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Doxil

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Doxil

Indications
Dosage
How Supplied

INDICATIONS

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.

AIDS-Related Kaposi's Sarcoma

DOXIL (doxorubicin hcl liposome injection) is indicated for the treatment of AIDS-related Kaposi's sarcoma in patients after failure of prior systemic chemotherapy or intolerance to such therapy.

Multiple Myeloma

DOXIL (doxorubicin hcl liposome injection) 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.

DOSAGE AND ADMINISTRATION

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]. DOXIL (doxorubicin hcl liposome injection) must not be given by the intramuscular or subcutaneous route.

Until specific compatibility data are available, it is not recommended that DOXIL (doxorubicin hcl liposome injection) be mixed with other drugs.

DOXIL (doxorubicin hcl liposome injection) should be considered an irritant and precautions should be taken to avoid extravasation. With intravenous administration of DOXIL (doxorubicin hcl liposome injection) , 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.

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], 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]. Pretreatment with or concomitant use of antiemetics should be considered.

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-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.

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 (doxorubicin hcl liposome injection) 30 mg/m² should be administered as a 1-hr intravenous infusion on day 4 following bortezomib. With the first DOXIL (doxorubicin hcl liposome injection) 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.

Dose Modification Guidelines

DOXIL (doxorubicin hcl liposome injection) 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].

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. I f 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 (doxorubicin hcl liposome injection) in combination with bortezomib who experience handfoot syndrome or stomatitis, the DOXIL (doxorubicin hcl liposome injection) dose should be modified as described in Tables 1 and 3 above. Table 4 describes dosage adjustments for DOXIL (doxorubicin hcl liposome injection) and bortezomib combination therapy. For bortezomib dosing and dosage adjustments, see manufacturer's prescribing information.

Table 4: Dosage adjustments for DOXIL (doxorubicin hcl liposome injection) + 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: 3 Platelet count < 25,000/mm³ Hemoglobin < 8g/dL 3 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 prescribing information for dosage adjustments in patients with neuropathic pain.

Patients With Impaired Hepatic Function

Limited clinical experience exists in treating patients with hepatic impairment with DOXIL (doxorubicin hcl liposome injection) . Based on experience with doxorubicin HCl, it is recommended that the DOXIL (doxorubicin hcl liposome injection) dosage be reduced if the bilirubin is elevated as follows: serum bilirubin 1.2 to 3.0 mg/dL - give ½ normal dose; serum bilirubin > 3 mg/dL - give ¼ normal dose.

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

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 (doxorubicin hcl liposome injection) 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 (doxorubicin hcl liposome injection) . Diluted DOXIL (doxorubicin hcl liposome injection) 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 (doxorubicin hcl liposome injection) 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.

Procedure for Proper Handling and Disposal

Caution should be exercised in the handling and preparation of DOXIL (doxorubicin hcl liposome injection) .

The use of gloves is required.

If DOXIL (doxorubicin hcl liposome injection) comes into contact with skin or mucosa, immediately wash thoroughly with soap and water.

DOXIL (doxorubicin hcl liposome injection) should be considered an irritant and precautions should be taken to avoid extravasation. With intravenous administration of DOXIL (doxorubicin hcl liposome injection) , 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 (doxorubicin hcl liposome injection) must not be given by the intramuscular or subcutaneous route.

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

HOW SUPPLIED

Dosage Forms And Strengths

  • 20 mg/10 mL single use vial
  • 50 mg/30 mL single use vial

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.

Refrigerate unopened vials of DOXIL (doxorubicin hcl liposome injection) 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 (doxorubicin hcl liposome injection) .

The following packages of six individually cartoned vials are available:

Table 19

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

Manufactured by: Ben Venue Laboratories, Inc., Bedford, OH 44146. Distributed by: Ortho Biotech Products, LP Raritan, NJ 08869-0670. FDA revision date: 6/10/2008

REFERENCES

1. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165.

2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html

3. NIH [2002]. 1999 recommendations for the safe handling of cytotoxic drugs. U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, NIH Publication No. 92-2621.

4. American Society of Health-System Pharmacists. (2006) ASHP Guidelines on Handling Hazardous Drugs.

5. Polovich, M., White, J. M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd. ed.) Pittsburgh, PA: Oncology Nursing Society.

Last reviewed on RxList: 7/8/2008
This monograph has been modified to include the generic and brand name in many instances.

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