Drug Description

Doxorubicin is an anthracycline glycoside antineoplastic antibiotic produced by Streptomyces peucetius var. caesius. [1]

References

[1] AHFS Drug Information 2008; p. 1048

HIV/AIDS-Related Uses

Doxorubicin hydrochloride (HCl) encapsulated in polyethylene glycol (PEG)-stabilized liposomes was approved by the FDA on November 17, 1995, for use as first-line therapy for the treatment of advanced AIDS-related Kaposi's sarcoma (KS) disease that has progressed despite prior combination chemotherapy or in patients who are intolerant of such combination therapy. [1] [2] The conventional, nonencapsulated formulations of the drug have also been used in the palliative treatment of AIDS-related KS. [3]

References

[1] AHFS Drug Information 2008; p. 1039

[2] FDA Doxil Prescribing Information, 06/10/08, p. 2. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/050718s033lbl.pdf. Accessed 05/21/09.

[3] AHFS Drug Information 2008; p. 1039

Dosing Information

Intravenous. [1]

Dosage Form

Doxorubicin HCl (liposomal) for injection at a concentration of 2 mg/mL: in 10-mL sterile, single-use vials that each contain the equivalent of doxorubicin 20 mg and in 30-mL sterile, single-use vials that each contain the equivalent of doxorubicin 50 mg. [2]

For patients with AIDS-related Kaposi's sarcoma, doxorubicin HCl liposome injection should be administered intravenously at a dose of 20 mg/m2. An initial rate of 1 mg/min should be used to minimize the risk of infusion-related reactions. If no infusion-related adverse reactions are observed, the infusion rate should be increased to complete the administration of the drug over one hour. The dose should be repeated once every three weeks, for as long as patients respond satisfactorily and tolerate treatment. [3]

Liposomal encapsulation can substantially affect a drug's functional properties relative to those of the unencapsulated drug. Therefore do not substitute one drug for the other. [4]

Do not administer as a bolus injection or an undiluted solution. [5]

Dosage of the infusion should be reduced in patients with impaired hepatic function. Based on experience with doxorubicin HCl, it is recommended that the liposomal doxorubicin dosage be reduced if the bilirubin is elevated. [6]

Storage

Refrigerate unopened vials between 2 C to 8 C (36 F to 46 F) and protect from freezing. Prolonged freezing may adversely affect liposomal drug products; however, short-term (less than 1 month) freezing does not appear to have a deleterious effect on the drug. [7] When shipped, vials of doxorubicin HCl for injection are packaged with a gel refrigerant (blue ice) to maintain a temperature between 2 C to 8 C (36 F to 46 F). [8]

References

[1] AHFS Drug Information 2008; p. 1048

[2] FDA Doxil Prescribing Information, 06/10/08, p. 32. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/050718s033lbl.pdf. Accessed 05/21/09.

[3] FDA Doxil Prescribing Information, 06/10/08, pp. 3,4. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/050718s033lbl.pdf. Accessed 05/21/09.

[4] FDA Doxil Prescribing Information, 06/10/08, p. 3. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/050718s033lbl.pdf. Accessed 05/21/09.

[5] FDA Doxil Prescribing Information, 06/10/08, p. 3. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/050718s033lbl.pdf. Accessed 05/21/09.

[6] FDA Doxil Prescribing Information, 06/10/08, pp. 2, 7. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/050718s033lbl.pdf. Accessed 05/21/09.

[7] FDA Doxil Prescribing Information, 06/10/08, p. 32. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/050718s033lbl.pdf. Accessed 05/21/09.

[8] AHFS Drug Information 2008; p. 1048

Pharmacology

Doxorubicin is an anthracycline cytostatic antibiotic with activity against a variety of malignancies, including KS. Both in vitro and in vivo, liposomal doxorubicin has been shown to inhibit KS cell growth. Doxorubicin intercalates between DNA strands, inhibiting topoisomerase II activity and inducing tumor cell DNA fragmentation. Additionally, liposomal doxorubicin induces expression of monocyte chemoattractant protein-1, which results in intralesional recruitment of phagocytic cells in patients with KS. The mechanism by which liposome encapsulation apparently enhances doxorubicin accumulation in AIDS-associated KS is not fully understood, but the passage of liposomal particles through endothelial cell gaps, reported to be present in certain solid tumors and known to be present in KS-like lesions, may contribute to the enhanced accumulation. Once within the tumor, the active ingredient doxorubicin is presumably released locally as the liposomes degrade and become permeable in situ. Doxorubicin-induced apoptosis may be an integral component of the cellular mechanism of action relating to therapeutic effects, toxicities, or both. [1]

Doxorubicin is extremely irritating to tissues and therefore must be administered by intravenous (IV) infusion. Following IV infusion of a single 10- or 20-mg/m2 dose of liposomal doxorubicin HCl in patients with AIDS-related KS, average peak plasma doxorubicin (mostly bound to liposomes) concentrations are 4.33 mcg/mL or 10.1 mcg/mL, respectively; following a 15-minute infusion they are 4.12 mcg/mL; and following a 30-minute infusion, they are 8.34 mcg/mL. Following IV infusion over 15 minutes of a 40-mg/m2 dose of liposomal doxorubicin HCl in patients with AIDS-related KS, peak plasma concentrations averaged 20.1 mcg/mL. [2]

Encapsulation in PEG-stabilized liposomes substantially slows the rate of distribution into the extravascular space. As a result, the liposomally encapsulated drug distributes mainly in intravascular fluid, whereas nonencapsulated drug distributes widely into the extravascular fluids and tissues. Doxorubicin does not cross the blood-brain barrier or achieve a measurable concentration in cerebrospinal fluid. Trace amounts of doxorubicin have been found in fetal mice whose mothers received the drug during pregnancy, and there are limited data to indicate that nonencapsulated doxorubicin crosses the human placenta. Nonencapsulated drug is distributed into milk, and it achieves concentrations that often exceed those in plasma; doxorubicinol (the major metabolite) also distributes into milk. [3]

Liposomal doxorubicin HCl is in FDA Pregnancy Category D. Liposomal doxorubicin can cause fetal harm when administered to a pregnant woman. Adequate and well-controlled studies have not been done in pregnant women to assess doxorubicin's effects on fertility and pregnancy. Use of the drug is not recommended during pregnancy. Women of childbearing age should be advised to avoid pregnancy during treatment and, in general, use of contraception is recommended during any cytotoxic drug therapy. If liposomal doxorubicin is to be used during pregnancy or if the patient becomes pregnant during therapy, the patient should be apprised of the potential hazard to the fetus. If pregnancy occurs in the first few months following treatment with liposomal doxorubicin, the prolonged half-life of the drug must be considered. 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. Limited in vitro and in vivo assays have shown that the liposome component of liposomal doxorubicin is not mutagenic. [4] [5]

It is not known whether this drug is excreted in human milk. Because many drugs, including anthracyclines, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from liposomal doxorubicin, mothers should discontinue nursing prior to taking this drug. [6]

Protein binding of liposomal doxorubicin has not been determined. [7] Plasma concentrations of liposomally encapsulated doxorubicin HCl appear to decline in a biphasic manner. Following IV administration of a single 10- to 40-mg/m2 dose of doxorubicin HCl as a liposomal injection in patients with AIDS-related KS, the initial plasma half-life of doxorubicin averaged 3.76 to 5.2 hours, whereas the terminal elimination half-life averaged 39.1 to 55 hours. Plasma clearance of liposomal doxorubicin HCl appears to be substantially slower than that of nonencapsulated doxorubicin. [8]

References

[1] Wolters Kluwer Health, Inc. Doxorubicin Hydrochloride, Facts and Comparisons 4.0 [online]. Available at: http://www.factsandcomparisons.com. Accessed 05/21/09.

[2] AHFS Drug Information 2008; p. 1048

[3] AHFS Drug Information 2008; p. 1048

[4] Wolters Kluwer Health, Inc. Doxorubicin Hydrochloride, Facts and Comparisons 4.0 [online]. Available at: http://www.factsandcomparisons.com. Accessed 05/21/09.

[5] Wolters Kluwer Health, Inc. Doxil Prescribing Information, 06/10/08, p. 12. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/050718s033lbl.pdf. Accessed 05/21/09.

[6] FDA Doxil Prescribing Information, 06/10/08, p. 19. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/050718s033lbl.pdf. Accessed 05/21/09.

[7] Wolters Kluwer Health, Inc. Doxorubicin Hydrochloride, Facts and Comparisons 4.0 [online]. Available at: http://www.factsandcomparisons.com. Accessed 05/21/09.

[8] AHFS Drug Information 2008; p. 1048

Adverse Events/Toxicity

The most common adverse reactions observed with liposomal doxorubicin are asthenia, fatigue, fever, nausea, stomatitis, vomiting, diarrhea, constipation, anorexia, hand-foot syndrome (developed palmar-plantar skin eruptions characterized by swelling, pain, erythema and, for some patients, desquamation of the skin on the hands and the feet), rash and neutropenia, thrombocytopenia and anemia. Additional adverse effects associated with liposomal doxorubicin HCl use include allergic reaction, pneumonia, postirradiation erythema recall (darkening or reddening of skin), tachycardia, chest pain, edema, and infection. [1]

The FDA has issued a boxed warning for doxorubicin HCl liposome injection for adverse infusion reactions, myelosuppresion, cardiotoxicity, liver impairment, and accidental substitution. [2]

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 cumulative dose of doxorubicin HCl that 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. In a clinical trial of 250 patients on cumulative liposomal doxorubicin HCl doses of 450 to 550 mg/m2, the risk of cardiac toxicity was 11%. Doxorubicin HCl should be administered to patients with a history of cardiovascular disease only when the benefit outweighs the risk to the patient. [3]

Acute infusion-related reactions, including flushing, shortness of breath, facial swelling, headache, chills, back pain, tightness in the chest or throat, and hypotension, have occurred in up to 7.1% of patients treated with liposomal doxorubicin HCl. The initial infusion rate should be 1 mg/min to minimize the risk of infusion reactions. [4]

Severe myelosuppression may occur, most commonly as leukopenia in patients with AIDS-related KS. Myelosuppression appears to be dose-limiting at the recommended 20 mg/m2 dosage in this population. [5]

Accidental substitution of doxorubicin HCl liposome injection for doxorubicin HCl has resulted in severe side effects.The liposomal form should not be substituted for nonencapsulated doxorubicin HCl on a mg-per-mg basis. Liposomal doxorubicin HCl should be administered only under the supervision of a physician experienced in the use of cancer chemotherapeutic agents. [6]

References

[1] FDA Doxil Prescribing Information, 06/10/08, pp. 13, 15-6. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/050718s033lbl.pdf. Accessed 05/21/09.

[2] FDA Doxil Prescribing Information, 06/10/08, p. 2. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/050718s033lbl.pdf. Accessed 05/21/09.

[3] FDA Doxil Prescribing Information, 06/10/08, pp. 2, 9. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/050718s033lbl.pdf. Accessed 05/21/09.

[4] FDA Doxil Prescribing Information, 06/10/08, p. 10. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/050718s033lbl.pdf. Accessed 05/21/09.

[5] FDA Doxil Prescribing Information, 06/10/08, p. 11. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/050718s033lbl.pdf. Accessed 05/21/09.

[6] FDA Doxil Prescribing Information, 06/10/08, pp. 2, 3. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/050718s033lbl.pdf. Accessed 05/21/09.

Drug and Food Interactions

Formal drug interaction studies of PEG-stabilized liposomal doxorubicin have not been performed to date. However, drugs known to interact with nonencapsulated doxorubicin HCl should be considered to interact with the encapsulated liposomal formulation. [1]

Doxorubicin may potentiate the toxicity of other antineoplastic therapies and vice versa. Combined therapy with other myelosuppresive agents may increase the severity of hematologic toxicity. Evidence suggests that concomitant use of cyclosporine and doxorubicin may result in more severe and prolonged hematologic toxicity, and seizures or coma may occur. [2]

Doxorubicin-induced cardiotoxicity may be potentiated by concomitant use of calcium channel blocking agents. Phenobarbital has increased the elimination of doxorubicin. Doxorubicin has decreased serum phenytoin concentrations. Streptozocin may inhibit hepatic metabolism of doxorubicin. [3]

References

[1] AHFS Drug Information 2008; p. 1046

[2] AHFS Drug Information 2008; p. 1046

[3] AHFS Drug Information 2008; p. 1046

Contraindications

Liposomal doxorubicin is contraindicated in patients who have a history of hypersensitivity to a conventional formulation of doxorubicin HCl or the components of the liposomal injection. Liposomal doxorubicin is contraindicated in nursing mothers. [1]

References

[1] FDA Doxil Prescribing Information, 06/10/08, p. 8. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/050718s033lbl.pdf. Accessed 05/21/09.

Clinical Trials

Click here to search ClinicalTrials.gov for trials that use Clorhidrato de doxorrubicina liposómica.

Chemistry

CAS Name

5,12-Naphthacenedione, 10-((3-amino- 2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy)- 7,8,9,10-tetrahydro-6,8,11-trihydroxy-8- (hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- [1]

CAS Number

25316-40-9 [2]

Molecular Formula

C27-H29-N-O11.HCl

Elemental Composition

C59.67%, H5.38%, N2.58%, O32.38% (base)

Molecular Weight

579.99

Melting Point

204 C to 205 C

Physical Description

Orange-red colored thin needles. [3] Translucent, red, liposmal dispersion upon dilution. [4]

Stability

The appropriate dose of liposomal doxorubicin HCl up to 90 mg must be diluted in 250 mL of 5% Dextrose Injection, USP prior to administration. Doses that exceed 90 mg should be diluted in 500 mL of 5% Dextrose Injection, USP prior to administration. Aseptic technique must be observed, because no preservative or bacteriostatic agent is present in the formulation. Once diluted, liposomal doxorubicin should be refrigerated between 2 C to 8 C (36 F to 46 F) and must be administered within 24 hours. [5]

Solubility

Soluble in water, methanol, and aqueous alcohols. [6]

References

[1] ChemIDplus Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 05/21/09.

[2] ChemIDplus Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 05/21/09.

[3] MERCK Index 2006; p. 582

[4] FDA Doxil Prescribing Information, 06/10/08, p. 20. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/050718s033lbl.pdf. Accessed 05/21/09.

[5] FDA Doxil Prescribing Information, 06/10/08, p. 7. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/050718s033lbl.pdf. Accessed 05/21/09.

[6] Merck Index 2001; p. 606

Further Reading

Doxil Prescribing Information from the FDA Web site. A more current version may be available on the manufacturer's Web site.
Cooley T, Henry D, Tonda M, Sun S, O'Connell M, Rackoff W. A randomized, double-blind study of pegylated liposomal doxorubicin for the treatment of AIDS-related Kaposi's sarcoma. Oncologist. 2007 Jan;12(1):114-23.
Di Lorenzo G, Di Trolio R, Montesarchio V, Palmieri G, Nappa P, Delfino M, De Placido S, Dezube BJ. Pegylated liposomal doxorubicin as second-line therapy in the treatment of patients with advanced classic Kaposi sarcoma: a retrospective study. Cancer. 2008 Mar 1;112(5):1147-52.
Di Trolio R, Di Lorenzo G, Delfino M, De Placido S. Role of pegylated lyposomal doxorubicin (PLD) in systemic Kaposi's sarcoma: a systematic review. Int J Immunopathol Pharmacol. 2006 Apr-Jun;19(2):253-63. Review.
Little RF, Aleman K, Kumar P, Wyvill KM, Pluda JM, Read-Connole E, Wang V, Pittaluga S, Catanzaro AT, Steinberg SM, Yarchoan R. Phase 2 study of pegylated liposomal doxorubicin in combination with interleukin-12 for AIDS-related Kaposi sarcoma. Blood. 2007 Dec 15;110(13):4165-71. Epub 2007 Sep 10.
Udhrain A, Skubitz KM, Northfelt DW. Pegylated liposomal doxorubicin in the treatment of AIDS-related Kaposi's sarcoma. Int J Nanomedicine. 2007;2(3):345-52. Review.

Manufacturer Information

Doxil

Ortho Biotech
P.O. Box 6914
430 Rt. 22 East
Bridgewater, NJ 08807-0914
Phone: 800-682-6532
Fax: 800-682-6532