administered over a 60-min period.
AIDS-KS Patients: 20 mg/m2 IV every 2-3 weeks. Intervals shorter than 10 days should be avoided as drug accumulation and increased toxicity cannot be ruled out. Patients should be treated for 2-3 months to achieve a therapeutic response. Treatment should be continued as needed to maintain a therapeutic response.
Caelyx, diluted in Dextrose 5% in Water 250 mL, is administered by IV infusion over 30 min.
Multiple Myeloma: 30 mg/m2 on day 4 of the bortezomib 3-week regimen as a 1-hr infusion administered immediately after the bortezomib infusion. The bortezomib regimen consists of 1.3 mg/m2 on days 1, 4, 8 and 11 every 3 weeks. The dose should be repeated as long as patients respond satisfactorily and tolerate treatment.
For doses <90 and ≥90 mg, dilute Caelyx in 5% (50 mg/mL) glucose solution for infusion 250 mL and 500 mL, respectively.
The IV catheter and tubing should be flushed with 5% glucose solution for infusion between administration of the 2 medicinal products. Day 4 dosing of both medicinal products may be delayed up to 48 hrs as medically necessary. Doses of bortezomib should be at least 72 hrs apart. The 1st infusion of Caelyx should be administered over 90 min, as follows: 10 mL over first 10 min, 20 mL over next 10 min, and 40 mL over next 10 min. Complete the infusion over a total of 90 min.
Subsequent doses of Caelyx will be administered over 1 hr, as tolerated. If an infusion reaction to Caelyx occurs, stop the infusion and after the symptoms resolve, attempt to administer the remaining Caelyx over 90 min, as follows: 10 mL over first 10 min, 20 mL over next 10 min, and 40 mL over next 10 min. Complete the remaining infusion over a total of 90 min.
Infusion may be given through a peripheral vein or a central line.
For multiple myeloma patients treated with Caelyx in combination with bortezomib, see Table 4; and for those who experience PPE or stomatitis, the Caelyx dose should be modified as described in Tables 5 and 6, respectively (see Tables 5 and 6). For more detailed information on bortezomib dosing and dosage adjustments, see the prescribing information for bortezomib.

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All Patients: If the patient experiences early symptoms or signs of infusion reaction, immediately discontinue the infusion, give appropriate premedications (antihistamine and/or short-acting corticosteroid) and restart at a slower rate.
Do not administer as a bolus injection or undiluted solution. It is recommended that the Caelyx infusion line be connected through the side port of an IV infusion of Dextrose 5% in Water to achieve further dilution, and minimize the risk of thrombosis and extravasation. The infusion may be given through a peripheral vein. Caelyx must not be given by the IM or SC route. Do not use with in-line filters.
To manage adverse events eg, PPE, stomatitis or hematologic toxicity, the dose may be reduced or delayed. Guidelines for Caelyx dose modification secondary to these adverse effects are provided in Tables 5 and 6 as follows. The toxicity grading in these tables is based on the National Cancer Institute Common Toxicity Criteria (NCI-CTC).
The tables for PPE (Table 5) and stomatitis (Table 6) provide the schedule followed for dose modification in clinical trials in the treatment of breast or ovarian cancer (modification of the recommended 4-week treatment cycle): If these toxicities occur in patients with AIDS-related KS, the recommended 2- to 3-week treatment cycle can be modified in a similar manner.
The table for hematologic toxicity (Table 7) provides the schedule followed for dose modification in clinical trials in the treatment of patients with breast or ovarian cancer only. Dose modification in patients with AIDS-KS is addressed in Adverse Reactions. Guidelines for Caelyx dose modification are as follows.

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Patients with Impaired Hepatic Function: Caelyx pharmacokinetics determined in a small number of patients with elevated total bilirubin levels do not differ from patients with normal total bilirubin; however, until further experience is gained, the Caelyx dosage in patients with impaired hepatic function should be reduced based on the experience from the breast and ovarian clinical trial programs as follows: At initiation of therapy, if the bilirubin is between 1.2-3 mg/dL, the 1st dose is reduced by 25%. If the bilirubin is >3 mg/dL, the 1st dose is reduced by 50%. If the patient tolerates the 1st dose without an increase in serum bilirubin or liver enzymes, the dose for cycle 2 can be increased to the next dose level ie, if reduced by 25% for the 1st dose, increase to full dose for cycle 2; if reduced by 50% for the 1st dose, increase to 75% of full dose for cycle 2. The dosage can be increased to full dose for subsequent cycles if tolerated. Caelyx can be administered to patients with liver metastases with concurrent elevation of bilirubin and liver enzymes up to 4 times the upper limit of the normal range. Prior to Caelyx administration, evaluate hepatic function using conventional clinical laboratory tests eg, ALT/AST, alkaline phosphatase and bilirubin.
Patients with Impaired Renal Function: As doxorubicin is metabolised by the liver and excreted in the bile, dose modification should not be required with Caelyx. Population-based analysis confirms that changes in renal function over the range tested (estimated creatinine clearance 30-156 mL/min) do not alter the pharmacokinetics of Caelyx. No pharmacokinetic data are available in patients with creatinine clearance of <30 mL/min.
AIDS-KS Patients with Splenectomy: As there is no experience with Caelyx in patients with splenectomy, treatment with Caelyx is not recommended.
Children: Limited phase I safety data indicate that doses up to 60 mg/m2 every 4 weeks are well-tolerated in pediatric patients1; however, effectiveness in patients <18 years has not been established.
Elderly: Population-based analysis demonstrates that age across the range tested (21-75 years) does not significantly alter the pharmacokinetics of Caelyx.
1Inclusion of this phrase dependent upon local approval.
2In the EU, the statement reads, "Safety and effectiveness in patients <18 years of age has not been established."
Overdosage
Symptoms: Acute overdosage with doxorubicin HCl worsens the toxic effects of mucositis, leukopenia and thrombocytopenia.
Treatment: Treatment of acute overdosage of the severely myelosuppressed patient consists of hospitalisation, antibiotics, platelet and granulocyte transfusions, and symptomatic treatment of mucositis.
Contraindications
Hypersensitivity reactions to any of the components of Caelyx or to doxorubicin HCl.
Caelyx should not be used to treat AIDS-KS that may be effectively treated with local therapy or systemic α-interferon.
Use in pregnancy & lactation: Caelyx should not be administered during pregnancy or while breastfeeding.
Caelyx is embryotoxic in rats and embryotoxic and abortifacient in rabbits. Teratogenicity cannot be ruled out. There is no experience with Caelyx in pregnant women. Therefore, administration to pregnant women is not recommended. Women of childbearing potential should be advised to avoid pregnancy while they or their male partner are receiving Caelyx and in 6 months following discontinuation of Caelyx therapy.
It is not known whether Caelyx is excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Caelyx, mothers should discontinue nursing prior to taking this drug. Health experts recommend that HIV-infected women do not breastfeed their infants under any circumstances in order to avoid transmission of HIV.
Warnings
Experience with Caelyx at high cumulative doses is too limited to have established its effect on the myocardium. It should therefore be assumed that Caelyx will have myocardial toxicity similar to conventional formulations of doxorubicin HCl. With these formulations of doxorubicin HCl, serious irreversible myocardial toxicity leading to congestive heart failure often unresponsive to cardiac supportive therapy may be encountered as the total dosage of doxorubicin HCl approaches 550 mg/m2. Prior use of other anthracyclines or anthracenediones will reduce the total doses of doxorubicin HCl can be given without cardiac toxicity. Cardiac toxicity also may occur at lower cumulative doses in patients with prior mediastinal irradiation or who are receiving concurrent cyclophosphamide therapy.
Caelyx should be administered to patients with a history of cardiovascular disease only when the benefit outweighs the risk to the patient.
Acute infusion-associated reactions (flushing, shortness of breath, facial swelling, headache, chills, back pain, tightness in the chest or throat and/or hypotension) have occurred in about 7% of patients treated with Caelyx. In most patients, these reactions resolve over the course of several hours to 1 day, once the infusion is terminated. In some patients, the reaction resolves by slowing the infusion rate (see Infusion-Associated Reactions under Precautions).
Severe myelosuppression may occur.
Dosage should be reduced in patients with impaired hepatic function (see Dosage & Administration).
Accidental substitution of Caelyx for doxorubicin HCl has resulted in severe side effects. Caelyx exhibits unique pharmacokinetic properties compared to doxorubicin HCl and should not be substituted on a mg/mg basis (see Dosage & Administration).
Caelyx should be administered only under supervision of a physician who is experienced in the use of cancer chemotherapeutic agents.
Special Precautions
Cardiac Risk: All patients receiving Caelyx should routinely undergo frequent electrocardiogram (ECG) monitoring. Transient ECG changes eg, T-wave flattening, ST segment depression and benign arrhythmias are not considered mandatory indications for the suspension of Caelyx therapy. However, reduction of the QRS complex is considered more indicative of cardiac toxicity. If this change occurs, the most definitive test for anthracycline myocardial injury ie, endomyocardial biopsy, should be considered (see Adverse Reactions).
More specific methods for the evaluation and monitoring of cardiac functions as compared to ECG are a measurement of left ventricular ejection fraction (LVEF) by echocardiography, or preferably by multigated angiography (MUGA). These methods should be applied routinely before the initiation of Caelyx therapy and should be repeated periodically during treatment. In a phase III clinical trial comparing Caelyx (50 mg/m2 every 4 weeks) versus doxorubicin (60 mg/m2 every 3 weeks), the risk of developing a cardiac event as a function of cumulative anthracycline dose was significantly lower with Caelyx than with 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 Caelyx. The evaluation of left ventricular function is considered to be mandatory before each additional administration of Caelyx which exceeds a lifetime cumulative anthracycline dose of 600 mg/m2 in patients without prior anthracycline exposure.
For patients who have received prior adjuvant anthracylines (epirubicin or doxorubicin), LVEF assessments should be performed before each additional administration of Caelyx that exceeds a lifetime, doxorubicin-equivalent, cumulative anthracycline dose of 450 mg/m2.
The evaluation tests and methods mentioned previously concerning the monitoring of cardiac performance during anthracycline therapy should be employed in the following order: ECG monitoring, measurement of LVEF, endomyocardial biopsy. If a test result indicates possible cardiac injury associated with Caelyx therapy, the benefit of continued therapy must be carefully weighed against the risk of myocardial injury.
In patients with cardiac disease requiring treatment, administer Caelyx only when the benefit outweighs the risk to the patient.
Caution should be exercised in patients with impaired cardiac function who receive Caelyx.
Whenever cardiomyopathy is suspected ie, the LVEF has substantially decreased relative to pre-treatment values and/or LVEF is lower than a prognostically relevant value (eg, <45%), endomyocardial biopsy may be considered and the benefit of continued therapy must be carefully evaluated against the risk of developing irreversible cardiac damage.
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 observed in patients who have received other anthracyclines. The total dose of doxorubicin HCl should also take into account any previous (or concomitant) therapy with cardiotoxic compounds eg, other anthracyclines/anthraquinones or eg, 5-fluorouracil. Cardiac toxicity may also occur at cumulative anthracycline doses <450 mg/m2 in patients with prior mediastinal irradiation or in those receiving concurrent cyclophosphamide therapy.
The cardiac safety profile for the dosing schedule recommended for both breast and ovarian cancer (50 mg/m2) is similar to the 20 mg/m2 profile in patients with AIDS-KS (see Adverse Reactions).
Myelosuppression: Many patients treated with Caelyx have baseline myelosuppression due to such factors as their preexisting HIV disease or numerous concomitant or previous medications or tumors involving bone marrow. In the pivotal trial in patients with ovarian cancer treated at a dose of 50 mg/m2, myelosuppression was generally mild to moderate, reversible and was not associated with episodes of neutropenic infection or sepsis. Moreover, in a controlled clinical trial of Caelyx versus topotecan, the incidence of treatment-related sepsis was substantially less in the Caelyx-treated ovarian cancer patients as compared to the topotecan treatment group. A similar low incidence of myelosuppression was seen in patients with metastatic breast cancer receiving Caelyx in a 1st-line clinical trial. In contrast to the experience in patients with breast or ovarian cancer, myelosuppression appears to be the dose-limiting adverse event in patients with AIDS-KS. Because of the potential for bone marrow suppression, periodic blood counts must be performed frequently during the course of Caelyx therapy, and at a minimum, prior to each dose of Caelyx.
Persistent severe myelosuppression, although not seen in patients with breast or ovarian cancer, may result in superinfection or hemorrhage.
Given the difference in pharmacokinetic profiles and dosing schedules, Caelyx should not be used interchangeably with other formulations of doxorubicin HCl.
Combination chemotherapy with Caelyx has been extensively studied in solid tumor populations. Caelyx 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: It should be noted that each vial of Caelyx contains sucrose and is administered in Dextrose 5% in Water for IV infusion.
Infusion-Associated Reactions: Serious and sometimes life-threatening infusion reactions, which are characterized by allergic- 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 Caelyx. Very rarely, convulsions also have been observed in relation to infusion reactions (see Adverse Reactions). Temporarily stopping the infusion usually resolves these symptoms without further therapy. However, medications to treat these symptoms (eg, antihistamines, corticosteroids, adrenaline and anticonvulsants), as well as emergency equipment should be available for immediate use. In most patients, treatment can be resumed after all symptoms have resolved, without recurrence. Infusion reactions rarely recur after the 1st treatment cycle. To minimize the risk of infusion reactions, the initial dose should be administered at a rate no greater than 1 mg/min (see Dosage & Administration).
Effects on the Ability to Drive or Operate Machinery: Although Caelyx should not affect driving performance, in clinical studies to date, dizziness and somnolence were associated infrequently (<5%) with the administration of Caelyx. Patients who suffer from these effects should avoid driving and operating machinery.
Use In Pregnancy & Lactation
Caelyx should not be administered during pregnancy or while breastfeeding.
Caelyx is embryotoxic in rats and embryotoxic and abortifacient in rabbits. Teratogenicity cannot be ruled out. There is no experience with Caelyx in pregnant women. Therefore, administration to pregnant women is not recommended. Women of childbearing potential should be advised to avoid pregnancy while they or their male partner are receiving Caelyx and in 6 months following discontinuation of Caelyx therapy.
It is not known whether Caelyx is excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Caelyx, mothers should discontinue nursing prior to taking this drug. Health experts recommend that HIV-infected women do not breastfeed their infants under any circumstances in order to avoid transmission of HIV.
Adverse Reactions
Breast Cancer Patients: About 254 patients with advanced breast cancer who had not received prior chemotherapy for metastatic disease were treated with Caelyx at a dose of 50 mg/m2 every 4 weeks in a phase III clinical trial (197-328). The most frequently reported treatment-related adverse effects included PPE (48%) and nausea (37%) (see Table 7). These effects were mostly mild and reversible, with severe (grade III) cases reported in 17% and 3%, respectively, and no reported incidences of life-threatening (grade IV) cases for either PPE or nausea. Infrequently, these effects resulted in permanent treatment discontinuation (7% and 0%, respectively). Pronounced alopecia (or total hair loss) was seen in only 7% of Caelyx-treated patients as compared with 54% of patients treated with doxorubicin.
Hematologic adverse effects were infrequently reported, and were mostly mild or moderate in severity and manageable. Anemia, neutropenia, leukopenia and thrombocytopenia were infrequently reported at incidences of 5%, 4%, 2% and 1%, respectively. Life-threatening (grade IV) hematologic effects were reported at incidences of <1%. 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 (grades III and IV) 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 1st- or 2nd-line taxane-containing chemotherapy regimen and were subsequently treated with Caelyx at a dose of 50 mg/m2 every 4 weeks in a phase III clinical trial (C/I96-352), the safety profile was consistent with that reported for Caelyx in previous studies using the same dosage regimen (see Table 8). The proportion of patients experiencing clinically significant laboratory abnormalities was low and comparable numerically to the 254 breast cancer patients receiving Caelyx as 1st-line therapy, with the exception of leukopenia (20%).

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Adverse Reactions reported between 1% and 5% in 404 Caelyx-treated breast cancer patients, not previously reported in Caelyx clinical trials (≥1%) were breast pain, leg cramps, edema, leg edema, peripheral neuropathy, oral pain, ventricular arrhythmia, folliculitis, bone pain, musculoskeletal pain, thrombocythemia, cold sores (nonherpetic), fungal infection, epistaxis, upper respiratory tract infection, bullous eruption, dermatitis, erythematous rash, nail disorder, scaly skin, lacrimation and blurred vision.
Ovarian Cancer Patients: About 512 patients with ovarian cancer (a subset of 876 solid tumor patients) were treated with Caelyx at a dose of 50 mg/m2 in clinical trials. The most frequently reported treatment-related adverse effects included PPE (46.1%) and stomatitis (38.9%) (see Table 9). These effects were mainly mild, with severe (grade III) cases reported in 19.5% and 8%, respectively, and life-threatening (grade IV) cases reported in 0.6% and 0.8%, respectively. These resulted infrequently in permanent treatment discontinuation (<5% and <1%, respectively).

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Myelosuppression was mostly mild or moderate and manageable. Leukopenia was the most frequently reported hematological adverse effect, followed by anemia, neutropenia and thrombocytopenia. Life-threatening (grade IV) hematologic effects were reported at incidences of 1.6%, 0.4%, 2.9% and 0.2%, respectively. Growth factor support was required infrequently (<5%) and transfusion support was required in approximately 15% of patients (see Dosage & Administration).
Other less frequently (1-5%) reported adverse reactions included peripheral edema, oral moniliasis, vasodilation, 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, hypertonia, skin ulcer and dysuria.
In the subset of 410 patients with ovarian cancer, clinically significant laboratory abnormalities occurring in clinical trials with Caelyx included increases in total bilirubin (usually in patients with liver metastases) (5%) and serum creatinine levels (5%). Clinically significant measurements, measured by grades III and IV neutropenia (11.4%), anemia (5.7%) and thrombocytopenia (1.2%) were low. Increases in AST were less frequently (<1%) reported. Sepsis related to leukopenia was observed infrequently (<1%).
Solid Tumor Patients: In a larger cohort of 929 patients with solid tumors (including breast and ovarian cancer) predominantly treated at a dose of 50 mg/m2 every 4 weeks, the safety profile and incidence of adverse effects are comparable to those of the patients treated in the pivotal breast and ovarian cancer trials.
AIDS-KS Patients: Open-label and controlled clinical studies on AIDS-KS patients treated with Caelyx at a dose of 20 mg/m2 show that myelosuppression was the most frequent side effect considered related to Caelyx, occurring in approximately ½ of the patients.
Leukopenia is the most frequent adverse reaction experienced with Caelyx in this population; neutropenia, anemia and thrombocytopenia have been observed. These effects may occur early on in treatment. Hematological toxicity may require dose reduction, or suspension or delay of therapy. Temporarily suspend Caelyx treatment in patients when the ANC count is <1000/mm3 and/or the platelet count is <50,000/mm3. G-CSF (or GM-CSF) may be given as concomitant therapy to support the blood count when the ANC count is <1000/mm3 in subsequent cycles. The hematological toxicity for breast or ovarian cancer patients is less severe than in the AIDS-KS setting (see Ovarian Cancer Patients in the previous texts).
Other frequently (≥5%) observed side effects were nausea, asthenia, alopecia, fever, diarrhea, infusion-associated acute reactions and stomatitis.
Respiratory side effects frequently (≥5%) occurred in clinical studies of Caelyx and may be related to opportunistic infections in the AIDS population. Opportunistic infections (OIs) are observed in AIDS-KS patients after administration with Caelyx and are frequently observed in patients with HIV-induced immunodeficiency. The most frequently observed OIs in clinical studies were candidiasis, cytomegalovirus, herpes simplex, Pneumocystis carinii pneumonia and Mycobacterium avium complex.
Other less frequently (<5%) observed side effects included PPE, oral moniliasis, nausea and vomiting, weight loss, rash, mouth ulceration, dyspnea, abdominal pain, hypersensitivity reactions including anaphylactic reactions, vasodilatation, dizziness, anorexia, glossitis, constipation, paresthesia, retinitis and confusion.
Clinically significant laboratory abnormalities frequently (≥5%) occurred in clinical studies with Caelyx. These included increases in alkaline phosphatase and increases in AST and bilirubin which are believed to be related to the underlying disease and not Caelyx. Reduction in hemoglobin and platelets were less frequently (<5%) reported. Sepsis related to leukopenia was rarely (<1%) observed. Some of these abnormalities may have been related to the underlying HIV-infection and not Caelyx.
All Patients: 100 out of 929 patients (10.8%) with solid tumors were described as having an infusion-associated reaction during treatment with Caelyx as defined by the following COSTART terms: Allergic reaction, anaphylactoid reaction, asthma, face edema, hypotension, vasodilation, urticaria, back pain, chest pains, chills, fever, hypertension, tachycardia, dyspepsia, nausea, dizziness, dyspnea, pharyngitis, rash, pruritus, sweating, injection site reaction and drug interaction. 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 patients with AIDS-KS, infusion-associated reactions were characterised by flushing, shortness of breath, facial edema, headache, chills, back pain, tightness in the chest and throat, and/or hypotension and can be expected at the rate of 5-10%. Very rarely, convulsions have been observed in relation to infusion reactions. In all patients, infusion-associated reactions occurred primarily during the 1st infusion. Temporarily stopping the infusion usually resolves these symptoms without further therapy. In nearly all patients, Caelyx treatment can be resumed after all symptoms have resolved without recurrence. Infusion reactions rarely recur after the 1st treatment cycle with Caelyx.
Stomatitis has been reported in patients receiving continuous infusions of conventional doxorubicin HCl and was frequently reported in patients receiving Caelyx. It did not interfere with patients completing therapy and no dosage adjustments are generally required, unless stomatitis is affecting a patient's ability to eat. In this case, the dose interval may be extended by 1-2 weeks or the dose reduced.
Palmar-plantar erythrodysesthesia (PPE) is characterised by painful, macular reddening skin eruptions. In patients experiencing this event, it is generally seen after 2 or 3 cycles of treatment. In most patients, it clears in 1 or 2 weeks, with or without treatment with corticosteroids. Pyridoxine at a dose of 50-150 mg/day has been used for the prophylaxis and treatment of PPE. Other strategies to prevent and treat PPE, which may be initiated 4-7 days after treatment with Caelyx includes keeping hands and feet cool by exposing them to cool water (soaks, baths or swimming), avoiding excessive heat/hot water, and keeping them unrestricted (no socks, gloves or shoes that are tight fitting). It appears to be dose- and schedule-related and can be reduced by extending the dose interval of 1-2 weeks or reducing the dose. This reaction can be severe and debilitating in some patients, however, and may require discontinuation of treatment.
An increased incidence of congestive heart failure (CHF) is associated with doxorubicin therapy at cumulative lifetime doses >450 mg/m2 or at lower doses for patients with cardiac risk factors. Endomyocardial biopsies on 9 of 10 AIDS-KS patients receiving cumulative doses of Caelyx >460 mg/m2 indicate no evidence of anthracycline-induced cardiomyopathy. The recommended dose of Caelyx for AIDS-KS patients is 20 mg/m2 every 2-3 weeks. The cumulative dose at which cardiotoxicity would become a concern for these AIDS-KS patients (>400 mg/m2) would require >20 courses of Caelyx therapy over 40-60 weeks.
In addition, endomyocardial biopsies were performed in 8 solid tumor patients with cumulative anthracycline doses of 509-1680 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 doxorubicin, 10/254 patients randomized to receive Caelyx (treated at a dose of 50 mg/m2 every 4 weeks) versus 48/255 patients randomized to receive doxorubicin (treated at a dose of 60 mg/m2 every 3 weeks) 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 CHF. None of the 10 Caelyx patients who had cardiac toxicity by LVEF criteria developed signs and symptoms of CHF. In contrast, 10 of 48 doxorubicin patients who had cardiac toxicity by LVEF criteria also developed signs and symptoms of CHF.
In patients with solid tumors, including a subset of patients with breast and ovarian cancers, treated at a dose of 50 mg/m2/cycle with lifetime cumulative anthracycline doses up to 1532 mg/m2, the incidence of clinically significant cardiac dysfunction was low. Of the 929 patients treated with Caelyx 50 mg/m2/cycle, baseline measurement of LVEF and at least 1 follow-up measurement were conducted in 418 patients and assessed by MUGA scan. Of these 418 patients, 88 patients had a cumulative anthracycline dose of >400 mg/m2, an exposure level associated with an increased risk of cardiovascular toxicity with the conventional formulation of doxorubicin. Only 13 of these 88 patients (15%) had at least 1 clinically significant change in their LVEF, defined as an LVEF value <45% or a decrease of at least 20 points from baseline. Furthermore, only 1 patient (who received a cumulative dose of 944 mg/m2), discontinued study treatment because of clinical symptoms of CHF.
Although local necrosis following extravasation has been reported very rarely, Caelyx should be considered an irritant. Animal studies indicate that administration of doxorubicin HCl as a liposomal formulation reduces the potential for extravasation injury. If any signs or symptoms of extravasation occur (eg, 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 min may be helpful in alleviating the local reaction. Caelyx must not be given by the IM or SC route.
Recall of skin reaction due to prior radiotherapy has rarely occurred with Caelyx administration.
Drug Interactions
No formal drug interaction studies have been conducted with Caelyx, although phase II combination trials with conventional chemotherapy agents have been conducted in patients with gynecological malignancies. Caution should be exercised in the concomitant use of drugs known to interact with standard doxorubicin HCl. Caelyx, like other doxorubicin HCl preparations, may potentiate the toxicity of other anticancer therapies. Caelyx has been given as part of a combination therapy regimen (combined with either cyclophosphamide, taxanes or vinorelbine) to 230 patients with solid tumors (including ovarian or breast cancer). The doses of Caelyx and the combination agent used in these studies were as follows: Cyclophosphamide 600 mg/m2 + Caelyx 30 mg/m2 every 3 weeks, paclitaxel 175 mg/m2 + Caelyx 30 mg/m2 every 3 weeks, docetaxel 60 mg/m2 + Caelyx 30 mg/m2 every 3 weeks and vinorelbine 30 mg/m2 every 2 weeks + Caelyx 40 mg/m2 every 4 weeks. No new additive toxicities were noted. In patients with AIDS-KS, exacerbation of cyclophosphamide-induced hemorrhagic cystitis and enhancement of the hepatotoxicity of 6-mercaptopurine have been reported with standard doxorubicin HCl. Caution should be exercised when giving any other cytotoxic agents, especially myelotoxic agents, at the same time.
Incompatibilities: Do not mix with other drugs.
Caution For Usage
Instructions for Use/Handling: Do not use material that shows evidence of precipitation or any other particulate matter.
Caution should be exercised in handling Caelyx solution. The use of gloves is required. If Caelyx comes into contact with skin or mucosa, wash immediately and thoroughly with soap and water. Caelyx should be handled and disposed of in a manner consistent with that of other anticancer drugs.
Determine the dose of Caelyx to be administered (based upon the recommended dose and the patient's body surface area). Take the appropriate volume of Caelyx up into a sterile syringe. Aseptic technique must be strictly observed since no preservative of bacteriostatic agent is present in Caelyx.
The appropriate dose of Caelyx must be diluted in Dextrose 5% in Water prior to administration. For doses <90 mg, dilute Caelyx in 250 mL and for doses >90 mg, dilute Caelyx in Dextrose 5% in Water 500 mL, respectively.
The use of any diluent other than Dextrose 5% in Water for Infusion or the presence of any bacteriostatic agent eg, benzyl alcohol may cause precipitation of Caelyx.
It is recommended that the Caelyx infusion line be connected through the side port of an IV infusion of Dextrose 5% in Water. The infusion may be given through a peripheral vein. Do not use with in-line filters.
Storage
Unopened vials should be stored at 2°-8°C. Avoid freezing. After dilution with Dextrose 5% in Water for IV infusion, the diluted Caelyx solution should be used immediately. Diluted product not for immediate use should be stored at 2°-8°C for no longer than 24 hrs. Partially used vials should be discarded.
ATC Classification
L01DB01 - doxorubicin ; Belongs to the class of cytotoxic antibiotics, anthracyclines and related substances. Used in the treatment of cancer.
Presentation/Packing
Concentrate for infusion 2 mg/mL (vial, single-use, sterile, translucent, red susp) x 10 mL x 1's.
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