Daunoxome (Liposomal Daunorubicin)

DAUNOXOME®

NeXstar

Liposomal Daunorubicin

Antineoplastic

Action And Clinical Pharmacology: DaunoXome is a liposomal preparation of daunorubicin formulated to selectively target daunorubicin to solid tumors in situ. While in the circulation, this formulation protects the entrapped daunorubicin from chemical and enzymatic degradation, minimizes protein binding, and generally decreases uptake by normal tissues, as well as by the non-reticuloendothelial system. The specific mechanism by which DaunoXome is able to deliver daunorubicin to solid tumors in situ is not known. DaunoXome accumulates in tumor tissue and DaunoXome vesicles enter the tumor cells intact. Daunorubicin is then released over time directly into the cells, where it is able to exert its antineoplastic activity.

DaunoXome has a pharmacokinetic profile different from that of conventional daunorubicin. When administered i.v. over approximately 30 minutes as a single dose of 10, 20, 40, 60 or 80 mg/m DaunoXome undergoes monoexponential decline, although biexponential or Michaelis-Menton (saturation) kinetics occurred in some instances. Peak plasma levels at 40 mg/mranged from 14.8 to 22 µg/mL with a mean peak plasma level of 18 µg/mL. The mean terminal half-life at this dose was 4 hours and mean total body clearance was 10.5 mL/min.

Mean clearance for DaunoXome is 6.6 mL/min versus 223 mL/min for daunorubicin. When combined, these parameters indicate that DaunoXome produces a 36-fold increase in mean area under the plasma curve compared to conventional drug (375.3 vs 10.33 µg.hr/mL).

Indications And Clinical Uses: For the treatment of advanced HIV-related Kaposi’s sarcoma.

Contra-Indications: DaunoXome should not be given in conjunction with other chemotherapeutic agents that suppress blood counts.

Manufacturers’ Warnings In Clinical States: DaunoXome is an antineoplastic agent that should be prescribed by clinicians familiar with the use of antineoplastic agents, and having access to facilities for regular monitoring of the clinical, hematological and biochemical parameters, as well as cardiac function, before, during and following therapy.

Daunorubicin has been associated with cardiomyopathy and congestive heart failure. In the clinical experience with DaunoXome, congestive heart failure was observed once, and in this patient the cardiac event was probably not related to DaunoXome therapy. Nevertheless, there must be a presumption that cardiomyopathy and congestive heart failure are possible side effects of DaunoXome. Cardiac function should be evaluated in each patient, including history, physical examination, and appropriate measurements of cardiac ejection fraction as indicated.

DaunoXome should not be given to patients who have had a serious hypersensitivity reaction to previous doses of DaunoXome or to any of its constituents unless the benefit from such treatment warrants the risk.

Daunorubicin has been associated with local tissue necrosis at the site of drug infiltration. Although no such necrosis has been observed with DaunoXome, care should be taken to ensure that there is no extravasation of drug when DaunoXome is administered (see Dosage).

Pregnancy and Lactation: Safety for use in pregnant and lactating women has not been established. Therefore, DaunoXome should only be used during pregnancy if the possible benefits outweigh the potential risks. Breast-feeding should be discontinued during treatment.

Fertility/Mutagenicity: Daunorubicin, the active component of DaunoXome, has been shown in experimental animals to impair fertility. Daunorubicin is also teratogenic in experimental animals. For daunorubicin, there is positive evidence of human fetal risk. Daunorubicin is mutagenic both in vitro and in vivo, and a high incidence of mammary tumors was observed in rats treated with daunorubicin. Although no such studies have been conducted with DaunoXome, it is possible that the drug may exhibit a similar profile for carcinogenesis, teratogenesis, mutagenesis and impairments of fertility, as that of daunorubicin.

Children/Geriatrics: The safety and effectiveness in children and the elderly have not been established.

Occupational Hazards: DaunoXome may induce delayed nausea and vomiting; it should not be administered prior to driving, or the use of heavy machinery.

Precautions: All parenteral drug products should be inspected visually for particulate matter prior to administration wherever solution and container permit.

Procedures for proper handling and disposal of anticancer drugs should be followed.

The primary toxicity of DaunoXome is myelosuppression and, as such, close patient observation and frequent monitoring of the blood cell counts is mandated. In patients with malignancies or with HIV infection, the immune system is already compromised, and the use of a cytotoxic agent decreasing the white blood cell count may cause further immunosuppression and make the patient more susceptible to intercurrent or opportunistic infections.

Drug Interactions: No interactions between DaunoXome and other drugs have been observed to date. DaunoXome has been safely administered during antiretroviral therapy with zidovudine (AZT), dideoxycytidine (ddC, zalcitabine) and dideoxyinosine (ddI, didanosine) and with the colony stimulating factor G-CSF (filgrastim). Although interaction of DaunoXome with other drugs has not been observed, patients requiring concomitant drug therapy should be monitored closely.

Adverse Reactions: Daunorubicin has been associated with cardiomyopathy and congestive heart failure. Although no such side effects have been attributable to DaunoXome in clinical trials, these side effects may occur. Therefore, cardiac function should be evaluated in each patient, including history, physical examination, and appropriate measures of cardiac ejection fraction, as indicated.

Daunorubicin has also been associated with local tissue necrosis at the site of drug infiltrations. No such local necrosis has been observed with DaunoXome. Nonetheless, care should be taken to ensure that there is no infiltration of drug when DaunoXome is administered i.v.

The primary toxicity of DaunoXome is myelosuppression and, as such, close patient observation and frequent monitoring of the blood cell counts is mandated. In patients with malignancies or with HIV infection, the immune system is already compromised, and the use of a cytotoxic agent decreasing the white blood cell count may cause further immunosuppression and make the patient more susceptible to intercurrent or opportunistic infections.

Back pain, flushing and chest tightness were occasionally reported during the clinical trials. This syndrome may occur during a patient’s initial infusion and may also occur in patients who have previously been exposed to DaunoXome without prior side effects. This combination of symptoms does not always appear to be dose related, and generally occurs during the first 10 minutes of the infusion. The etiology is unclear. The symptoms usually subside when the infusion is slowed or halted, and acetaminophen may be used for analgesia. Other allergic or immune reactions have been reported to be associated with hypotension.

Various other reactions, that were manageable and that did not result in patient withdrawal, such as headache, fatigue, chills, mucositis, lightheadedness, nausea and vomiting, mild hair loss, diarrhea have also been reported.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: No experience exists for an overdose with DaunoXome. The primary anticipated toxicity from such an overdose would be myelosuppression, and under these circumstances bone marrow function should be carefully monitored with appropriate therapy for any severe side effects.

Dosage And Administration: The dosage must be adjusted individually. Therapy should be instituted at 40 mg/mevery 2 weeks and therapy should be continued as long as disease control can be maintained.

There are no preservative or bacteriostatic agents in DaunoXome or in its diluent. Therefore, aseptic technique must be strictly observed in handling of the drug.

DaunoXome should be diluted with 5% Dextrose Injection (D5W) before administration. The recommended concentration after dilution is between 0.2 mg and 1 mg daunorubicin/mL of solution. DaunoXome should be administered i.v. over a 30 to 60 minute period and within 6 hours of dilution with D5W.

Caution: DaunoXome should not be mixed with saline, bacteriostatic agents such as benzyl alcohol, or any other solution. Saline and bacteriostatics, such as benzyl alcohol, should not be used as diluents for DaunoXome. Use only 5% Dextrose for dilution.

The use of an in-line filter is not recommended for the i.v. infusion of DaunoXome, unless the mean pore diameter of the filter is greater than or equal to 5 µm.

Myelosuppression is a known reaction to DaunoXome therapy. The colony stimulating factor G-CSF (filgrastim) has been used to manage patients whose absolute neutrophil count (ANC) fell below 1 000/mm

If any signs or symptoms of extravasation have occurred, immediately terminate the infusion. If it is known or suspected that s.c. extravasation has occurred, the following steps are recommended: elevation of the affected limb; local intermittent application of ice for up to 2 days; consultation with a physician; close observation of the injection site.

Use Aseptic Technique: Aseptic technique must be strictly observed in all handling, since no preservative or bacteriostatic agent is present in DaunoXome or in the materials recommended for dilution. The product should be used within 6 hours of dilution in 5% Dextrose Injection.

Withdraw the calculated volume of DaunoXome into a sterile syringe. Instill the DaunoXome preparation into a sterile container with the correct amount of 5% Dextrose Injection (D5W) and administer within 6 hours. The recommended concentration after dilution is between 0.2 mg and 1 mg daunorubicin/mL of solution. Infuse over a 30 to 60 minute period. As with all parenteral drug products, inspect the solution visually for particulate matter prior to administration.

Caution: The only fluid which may be mixed with DaunoXome is D5W; DaunoXome should not be mixed with saline, bacteriostatic agents such as benzyl alcohol, or any other solution.

An in-line filter is not recommended for the i.v. infusion of DaunoXome. However, if such a filter is used, the mean pore diameter of the filter should not be less than 5 µm.

Procedures for proper handling and disposal of anticancer drugs should be followed.

To date, no incompatibilities of DaunoXome with other drugs have been reported. However, it is known that the active component daunorubicin is physically incompatible with heparin sodium and with dexamethasone phosphate when directly admixed. A precipitate is produced with either drug. Additionally, because of the chemical instability of the glycosidic bond of daunorubicin, admixture into a highly alkaline media (pH >8.0) is not recommended.

DaunoXome should not be mixed with saline; aggregation of the liposomes may result. Admixtures containing bacteriostatic agents such as benzyl alcohol or other detergent-like molecules should be avoided as well because such compounds can rupture the bilayer wall of the liposomes causing premature leakage of the active drug.

Availability And Storage: Each mL of red and clear to slightly opalescent, sterile, pyrogen-free, preservative-free, liposomal emulsion contains: daunorubicin 2 mg (encapsulated in liposomes). Nonmedicinal ingredients: calcium chloride, cholesterol, citric acid, distearoyl phosphatidylcholine, glycine, sucrose and water for injection. Single dose glass vials of 25 mL (50 mg). Store at 2 to 8°C. Do not freeze. Protect against exposure to light. Do not store partially used vials for future patient use. Vials are for single use only.

DAUNOXOME® NeXstar Liposomal Daunorubicin Antineoplastic

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