Professional Drug Information > Caelyx

Doxorubicin, Liposomal (Systemic)

VA CLASSIFICATION
Primary: AN200

Commonly used brand name(s): Caelyx; Doxil.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antineoplastic—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.


Accepted

Kaposi's sarcoma (KS), acquired immunodeficiency syndrome (AIDS)–associated (treatment)—Liposomal doxorubicin is indicated for treatment of patients with AIDS-associated KS disease that has progressed in spite of prior combination chemotherapy or patients who are intolerant of such therapy ^{{17}{03}{05}{11}}.

Note: The treatment of AIDS-associated KS is dependent on the extent and severity of the KS and the patient's clinical condition^{05}{10}. For patients with minimal disease, local treatments such as excision, radiotherapy, or intralesional chemotherapy may be adequate^{04}{05}. However, for those with severe cutaneous or systemic disease, systemic chemotherapy may be required^{05}{09}{10}. Patients with severe debilitation due to their general condition are best served by optimal palliative care^{04}{05}.


Carcinoma, ovarian¹—Liposomal doxorubicin is indicated for treatment of ovarian carcinoma that is refractory to both paclitaxel- and platinum-based chemotherapy regimens. Refractory disease is defined as disease that has progressed while the patient is on treatment, or within 6 months of completing treatment.^{06}{08}{17}

[Carcinoma, breast (treatment)]¹—Liposomal doxorubicin is indicated for first-line treatment or treatment at some point in the management of locally advanced and metastatic breast carcinoma.^{{18}{19}{20}{21}{22}{23}{24}{25}{26}{27}{28}{29}{30}{31}}

¹ Not included in Canadian product labeling.

Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Source—
    Doxorubicin is isolated from Streptomyces peucetius var. caesius^{04}{17}. Liposomal doxorubicin is doxorubicin encapsulated in long-circulating liposomes^{17}. Liposomes are microscopic vesicles, composed of a phospholipid bilayer, that are capable of encapsulating active drugs^{17}. Liposomal doxorubicin is supplied as a sterile, translucent, red liposomal dispersion^{17}.
Molecular weight—
    579.99 (as hydrochloride)^{17}

Mechanism of action/Effect:

Doxorubicin is an anthracycline cytostatic antibiotic with activity against a variety of malignancies including Kaposi's sarcoma (KS)^{04}{14}. Liposomal doxorubicin has been shown to inhibit the growth of KS cells both in vitro and in vivo^{04}. KS spindle cell cultures are more sensitive to liposomal doxorubicin than are cultures of normal monocytes or normal endothelial or smooth muscle cells^{04}.

Tumor cell DNA fragmentation induced by doxorubicin is a result of topoisomerase II inhibition, which occurs when doxorubicin intercalates between DNA strands^{04}. The antitumor activity and toxicity of doxorubicin may also relate to the formation of intracellular oxygen free radicals, which are produced by reduction of the doxorubicin molecule^{04}. In addition, liposomal doxorubicin induces expression of monocyte chemoattractant protein-1, which results in intralesional recruitment of phagocytic cells in patients with KS^{04}.

The mechanism by which liposome encapsulation apparently enhances doxorubicin accumulation in lesions of acquired immunodeficiency syndrome (AIDS)–associated KS is not fully understood^{03}{12}. However, polyethylene glycol (PEG)–containing liposomes of the same size and exhibiting approximately the same rate of plasma clearance as those used to encapsulate the doxorubicin, but containing entrapped colloidal gold designed to serve as a marker for following liposome distribution by light and electron microscopy, have been shown to enter solid colon tumors implanted in mice and KS-like lesions in human immunodeficiency virus (HIV)–transgenic mice^{03}{09}{12}.

Extravasation of liposomes also may occur by passage of the particles through endothelial cell gaps, which are reported to be present in certain solid tumors and which are known to be present in KS-like lesions^{03}. These processes may contribute to the enhanced accumulation of doxorubicin in lesions of AIDS-associated KS after administration of PEG-liposomal doxorubicin^{03}.

Once within the tumor, the active ingredient, doxorubicin, is presumably available to be released locally as the liposomes degrade and become permeable in situ^{03}.

Distribution:

Limited to vascular fluid^{17}.

Vol_D—Steady-state: 2.7 to 2.8 liters per square meter of body surface area for doses of 20 and 10 mg per square meter of body surface area (mg/m²), respectively^{17}.

Note: During circulation, at least 90% of liposomal doxorubicin remains encapsulated. This circulation is represented by a large area under the plasma concentration–time curve (AUC) of 277 and 590 mcg per mL (mcg/mL) per hour for doses of 10 and 20 mg/m², respectively^{17}. At a 50 mg/m² dose, the AUC is expected to be more than proportional when compared with the lower doses.^{17}


Protein binding:

Protein binding of liposomal doxorubicin has not been determined; however, the active ingredient, doxorubicin, binds extensively to tissues (70%)^{17}.

Biotransformation:

The major metabolite of standard doxorubicin is doxorubicinol; after administration of 10 or 20 mg/m ² of liposomal doxorubicin, doxorubicinol was detectable in plasma at very low levels (0.8 to 26.2 nanograms per mL)^{04}{17}. Metabolites of doxorubicin, including doxorubicinol and the sulfate and glucuronide conjugates of the 7-deoxyaglycones, were detected in small quantities in the urine^{04}.

Half-life:

First phase—4.7 and 5.2 hours for doses of 10 and 20 mg/m², respectively^{17}.

Second phase—52.3 and 55 hours for doses of 10 and 20 mg/m ², respectively^{17}.

Because the pharmacokinetics at a dose of 50 mg/m ² are reported to be nonlinear, the elimination half-life is expected to be longer and the clearance lower at this dose compared with a 20 mg/m² dose.^{17}

Peak serum concentration:

4.1 and 8.3 mcg/mL for doses of 10 and 20 mg/m², respectively^{17}.

Elimination:
    Renal—Total plasma clearance of liposomal doxorubicin is slower than total plasma clearance of standard doxorubicin^{04}, with a rate of 0.041 and 0.056 liters per hour per square meter of body surface area (L/h/m²) for doses of 20 and 10 mg/m², respectively^{17}.
    Renal elimination of PEG-liposomal doxorubicin is slower than elimination of the standard doxorubicin: 5.5% of an injected dose of liposomal doxorubicin was recovered in urine after 72 hours, compared with 11% of an injected dose of standard doxorubicin after only 24 hours^{04}.


Precautions to Consider

Cross-sensitivity and/or related problems

Patients hypersensitive to other doxorubicin formulations may be hypersensitive to liposomal doxorubicin also^{17}.

Carcinogenicity/Mutagenicity

Secondary acute myelogenous leukemia has been reported in patients treated with topoisomerase II inhibitors, including anthracyclines.^{17}

Studies to evaluate the carcinogenic potential of liposomal doxorubicin injection have not been performed; however, the active ingredient, doxorubicin, is carcinogenic and mutagenic in experimental models^{17}. The liposome component of liposomal doxorubicin demonstrated no mutagenic effects in the Ames test, mouse lymphoma assay, an in vitro chromosomal aberration assay, and an in vivo mammalian micronucleus assay^{17}.

Pregnancy/Reproduction
Fertility—
Adequate and well-controlled studies in humans have not been done^{17}. However, fertility studies in mice have shown that liposomal doxorubicin causes ovarian and testicular degeneration at two times the 50 mg/m² human dose^{17}. Studies in dogs have shown that liposomal doxorubicin causes atrophy of the seminiferous tubules and diminished spermatogenesis at a dose one half the 50 mg/m² human dose^{17}. Studies in rats have shown that liposomal doxorubicin causes testicular degeneration at 3.3% of the 50 mg/m² human dose^{17}.

Pregnancy—
Adequate and well-controlled studies in humans have not been done^{17}. However, use is not recommended during pregnancy^{17}. Women of childbearing age should be advised to avoid pregnancy during treatment^{14}. If pregnancy occurs within the first few months after treatment, the prolonged half-life of the drug must be considered.^{17}

In general, use of a contraceptive method is recommended during cytotoxic drug therapy.

FDA Pregnancy Category D^{17}.

Breast-feeding

It is not known whether liposomal doxorubicin is distributed into breast milk^{17}. However, breast-feeding is not recommended while liposomal doxorubicin is being administered because of the potential risk of adverse reactions in the infant^{17}{14}.

Pediatrics

Appropriate studies on the relationship of age to the effects of liposomal doxorubicin have not been performed in the pediatric population^{17}. Safety and efficacy have not been established^{17}. However, cardiotoxicity may occur frequently with the active ingredient, doxorubicin, in children up to 2 years of age^{02}.


Geriatrics


In clinical studies, 29% of the 373 ovarian cancer patients were 60 to 69 years of age, while 22.8% were 70 years of age and older. There were no overall differences observed between these patients and younger patients, but greater sensitivity of some older patients to the medication cannot be ruled out.^{17}. The active ingredient, doxorubicin, may increase the risk of cardiotoxicity in patients 70 years of age or older^{02}. There is insufficient data to evaluate the comparative efficacy of liposomal doxorubicin according to age.^{17}


Dental

The leukopenic and thrombocytopenic effects of liposomal doxorubicin may result in an increased incidence of certain microbial infections of the mouth, delayed healing, and gingival bleeding. If leukopenia or thrombocytopenia occurs, dental work should be deferred until blood counts have returned to normal. Patients should be instructed in proper oral hygiene, including caution in use of regular toothbrushes, dental floss, and toothpicks.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Anthracenedione antineoplastic agents, prior use of or
» Daunorubicin, prior use of or
» Doxorubicin, prior use of or
» Idarubicin, prior use of or
» Mitoxantrone, prior use of    (use of liposomal doxorubicin in a patient who previously has received anthracenedione antineoplastic agents, daunorubicin, doxorubicin, idarubicin, or mitoxantrone increases the risk of cardiotoxicity; dosage adjustment is necessary ^{17})


Blood dyscrasia–causing medications (see Appendix II )    (leukopenic and/or thrombocytopenic effects of liposomal doxorubicin may be increased with concurrent or recent therapy if these medications cause the same effects; dosage adjustment of liposomal doxorubicin, if necessary, should be based on blood counts^{17})


» Bone marrow depressants, other (see Appendix II    (additive bone marrow depression, including severe dermatitis and/or mucositis, may occur; dosage reduction may be required when two or more bone marrow depressants are used concurrently or consecutively)


Cyclophosphamide or
Dactinomycin or
Mitomycin or
Radiation therapy to mediastinal area    (concurrent use may result in increased cardiotoxicity^{02})

    (concurrent use of cyclophosphamide with liposomal doxorubicin may potentiate cyclophosphamide-induced hemorrhagic cystitis^{02})


Hepatotoxic medications (see Appendix II )    (concurrent use may increase the risk of toxicity; for example, high-dose methotrexate may impair liver function and increase toxicity of subsequently administered liposomal doxorubicin^{02})


Vaccines, killed virus    (because normal defense mechanisms may be suppressed by liposomal doxorubicin therapy, the patient's antibody response to the vaccine may be decreased. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year )


» Vaccines, live virus    (because normal defense mechanisms may be suppressed by liposomal doxorubicin therapy, concurrent use with a live virus vaccine may potentiate the replication of the vaccine virus, may increase the side/adverse effects of the vaccine virus, and/or may decrease the patient's antibody response to the vaccine; immunization of these patients should be undertaken only with extreme caution after careful review of the patient's hematologic status and only with the knowledge and consent of the physician managing the liposomal doxorubicin therapy. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year. Patients with leukemia in remission should not receive live virus vaccine until at least 3 months after their last chemotherapy. In addition, immunization with oral poliovirus vaccine should be postponed in persons in close contact with the patient, especially family members^{13})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
» Cardiac function tests    (echocardiography and radionuclide scans may be altered^{17})

With physiology/laboratory test values
Alanine aminotransferase (ALT [SGPT]), serum
Alkaline phosphatase, serum or
Aspartate aminotransferase (AST [SGOT]), serum    (values may be increased^{17})


Bilirubin, serum    (concentrations may be increased^{17})


Blood urea nitrogen (BUN) or
Creatinine, serum    (values rarely may be increased^{17})


Calcium, serum    (concentrations may be decreased^{17})


Glucose, blood    (concentrations may be increased^{17})


» Hemoglobin/hematocrit or
» Leukocyte counts or
» Platelet counts    (may be decreased^{17})


Prothrombin time    (may be prolonged^{17})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Bone marrow depression^{17}
» Cardiovascular disease, history of    (may increase risk for cardiotoxicity^{17})


» Chickenpox, existing or recent (including recent exposure) or
» Herpes zoster    (risk of severe generalized disease)


» Heart disease    (cardiotoxicity may occur at lower cumulative doses^{17})


» Hepatic function impairment    (slowed excretion may occur^{17}. Reduction in dosage is recommended^{06}{17}; one half of the normal dose is recommended in patients with serum bilirubin concentrations of 1.2 to 3 mg per 100 mL; one quarter of the normal dose is recommended in patients with serum bilirubin concentrations of greater than 3 mg per 100 mL)


» Sensitivity to doxorubicin or to liposomal components ^{17}
» Tumor cell infiltration of the bone marrow
» Caution should be used also in patients with inadequate bone marrow reserves due to previous cytotoxic drug or radiation therapy.

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Alanine aminotransferase (ALT [SGPT]) values, serum and
Alkaline phosphatase values, serum and
Aspartate aminotransferase (AST [SGOT]) values, serum and
Bilirubin concentrations, serum    (recommended prior to initiation of therapy and at periodic intervals during therapy^{17})


» Echocardiography and
Electrocardiogram (ECG) studies and
» Radionuclide angiography determination of ejection fraction     (recommended prior to initiation of therapy and at periodic intervals during therapy^{17})


» Hematocrit or hemoglobin and
» Leukocyte count, total and, if appropriate, differential and
» Platelet count    (determinations recommended prior to initiation of therapy and at periodic intervals during therapy^{17})




Side/Adverse Effects

Note: Clinical studies of liposomal doxorubicin to treat Kaposi's sarcoma (KS) were performed only in patients with acquired immunodeficiency syndrome (AIDS)^{04}. Assessment of tolerability of liposomal doxorubicin is therefore complicated by underlying immune suppression and morbidity commonly present in these patients^{04}. Although liposomal doxorubicin was generally well tolerated, there was a strong likelihood that liposomal doxorubicin–related adverse effects would occur in the majority of the patients^{04}. In one study, 76% of patients reported at least one adverse effect that was probably or possibly related to liposomal doxorubicin and 30% of patients reported at least one severe adverse effect thought to be related to liposomal doxorubicin^{07}. However, the most common reason for termination of liposomal doxorubicin therapy in these studies was death from AIDS-related complications^{07}.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Anemia ^{{04}{06}{14}{17}}(unusual tiredness or weakness)
    
asthenia ^{03}{17}(loss of strength and energy)
    
fever^{17}
    
infusion reactions ^{04}{17}( chills; facial swelling; headache; low blood pressure; shortness of breath)
    
leukopenia^{17} ( fever or chills; cough or hoarseness ; lower back or side pain; painful or difficult urination)
    
neutropenia ^{{03}{04}{05}{08}{11}{14}{17}}( fever and sore throat)—usually asymptomatic
    
stomatitis ^{{03}{06}{08}{14}{17}}(sores in mouth and on lips )
    
thrombocytopenia ^{04}{14}{17}(black, tarry stools; unusual bleeding or bruising ; blood in urine or stools; pinpoint red spots on skin)—usually asymptomatic

Note: Some patients may experience infusion reactions during the initial few minutes of the first infusion of liposomal doxorubicin^{04}. Infusion reactions will resolve upon cessation of infusion^{07}. However, these reactions often do not prevent further treatment with liposomal doxorubicin^{04}. Patients who do not experience infusion reactions during the first cycle of liposomal doxorubicin therapy are unlikely to react to subsequent cycles^{04}.
Neutropenia is the most common treatment-related side effect^{{03} {04}{07}{17}}. In one study, 35% of enrolled patients had one or more episodes of grade 3 or 4 neutropenia^{05}. Neutropenia is manageable with the use of colony-stimulating factors^{07}. However, pre-existing immune system compromise complicates assessment of neutropenia and infectious events in patients with AIDS^{03}.


Incidence less frequent
    
Allergic reaction ^{04}{17}( chills; fever; skin rash or itching)

Note: Few data are available on the cardiotoxicity of liposomal doxorubicin^{04}. Although left ventricular failure has been reported in patients who received a high cumulative liposomal doxorubicin dose, some evidence suggests that the incidence and severity of these effects are lower than after similar doses of standard doxorubicin^{04}.
Palmar-plantar erythrodysesthesia, characterized by ulceration, erythema, and desquamation on the hands and feet with pain and inflammation, occurs in some patients, most commonly after 6 to 8 weeks of treatment^{04}. At recommended dosages of liposomal doxorubicin, the incidence of this syndrome is less than 5%^{04}. Although reactions may occasionally be severe and debilitating, they are more often mild, and most patients with the syndrome do not require dosage reduction or prolonged treatment delay^{04}. However, in severe cases, palmar-plantar erythrodysesthesia can be managed by withholding treatment until its resolution and by resuming therapy with longer intervals between doses^{06}{07}.


Incidence rare
    
Jaundice ^{04}{17}(yellowing of eyes and skin)

For treatment of Kaposi's sarcoma patients (in addition to those listed above)
Incidence less frequent
    
Cardiotoxicity ^{04}{17}(fast or irregular heartbeat; shortness of breath; swelling of the feet and lower legs)
    
dyspnea ^{17}( troubled breathing)
    
pain at injection site
    
palmar-plantar erythrodysesthesia ^{04}{06}{17}(reddening of skin; scaling of skin on hands and feet; swelling of skin; ulceration of skin)
    
pneumonia ^{17}(cough ; fever; shortness of breath; troubled breathing ; wheezing)
    
postirradiation erythema, recall ^{17}(darkening or redness of skin)
    
tachycardia ^{04}{17}(fast or irregular heartbeat)

Incidence rare
    
Diabetes mellitus or hyperglycemia^{{17} {17}}(blurred vision; flushed, dry skin; frequent urination; fruit-like breath odor; unusual thirst)
    
optic neuritis ^{17}( blurred vision; eye pain; loss of vision)


For treatment of refractory ovarian cancer patients (in addition to those listed above)
Incidence more frequent
    
Palmar-plantar erythrodysesthesia ^{17}( reddening of skin; scaling of skin on hands and feet; swelling of skin; ulceration of skin)

Incidence less frequent
    
Chest pain
    
edema (decreased urination; rapid weight gain; bloating or swelling of face, hands, lower legs, and/or feet)
    
infection (fever or chills ; cough or hoarseness; lower back or side pain; painful or difficult urination)

Incidence rare
    
Anaphylactoid reaction (cough; difficulty swallowing; hives; puffiness or swelling of the eyelids or around the eyes, face, lips or tongue; shortness of breath; tightness in chest ; wheezing)
    
cardiotoxicity ^{17}(fast or irregular heartbeat ; shortness of breath; swelling of the feet and lower legs)
    
pain at injection site^{17}




Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Diarrhea^{17}
    
nausea^{03}{14}{17}
    
vomiting^{{04}{08}{14}{17}}

Incidence less frequent
    
Back pain^{17}
    
dizziness^{17}
    
dysphagia^{17} (difficulty swallowing)

For treatment of Kaposi's sarcoma patients (in addition to those listed above)
Incidence more frequent
    
Oral moniliasis^{17} (creamy white, curd-like patches in mouth or throat; pain when eating or swallowing)

Incidence less frequent
    
Constipation ^{17}
    
headache^{17}


For treatment of refractory ovarian cancer patients (in addition to those listed above)
Incidence more frequent
    
Abdominal pain^{17}
    
anorexia^{17} (loss of appetite )
    
constipation^{17}
    
headache^{17}
    
mucous membrane disorder^{17} (changes in the lining of the mouth or nose)
    
pain^{17}
    
paresthesia^{17} (tingling, burning, or prickly sensations)
    
pharyngitis^{17} (sore throat)
    
rash^{17}

Incidence less frequent
    
Anxiety^{17}
    
conjunctivitis^{17} (redness, pain, swelling of eye, eyelid, or inner lining of eyelid; burning, dry or itching eyes; excessive tearing)
    
dysphagia^{17} (difficulty swallowing )
    
insomnia^{17} ( trouble sleeping)
    
myalgia^{17} (muscle aches)
    
pruritus^{17} (itching skin)
    
taste disturbance^{17} (change in taste ; bad, unusual, or unpleasant [after]taste)

Incidence rare
    
Ataxia^{17} (shakiness and unsteady walk; clumsiness, unsteadiness, trembling, or other problems with muscle control or coordination)
    
flu-like syndrome^{17} (chills; cough; fever; general feeling of discomfort or illness; joint pain; nausea; shivering ; sore throat; sweating; vomiting)
    
leukorrhea^{17} (increased white vaginal discharge)
    
parosmia^{17} (change in sense of smell)
    
thinking abnormal^{17}




Those not indicating need for medical attention
Incidence more frequent
    
Alopecia (loss of hair ^{{03}{04}{14}{17}})

For treatment of refractory ovarian cancer patients (in addition to those listed above)
Incidence more frequent
    
Dry skin^{17}

Incidence less frequent
    
Skin discoloration^{17} (change in skin color)
    
sweating^{17}




Those indicating the need for medical attention if they occur after medication is discontinued
    
Cardiotoxicity ^{04}{17}(fast or irregular heartbeat; shortness of breath; swelling of feet and lower legs)




Overdose
For specific information on the agents used in the management of liposomal doxorubicin overdose, see:    • Filgrastim in Colony Stimulating Factors (Systemic) monograph; and/or
   • Sargramostim in Colony Stimulating Factors (Systemic) monograph.


For more information on the management of overdose, contact a poison control center (see Poison Control Center Listing).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute
    
Mucositis (sores in mouth and on lips)
    
neutropenia ^{{03}{04}{05}{17}}(cough or hoarseness; fever or chills; lower back or side pain; painful or difficult urination)—usually asymptomatic
    
thrombocytopenia ^{{03}{04}{05}{17}}(black, tarry stools; unusual bleeding or bruising; blood in urine or stools; pinpoint red spots on skin)— usually asymptomatic


Treatment of overdose
Treatment of leukopenia includes antibiotic therapy and administration of colony stimulating factors (filgrastim [rG-CSF] or sargramostim [rGM-CSF])^{04}.

Treatment of overdose includes hospitalization of the patient, platelet and granulocyte transfusions, and symptomatic treatment of mucositis^{17}.

Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Doxorubicin, Liposomal (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to doxorubicin or liposomal component

Pregnancy—Use is not recommended; women of childbearing age should be advised to avoid pregnancy during treatment





Breast-feeding—Use is not recommended because of the potential for serious adverse effects in nursing infants





Use in children—Cardiotoxicity in children younger than 2 years old may occur frequently






Use in the elderly—Based on studies with the active ingredient, cardiotoxicity may be more frequent in patients 70 years of age and older
Other medications, especially anthracenedione antineoplastic agents, daunorubicin, doxorubicin, idarubicin, or mitoxantrone, live virus vaccines, other bone marrow depressants, or previous cytotoxic drug or radiation therapy
Other medical problems, especially bone marrow depression; cardiovascular disease, history of; chickenpox; heart disease; hepatic function impairment; herpes zoster; or tumor cell infiltration of bone marrow

Proper use of this medication
Caution in taking combination therapy; taking each medication at the right time

Importance of ample fluid intake and subsequent increase in urine output to aid in excretion of uric acid

Frequency of nausea and vomiting; importance of continuing medication despite stomach upset

» Proper dosing

Precautions while using this medication
» Importance of close monitoring by the physician^{17}

» Avoiding immunizations unless approved by the physician; other persons in patient's household should avoid immunizations with oral poliovirus vaccine; avoiding persons who have taken oral poliovirus vaccine, or wearing a protective mask that covers nose and mouth

Caution if bone marrow depression occurs
» Avoiding exposure to persons with infections, especially during periods of low blood counts; checking with physician immediately if fever or chills, cough or hoarseness, lower back or side pain, or painful or difficult urination occurs

» Checking with physician immediately if unusual bleeding or bruising; black, tarry stools; blood in urine or stools; or pinpoint red spots on skin occur

Caution in use of regular toothbrush, dental floss, or toothpick; physician, dentist, or nurse may suggest alternatives; checking with physician before having dental work done

Not touching eyes or inside of nose unless hands washed immediately before

Using caution to avoid accidental cuts with use of sharp objects such as safety razor or fingernail or toenail cutters

Avoiding contact sports or other situations where bruising or injury could occur
» Telling doctor or nurse right away about redness, pain, or swelling at injection site


Side/adverse effects
May cause adverse effects such as blood problems, loss of hair, and heart problems

Signs of potential side effects, especially anemia; asthenia; fever; infusion reaction; leukopenia; neutropenia; stomatitis; thrombocytopenia; allergic reaction; jaundice; cardiotoxicity; dyspnea; pain at injection site; palmar-plantar erythrodysesthesia; pneumonia; postirradiation erythema, recall; tachycardia; diabetes mellitus or hyperglycemia; optic neuritis; chest pain; edema; infection; and anaphylactoid reaction

Physician or nurse can help in dealing with side effects

Reddish urine for 1 to 2 days after administration may be alarming to patient although medically insignificant

Possibility of hair loss; normal hair growth should resume after treatment has ended


General Dosing Information
Patients receiving liposomal doxorubicin should be under the supervision of a physician experienced in cancer chemotherapy.^{17}

In patients with acquired immunodeficiency syndrome (AIDS)–associated Kaposi's sarcoma (KS) it is not known whether the combination of liposomal doxorubicin with other antineoplastic agents will improve response rates or quality of life (QOL) compared with currently used combination regimens or liposomal doxorubicin monotherapy^{04}. However, because tumor cells are heterogeneous and the development of tumor resistance to a single antineoplastic agent is probable, combinations of cancer chemotherapy agents generally are preferred to monotherapy^{04}. Nevertheless, liposomal doxorubicin is one of the most active single agents studied so far in patients with AIDS-associated KS^{04}. Furthermore, liposomal doxorubicin 20 mg per square meter of body surface area (mg/m ²) administered at 2- or 3-week intervals seems to be more efficacious than the best available combination regimens^{04}.

The recommended dose of liposomal doxorubicin for patients with AIDS-associated KS is 20 mg/m ² administered intravenously over a period of 30 minutes at 3-week intervals^{17}{04}. However, in several studies, liposomal doxorubicin was administered at 2-week intervals^{04}. Doses as high as 40 mg/m ² and treatment intervals of 1 week have been evaluated in patients with KS, but offer no clear advantages over 20 mg/m ² administered every 2 or 3 weeks^{04}.

Liposomal doxorubicin should be used with caution in patients who have previously received complete cumulative doses of other anthracycline or anthracenedione agents.^{17}

Unlike extravasation of standard doxorubicin, which may result in severe local inflammation and tissue damage, extravasation of liposomal doxorubicin was associated with only transient, mild irritation at the infusion site^{04}. However, liposomal doxorubicin should be considered an irritant and precautions should be taken to avoid extravasation^{17}. If extravasation of liposomal doxorubicin occurs during intravenous administration, as indicated by local burning or stinging (may also be painless), the infusion should be stopped immediately, and resumed, completing the dose, in another vein^{17}. Application of ice packs to the site of extravasation for 30 minutes may be necessary to relieve symptoms^{17}.

Patients who develop thrombocytopenia may require platelet transfusions.^{17}

Patients who develop leukopenia should be observed carefully for signs of infection^{17}. Antibiotic support may be required^{17}. Use of colony stimulating factors may be necessary ^{04}{17}.

Acute infusion-related hypersensitivity reactions can occur in some patients during the first infusion of liposomal doxorubicin, usually within the first few minutes after the start of the infusion^{04}. These acute reactions do not appear to occur with subsequent doses of liposomal doxorubicin in patients who do not react to the first cycle^{04}{17}. Reactions generally resolve within 1 day once the infusion is terminated^{04}. Slowing the infusion rate can sometimes eliminate this problem^{04}{17}. Most patients who react to liposomal doxorubicin are able to tolerate further infusions without complication^{04}.

Liposomal doxorubicin should be administered at an initial rate of 1 milligram per minute (mg/min) to minimize the risk of infusion reactions.^{17}

The pharmacokinetics of liposomal doxorubicin have not been studied in patients with hepatic impairment^{17}. However, standard doxorubicin is known to be eliminated in large part by the liver^{02}{17}. Therefore, dosage of liposomal doxorubicin should be reduced for patients with impaired hepatic function^{17}. A dose reduction of 50% is recommended if serum bilirubin concentrations are 1.2 to 3 mg per deciliter (mg/dL)^{17}. A dose reduction of 75% is recommended if serum bilirubin concentrations are > 3 mg/dL^{17}.

Dosage adjustment or discontinuation of therapy may be necessary for patients who experience stomatitis, bone marrow depression, or palmar-plantar erythrodysesthesia^{17}.

Safety considerations for handling this medication
There is limited but increasing evidence and concern that personnel involved in preparation and administration of parenteral antineoplastic agents may be at some risk because of the potential mutagenicity, teratogenicity, and/or carcinogenicity of these agents, although the actual risk is unknown. USP advisory panels recommend cautious handling both in preparation and disposal of antineoplastic agents. Precautions that have been suggested include:    • Use of a biological containment cabinet during reconstitution and dilution of parenteral medications and wearing of disposable surgical gloves and masks.
   • Use of proper technique to prevent contamination of the medication, work area, and operator during transfer between containers (including proper training of personnel in this technique).
   • Cautious and proper disposal of needles, syringes, vials, ampuls, and unused medication.
A number of medical centers have developed detailed guidelines for handling of antineoplastic agents.


Parenteral Dosage Forms

Note: Bracketed information in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.


DOXORUBICIN, LIPOSOMAL INJECTION

Usual adult dose
Kaposi's sarcoma (KS), acquired immunodeficiency syndrome (AIDS)-associated
Intravenous infusion (over thirty minutes), 20 mg per square meter of body surface area, repeated every three weeks, for as long as patient responds satisfactorily and tolerates treatment^{03}{12}{17}.

Note: Although AIDS-associated KS may respond to treatment with single or multiagent chemotherapy, disease recurrence is common because the underlying immunodeficiency is unremitting^{12}. Thus, multiple courses of therapy may be required to control the disease^{12}. This repeated use of cytotoxic chemotherapy in patients with AIDS can cause significant morbidity^{12}.


Carcinoma, ovarian (refractory) ¹
Intravenous infusion 40 to ^{06}{08}{15} 50 mg per square meter of body surface area, repeated every four weeks, for as long as the patient responds satisfactorily, shows no evidence of cardiotoxicity, and tolerates treatment (minimum of four courses). Initiate infusion at 1 mg/minute, and if no infusion-related reactions occur, the infusion rate may be increased to complete administration of the drug over one to two^{06}{08}{15} hours^{17}.

Note: The doses may be delayed or reduced to manage adverse events such as palmar-plantar erythrodysesthesia, stomatitis, or hematologic toxicity. Pretreatment with or concomitant use of antiemetics should be considered.^{17}


[Carcinoma, breast (treatment)]¹
Patients have benefited from intravenous doses of 30 to 50 mg per square meter of body surface area, repeated every 2 to 4 weeks.^{18}


Usual pediatric dose
Safety and efficacy have not been established^{17}.

Size(s) usually available:
U.S.—


2 mg per mL (single-dose vial) (Rx) [Doxil ( ammonium sulfate 2 mg) (histidine) (sucrose)]^{17}

Canada—


2 mg per mL (single-dose vial) (Rx) [Caelyx ( ammonium sulfate 2 mg) (histidine) (sucrose)]^{16}

Packaging and storage:
Store between 2 and 8 °C (36 and 46 °F)^{17}, unless otherwise specified by manufacturer. Do not freeze for longer than 1 month^{17}.

Preparation of dosage form:
Liposomal doxorubicin (up to a maximum of 90 mg) must be diluted in 250 mL of 5% dextrose injection for administration by intravenous infusion.^{17}

Stability:
Diluted liposomal doxorubicin is stable for 24 hours when stored between 2 and 8 °C (36 and 46 °F)^{17}. Undiluted liposomal doxorubicin contains no preservatives or bacteriostatic agents^{17}. Aseptic techniques should be observed when handling liposomal doxorubicin^{17}.

Do not freeze for longer than 1 month^{17}. Long-term freezing may harm the liposomal component^{17}.

Incompatibilities:
Liposomal doxorubicin should be diluted only in 5% dextrose injection^{17}{04}. Liposomal doxorubicin should not be mixed with other medications, other diluents, or bacteriostatic agents^{17}. Mixing liposomal doxorubicin with any other diluent may cause precipitation ^{17}.


Caution:
Do not use if a precipitate is present^{17}.

Note: Liposomal doxorubicin is a red, translucent dispersion^{17}. In-line filters should not be used because liposomal doxorubicin is not a clear solution^{17}.
Great care should be taken to prevent exposure of the skin to liposomal doxorubicin^{17}. The use of gloves is recommended^{17}. Any liposomal doxorubicin solution that comes into contact with the skin or mucosa should be washed off thoroughly with soap and water^{17}.

Developed: 06/30/1998
Revised: 02/16/2001

References

1. Not used.
   

2. Doxorubicin package insert (Pharmacia—U.S.), Rev 12/94, Rec 3/95.
   

3. Northfelt DW, Martin FJ, Working P, et al. Doxorubicin encapsulated in liposomes containing surface-bound polyethylene glycol: pharmacokinetics, tumor localization, and safety in patients with AIDS-related Kaposi's sarcoma. J Clin Pharmacol 1996 Jan; 36(1): 55-63.
   

4. Coukell AJ, Spencer CM. Polyethylene glycol-liposomal doxorubicin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in the management of AIDS-related Kaposi's sarcoma. Drugs 1997 Mar; 53(3): 520-38.
   

5. Harrison M, Tomlinson D, Stewart S. Liposomal-entrapped doxorubicin: an active agent in AIDS-related Kaposi's sarcoma. J Clin Oncol 1995 Apr; 13(4): 914-20.
   

6. Uziely B, Jeffers S, Isacson R, et al. Liposomal doxorubicin: antitumor activity and unique toxicities during two complementary phase I studies. J Clin Oncol 1995 Jul; 13(7): 1777-85.
   

7. Northfelt DW, Dezube BJ, Thommas JA, et al. Efficacy of pegylated-liposomal doxorubicin in the treatment of AIDS-related Kaposi's sarcoma after failure of standard chemotherapy. J Clin Oncol 1997 Feb; 15(2): 653-9.
   

8. Muggia FM, Hainsworth JD, Jeffers S. Phase II study of liposomal doxorubicin in refractory ovarian cancer: antitumor activity and toxicity modification by liposomal encapsulation. J Clin Oncol 1997 Mar; 15(3): 987-93.
   

9. Gill PS, Espina BM, Muggia F, et al. Phase I/II clinical and pharmacokinetic evaluation of liposomal daunorubicin. J Clin Oncol 1995 Apr; 13(4): 996-1003.
   

10. Gill PS, Wernz J, Scadden DT, et al. Randomized phase III trial of liposomal daunorubicin versus doxorubicin, bleomycin, and vincristine in AIDS-related Kaposi's sarcoma. J Clin Oncol 1996 Aug; 14(8): 2353-64.
    

11. Bergin C, O'Leary A, McCreary C, et al. Treatment of Kaposi's sarcoma with liposomal doxorubicin. Am J Health-Syst Pharm 1995 Sep 15; 52(18): 2001-4.
    

12. Amantea MA, Forrest A, Northfelt DW, et al. Population pharmacokinetics and pharmacodynamics of pegylated-liposomal doxorubicin in patients with AIDS-related Kaposi's sarcoma. Clin Pharmacol Ther 1997 Mar; 61(3): 301-11.
    

13. Centers for Disease Control and Prevention (CDC). Update: vaccine side effects, adverse reactions, contraindications, and precautions. Recommendations of the Advisory Committee on Immunization Practices (ACIP) [published erratum appears in MMWR Morb Mortal Wkly Rep 1997 Mar 14; 46(10): 227]. MMWR Morb Mortal Wkly Rep 1996 Sep; 45(RR-12): 1-35.
    

14. Linsky KF, Ignoffo RJ. Liposomal doxorubicin. Cancer Pract 1996 Sep-Oct; 4(5): 288-90.
    

15. Reviewer's comment, 6/98.
    

16. Health Canada WWW site. Press release (7/20/98): doxorubicin HCl liposomal injection.
    

17. Product Information: Doxil®, doxorubicin HCl liposome. ALZA Pharmaceuticals, Mountain View, CA, (PI revised 7/1999) reviewed 4/2000.
    

18. Reviewers' consensus on the use of liposomal doxorubicin for the treatment of locally advanced and metastatic breast carcinoma, 8/3/00.
    

19. Smith FP, Barr F, Hendricks C, et al. Phase II study of Doxil® (pegylated liposomal doxorubicin) in doxorubicin-resistant, MBC. Proc Am Soc Clin Oncol 1999; 18: 137a [Abst 524].
    

20. Hurley J, Restrepo A, Boggs J, et al. The use of neoadjuvant Doxil® in the treatment of stage III breast cancer. Proc Am Soc Clin Oncol 1999; 18: 96a [Abst 359].
    

21. Gebbia V, Mauceri G, Fallica G, et al. Pegylated liposomal doxorubicin with escalating dose vinorelbine in MBC: a dose finding study. Proc Am Soc Clin Oncol 1999; 18: 211a [Abst 811].
    

22. Woll PJ, Carmichael J, Chan S, et al. Phase II study results on safety and tolerability of Caelyx® (Doxil®) in combination with paclitaxel in the treatment of metastatic breast cancer. Proc Am Soc Clin Oncol 1999; 18: 117a [Abst 442].
    

23. Silverman P, Overmoyer B, Holder L, et al. Doxil® and intravenous cyclophosphamide as first-line therapy for patients with MBC: interim results of an ongoing trial. Proc Am Soc Clin Oncol 1999; 18: 115a [Abst 435].
    

24. Holder L, Overmoyer B, Silverman P, et al. Doxil® and oral cyclophosphamide as first-line therapy for patients with MBC: preliminary results of a pilot trial. Proc Am Soc Clin Oncol 1998; 17: 146a [Abst 556].
    

25. Hamilton A, Coleman R, Mauriac L, et al. EORTC 10968: Phase I study of Caelyx® at a six-week interval in patients with MBC. 21st annual San Antonio breast cancer symposium, San Antonio, TX; Dec 1998: [Abst 535].
    

26. Moore MR, Srinivasiah J, Feinberg BA, et al. Phase II randomized trial of doxorubicin + paclitaxel (AT) vs. doxorubicin HCl liposome injection (Doxil®) + paclitaxel (DT) in MBC. Proc Am Soc Clin Oncol 1998, 17: 160a [Abst 614].
    

27. Lyass O, Uziely B, Heching NI, et al. Therapeutic efficacy of pegylated liposomal doxorubicin in MBC after prior chemotherapy: analysis of the Hadassah Medical center (HMC) experience. 21st annual San Antonio breast cancer symposium, San Antonio, TX; Dec 1998: [Abst 537].
    

28. Ramirez, MR, Marcom PK, Sutton LM, et al. A phase I study of Doxil® and vinorelbine in MBC. 21st annual San Antonio breast cancer symposium, San Antonio, TX; Dec 1998: [Abst 240].
    

29. Sparano JA, Malik UR, Einzig A, et al. Phase I trial of liposomal doxorubicin (Doxil®) and docetaxel (Taxotere) in patients with advanced breast cancer (ABC). 21st annual San Antonio breast cancer symposium, San Antonio, TX; Dec 1998: [Abst 235].
    

30. Ranson MR, Carmichael J, O'Byrne K, et al. Treatment of advanced breast cancer (ABC) with sterically stabilized liposomal doxorubicin: results of a multicenter phase II trial. J Clin Oncol 1997; 15(10): 3185-91.
    

31. Jahanzeb M, Frankel C, Vogel C. Rationale for trials studying pegylated liposomal doxorubicin in MBC. Oncology 1997; 11 (10, Suppl 11): 45-53.
    

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