Doxorubicin (Liposomal)- Doxil®

Doxorubicin (Liposomal) - Doxil®

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Usual Diluents

D5W

Dilution Data

Dilution summary:
[Doses <90 mg] [250 ml D5W] [Initial rate: ≤1 mg/min. If no rxn's, subsequent infusions over 1 hour]
[Doses ≥90 mg] [500 ml D5W] [Initial rate: ≤1 mg/min. If no rxn's, subsequent infusions over 1 hour]

Preparation for Intravenous Administration:
Each 10-mL vial contains 20 mg doxorubicin HCl at a concentration of 2 mg/mL. Each 30-mL vial contains 50 mg doxorubicin HCl at a concentration of 2 mg/mL.

DOXIL doses up to 90 mg must be diluted in 250 mL of 5% Dextrose Injection, USP prior to administration. Doses exceeding 90 mg should be diluted in 500 mL of 5% Dextrose Injection, USP prior to administration. Aseptic technique must be strictly observed since no preservative or bacteriostatic agent is present in DOXIL. Diluted DOXIL should be refrigerated at 2°C to 8°C (36°F to 46°F) and administered within 24 hours.

Do not use with in-line filters.
Do not mix with other drugs.
Do not use with any diluent other than 5% Dextrose Injection.
Do not use any bacteriostatic agent, such as benzyl alcohol.

DOXIL is not a clear solution but a translucent, red liposomal dispersion.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if a precipitate or foreign matter is present.

Rapid flushing of the infusion line should be avoided.

Refrigerate unopened vials of DOXIL at 2°–8°C (36°–46°F). Avoid freezing. Prolonged freezing may adversely affect liposomal drug products; however, short-term freezing (less than 1 month) does not appear to have a deleterious effect on DOXIL.

Stability / Miscellaneous

WARNINGS/PRECAUTIONS - See package insert.	CLINICAL PHARMACOLOGY	INDICATIONS
CONTRAINDICATIONS	DOSAGE AND ADMINISTRATION	RECONSTITUTION / DILUTION
	HOW SUPPLIED
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DESCRIPTION
DOXIL (doxorubicin HCl liposome injection) is doxorubicin hydrochloride (HCl) encapsulated in STEALTH® liposomes for intravenous administration.

Doxorubicin is an anthracycline topoisomerase inhibitor isolated from Streptomyces peucetius var. caesius.
The molecular formula of the drug is C27 H29 NO11•HCl; its molecular weight is 579.99.

DOXIL is provided as a sterile, translucent, red liposomal dispersion in 10-mL or 30-mL glass, single use vials. Each vial contains 20 mg or 50 mg doxorubicin HCl at a concentration of 2 mg/mL and a pH of 6.5. The STEALTH® liposome carriers are composed of N-(carbonyl-methoxypolyethylene glycol 2000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine sodium salt (MPEG-DSPE), 3.19 mg/mL; fully hydrogenated soy phosphatidylcholine (HSPC), 9.58 mg/mL; and cholesterol, 3.19 mg/mL. Each mL also contains ammonium sulfate, approximately 2 mg; histidine as a buffer; hydrochloric acid and/or sodium hydroxide for pH control; and sucrose to maintain isotonicity. Greater than 90% of the drug is encapsulated in the STEALTH® liposomes.

CLINICAL PHARMACOLOGY

Mechanism of Action
The active ingredient of DOXIL is doxorubicin HCl. The mechanism of action of doxorubicin HCl is thought to be related to its ability to bind DNA and inhibit nucleic acid synthesis. Cell structure studies have demonstrated rapid cell penetration and perinuclear chromatin binding, rapid inhibition of mitotic activity and nucleic acid synthesis, and induction of mutagenesis and chromosomal aberrations.

DOXIL is doxorubicin HCl encapsulated in long-circulating STEALTH® liposomes. Liposomes are microscopic vesicles composed of a phospholipid bilayer that are capable of encapsulating active drugs. The STEALTH® liposomes of DOXIL are formulated with surface-bound methoxypolyethylene glycol (MPEG), a process often referred to as pegylation, to protect liposomes from detection by the mononuclear phagocyte system (MPS) and to increase blood circulation time.

STEALTH® liposomes have a half-life of approximately 55 hours in humans. They are stable in blood, and direct measurement of liposomal doxorubicin shows that at least 90% of the drug (the assay used cannot quantify less than 5–10% free doxorubicin) remains liposome-encapsulated during circulation.

It is hypothesized that because of their small size (ca. 100 nm) and persistence in the circulation, the pegylated DOXIL liposomes are able to penetrate the altered and often compromised vasculature of tumors. This hypothesis is supported by studies using colloidal gold-containing STEALTH® liposomes, which can be visualized microscopically. Evidence of penetration of STEALTH® liposomes from blood vessels and their entry and accumulation in tumors has been seen in mice with C-26 colon carcinoma tumors and in transgenic mice with Kaposi's sarcoma-like lesions. Once the STEALTH® liposomes distribute to the tissue compartment, the encapsulated doxorubicin HCl becomes available. The exact mechanism of release is not understood.

1. INDICATIONS AND USAGE

1.1 Ovarian Cancer
DOXIL (doxorubicin HCl liposome injection) is indicated for the treatment of patients with ovarian cancer whose disease has progressed or recurred after platinum-based chemotherapy.

1.2 AIDS-Related Kaposi's Sarcoma
DOXIL is indicated for the treatment of AIDS-related Kaposi's sarcoma in patients with disease that has progressed on prior combination chemotherapy or in patients who are intolerant to such therapy.

The treatment of patients with AIDS-related Kaposi's sarcoma is based on objective tumor response rates. No results are available from controlled trials that demonstrate a clinical benefit resulting from this treatment, such as improvement in disease-related symptoms or increased survival.

1.3 Multiple Myeloma
DOXIL in combination with bortezomib is indicated for the treatment of patients with multiple myeloma who have not previously received bortezomib and have received at least one prior therapy.

2. DOSAGE AND ADMINISTRATION

2.1 Usage and Administration Precautions
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.

Do not administer as a bolus injection or an undiluted solution. Rapid infusion may increase the risk of infusion-related reactions [see Warnings and Precautions (5.2)]. DOXIL must not be given by the intramuscular or subcutaneous route.

Until specific compatibility data are available, it is not recommended that DOXIL be mixed with other drugs.

DOXIL should be considered an irritant and precautions should be taken to avoid extravasation. With intravenous administration of DOXIL, extravasation may occur with or without an accompanying stinging or burning sensation, even if blood returns well on aspiration of the infusion needle. If any signs or symptoms of extravasation have occurred, the infusion should be immediately terminated and restarted in another vein. The application of ice over the site of extravasation for approximately 30 minutes may be helpful in alleviating the local reaction

2.2 Patients With Ovarian Cancer
DOXIL (doxorubicin HCl liposome injection) should be administered intravenously at a dose of 50 mg/m2 (doxorubicin HCl equivalent) at an initial rate of 1 mg/min to minimize the risk of infusion reactions. If no infusion-related adverse reactions are observed, the rate of infusion can be increased to complete administration of the drug over one hour. The patient should be dosed once every 4 weeks, for as long as the patient does not progress, shows no evidence of cardiotoxicity [see Warnings and Precautions (5.1)], and continues to tolerate treatment. A minimum of 4 courses is recommended because median time to response in clinical trials was 4 months. To manage adverse reactions such as hand-foot syndrome (HFS), stomatitis, or hematologic toxicity the doses may be delayed or reduced [see Dosage and Administration (2.5)]. Pretreatment with or concomitant use of antiemetics should be considered.

2.3 Patients With AIDS-Related Kaposi's Sarcoma
DOXIL (doxorubicin HCl liposome injection) should be administered intravenously at a dose of 20 mg/m2 (doxorubicin HCl equivalent). An initial rate of 1 mg/min should be used to minimize the risk of infusion-relatedreactions. If no infusion-related adverse reactions are observed, the infusionrate 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.

2.4 Patients With Multiple Myeloma
Bortezomib is administered at a dose of 1.3 mg/m2 as intravenous bolus on days 1, 4, 8 and 11, every three weeks. DOXIL 30 mg/m2 should be administered as a 1-hr intravenous infusion on day 4 following bortezomib. With the first DOXIL dose, 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. Patients may be treated for up to 8 cycles until disease progression or the occurrence of unacceptable toxicity.

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2.5 Dose Modification Guidelines
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DOXIL exhibits nonlinear pharmacokinetics at 50 mg/m2; therefore, dose adjustments may result in a non-proportional greater change in plasma concentration and exposure to the drug [see Clinical Pharmacology (12.3)].

Patients should be carefully monitored for toxicity. Adverse reactions, such as HFS, hematologic toxicities, and stomatitis may be managed by dose delays and adjustments. Following the first appearance of a Grade 2 or higher adverse reactions, the dosing should be adjusted or delayed as described in the following tables. Once the dose has been reduced, it should not be increased at a later time.

Recommended Dose Modification Guidelines
Table 1: Hand-Foot Syndrome (HFS)

Toxicity Grade	Dose Adjustment
1 (mild erythema, swelling, or desquamation not interfering with daily activities)	Redose unless patient has experienced previous Grade 3 or 4 HFS. If so, delay up to 2 weeks and decrease dose by 25%. Return to original dose interval.
2 (erythema, desquamation, or swelling interfering with, but not precluding normal physical activities; small blisters or ulcerations less than 2 cm in diameter)	Delay dosing up to 2 weeks or until resolved to Grade 0-1. If after 2 weeks there is no resolution, DOXIL should be discontinued. If resolved to Grade 0-1 within 2 weeks, and there are no prior Grade 3-4 HFS, continue treatment at previous dose and return to original dose interval. If patient experienced previous Grade 3-4 toxicity, continue treatment with a 25% dose reduction and return to original dose interval.
3 (blistering, ulceration, or swelling interfering with walking or normal daily activities; cannot wear regular clothing)	Delay dosing up to 2 weeks or until resolved to Grade 0-1. Decrease dose by 25% and return to original dose interval. If after 2 weeks there is no resolution, DOXIL should be discontinued.
4 (diffuse or local process causing infectious complications, or a bed ridden state or hospitalization)	Delay dosing up to 2 weeks or until resolved to Grade 0-1. Decrease dose by 25% and return to original dose interval. If after 2 weeks there is no resolution, DOXIL should be discontinued.

Table 2: Hematological Toxicity

Grade	ANC	Platelets	Modification
1	1,500 - 1,900	75,000 - 150,000	Resume treatment with no dose reduction
2	1,000 - <1,500	50,000 -<75,000	Wait until ANC ≥ 1,500 and platelets ≥75,000; redose with no dose reduction
3	500 - 999	25,000 -<50,000	Wait until ANC ≥ 1,500 and platelets ≥ 75,000; redose with no dose reduction
4	<500	<25,000	Wait until ANC ≥ 1,500 and platelets ≥ 75,000; redose at 25% dose reduction or continue full dose with cytokine support

Table 3: Stomatitis

Toxicity Grade	Dose Adjustment
1 (painless ulcers, erythema, or mild soreness)	Redose unless patient has experienced previous Grade 3 or 4 toxicity. If so, delay up to 2 weeks and decrease dose by 25%. Return to original dose interval.
2 (painful erythema, edema, or ulcers, but can eat)	Delay dosing up to 2 weeks or until resolved to Grade 0-1. If after 2 weeks there is no resolution, DOXIL should be discontinued. If resolved to Grade 0-1 within 2 weeks and there was no prior Grade 3-4 stomatitis, continue treatment at previous dose and return to original dose interval. If patient experienced previous Grade 3-4 toxicity, continue treatment with a 25% dose reduction and return to original dose interval.
3 (painful erythema, edema, or ulcers, and cannot eat)	Delay dosing up to 2 weeks or until resolved to Grade 0-1. Decrease dose by 25% and return to original dose interval. If after 2 weeks there is no resolution, DOXIL should be discontinued.
4 (requires parenteral or enteral support)	Delay dosing up to 2 weeks or until resolved to Grade 0-1. Decrease dose by 25% and return to DOXIL original dose interval. If after 2 weeks there is no resolution, DOXIL should be discontinued.

Multiple Myeloma
For patients treated with DOXIL in combination with bortezomib who experience hand-foot syndrome or stomatitis, the DOXIL dose should be modified as described in Tables 1 and 3 above. Table 4 describes dosage adjustments for DOXIL and bortezomib combination therapy. For bortezomib dosing and dosage adjustments, see manufacturer's prescribing information.

Table 4: Dosage adjustments for DOXIL + bortezomib combination therapy

Patient status	DOXIL	bortezomib
Fever ≥38°C and ANC <1,000/mm3	Do not dose this cycle if before Day 4; if after Day 4, reduce next dose by 25%.	Reduce next dose by 25%
On any day of drug administration after Day 1 of each cycle: Platelet count <25,000/mm3 Hemoglobin <8g/dL ANC <500/mm3	Do not dose this cycle if before Day 4; if after Day 4 reduce next dose by 25% in the following cycles if bortezomib is reduced for hematologic toxicity.	Do not dose; if 2 or more doses are not given in a cycle, reduce dose by 25% in following cycles.
Grade 3 or 4 non-hematologic drug related toxicity	Do not dose until recovered to Grade <2 and reduce dose by 25% for all subsequent doses.	Do not dose until recovered to Grade <2 and reduce dose by 25% for all subsequent doses.
Neuropathic pain or peripheral neuropathy	No dosage adjustments.	See bortezomib manufacturer's prescribing information for dosage adjustments in patients with neuropathic pain.

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2.6 Patients With Impaired Hepatic Function
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Limited clinical experience exists in treating patients with hepatic impairment with DOXIL. Based on experience with doxorubicin HCl, it is recommended that the DOXIL dosage be reduced if the bilirubin is elevated as follows: serum bilirubin 1.2 to 3.0 mg/dL - give 50% of normal dose; serum bilirubin > 3 mg/dL - give 25% of normal dose.

No information, including dosage adjustments, is available for patients with multiple myeloma with hepatic impairment.

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2.7 Preparation for Intravenous Administration
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Each 10-mL vial contains 20 mg doxorubicin HCl at a concentration of 2 mg/mL.

Each 30-mL vial contains 50 mg doxorubicin HCl at a concentration of 2 mg/mL.

Do not use with in-line filters.
Do not mix with other drugs.
Do not use with any diluent other than 5% Dextrose Injection.
Do not use any bacteriostatic agent, such as benzyl alcohol.

DOXIL is not a clear solution but a translucent, red liposomal dispersion.

Rapid flushing of the infusion line should be avoided.

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2.8 Procedure for Proper Handling and Disposal
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Caution should be exercised in the handling and preparation of DOXIL.

The use of gloves is required.

If DOXIL comes into contact with skin or mucosa, immediately wash thoroughly with soap and water.

DOXIL should be considered an irritant and precautions should be taken to avoid extravasation. With intravenous administration of DOXIL, extravasation may occur with or without an accompanying stinging or burning sensation, even if blood returns well on aspiration of the infusion needle. If any signs or symptoms of extravasation have occurred, the infusion should be immediately terminated and restarted in another vein. DOXIL must not be given by the intramuscular or subcutaneous route.

DOXIL should be handled and disposed of in a manner consistent with other anticancer drugs. Several guidelines on this subject exist [see References (15)].

3. DOSAGE FORMS AND STRENGTHS
20 mg/10 mL single use vial
50 mg/30 mL single use vial

4. CONTRAINDICATIONS
DOXIL (doxorubicin HCl liposome injection) is contraindicated in patients who have a history of hypersensitivity reactions to a conventional formulation of doxorubicin HCl or the components of DOXIL [see Warnings and Precautions (5.2)].

DOXIL is contraindicated in nursing mothers [see Use in Specific Populations (8.3)].

HOW SUPPLIED/STORAGE AND HANDLING
DOXIL (doxorubicin HCl liposome injection) is supplied as a sterile, translucent, red liposomal dispersion in 10-mL or 30-mL glass, single use vials.

Each 10-mL vial contains 20 mg doxorubicin HCl at a concentration of 2 mg/mL.

Each 30-mL vial contains 50 mg doxorubicin HCl at a concentration of 2 mg/mL.

The following packages of six individually cartoned vials are available

mg in vial	fill volume	vial size	NDC #s
20 mg vial	10-mL	10-mL	17314-9600-1
50 mg vial	25-mL	30-mL	17314-9600-2

STEALTH® and DOXIL® are registered trademarks of ALZA Corporation

Reference(s)

1) [PACKAGE INSERT DATA] : Doxil® (doxorubicin hydrochloride) injectable, liposomal for intravenous use. [Ortho Biotech Products] LP Raritan, NJ 08869-0670. Revised: 01/2008.