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This medical policy (medical coverage guideline) is Copyright 2017, Blue Cross and Blue Shield of Florida (BCBSF). All Rights Reserved. You may not copy or use this document or disclose its contents without the express written permission of BCBSF. The medical codes referenced in this document may be proprietary and owned by others. BCBSF makes no claim of ownership of such codes. Our use of such codes in this document is for explanation and guidance and should not be construed as a license for their use by you. Before utilizing the codes, please be sure that to the extent required, you have secured any appropriate licenses for such use. Current Procedural Terminology (CPT) is copyright 2017 American Medical Association. All Rights Reserved. No fee schedules, basic units, relative values, or related listings are included in CPT. The AMA assumes no liability for the data contained herein. Applicable FARS/DFARS restrictions apply to government use. CPT® is a trademark of the American Medical Association. The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

09-J0000-91

Original Effective Date: 04/15/09

Reviewed: 04/08/15

Revised: 10/01/16

Subject: Doxorubicin HCl Liposome (Doxil®) Injection

THIS MEDICAL COVERAGE GUIDELINE IS NOT AN AUTHORIZATION, CERTIFICATION, EXPLANATION OF BENEFITS, OR A GUARANTEE OF PAYMENT, NOR DOES IT SUBSTITUTE FOR OR CONSTITUTE MEDICAL ADVICE. ALL MEDICAL DECISIONS ARE SOLELY THE RESPONSIBILITY OF THE PATIENT AND PHYSICIAN. BENEFITS ARE DETERMINED BY THE GROUP CONTRACT, MEMBER BENEFIT BOOKLET, AND/OR INDIVIDUAL SUBSCRIBER CERTIFICATE IN EFFECT AT THE TIME SERVICES WERE RENDERED. THIS MEDICAL COVERAGE GUIDELINE APPLIES TO ALL LINES OF BUSINESS UNLESS OTHERWISE NOTED IN THE PROGRAM EXCEPTIONS SECTION.

           
Dosage/ Administration Position Statement Billing/Coding Reimbursement Program Exceptions Definitions
           
Related Guidelines Other References Updates  
           

DESCRIPTION:

Liposomal doxorubicin formulations were developed to decrease the incidence of severe toxicity that has been observed with the conventional formulation of doxorubicin. The liposomal formulations incorporate doxorubicin into a liposomal carrier. In addition to the advantage of less toxicity, liposomal doxorubicin formulations are irritants, but not vesicants, upon extravasation. Liposomal doxorubicin (Doxil®) has been studied extensively in persons with AIDS-related advanced Kaposi’s sarcoma and refractory ovarian cancer. Liposomal doxorubicin was approved by the US Food and Drug Administration (FDA) in November 1995 as second-line treatment for Kaposi’s sarcoma. Under priority review in 1999, the FDA approved liposomal doxorubicin for metastatic ovarian cancer that is refractory to cisplatin- and paclitaxel-based chemotherapy. The approval was extended in 2005 to include ovarian cancer that has progressed or recurred following platinum-based chemotherapy. Liposomal doxorubicin was granted orphan designation by the FDA for the treatment of ovarian cancer in 1998 and multiple myeloma in 2004. In May 2007, the FDA approved liposomal doxorubicin as combination therapy with bortezomib (Velcade®) to treat persons with multiple myeloma who have received at least one prior therapy; efficacy of combination treatment was established in bortezomib-naïve subjects.

In 2012, due to a severe national shortage of Doxil, the FDA permitted temporary importation of Lipodox (doxorubicin hydrochloride liposome injection) by Sun Pharma Global FZE and its authorized distributor, Caraco Pharmaceutical Laboratories Ltd. The vials are manufactured in India at an FDA-inspected facility and contain the same active ingredient at the same concentration (2 mg/mL).

National Comprehensive Cancer Network (NCCN) guidelines support liposomal doxorubicin for the treatment of a variety of cancers including AIDS-related Kaposi’s sarcoma, invasive breast cancer, multiple myeloma, ovarian cancer, soft tissue sarcoma, non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, and endometrial carcinoma.

POSITION STATEMENT:

Liposomal doxorubicin (Doxil®) meets the definition of medical necessity when administered for ANY of the following indications:

1. AIDS-related Kaposi sarcoma (KS) when dosage does not exceed 20 mg/meter squared.

2. Desmoid tumor (a.k.a., aggressive fibromatosis) when dosage does not exceed 50 mg/meter squared.

3. First-line treatment of ovarian cancer (including fallopian tube carcinoma and primary peritoneal carcinoma) when dosage does not exceed 30 mg/meter squared.

4. Refractory, previously-treated ovarian cancer (including fallopian tube carcinoma and primary peritoneal carcinoma) when dosage does not exceed 50 mg/meter squared.

5. Invasive breast cancer when dosage does not exceed 50 mg/meter squared.

6. Soft tissue sarcoma when dosage does not exceed 50 mg/meter squared.

7. Anaplastic rhabdomyosarcoma (a.k.a., pleomorphic rhabdomyosarcoma) when dosage does not exceed 50 mg/meter squared.

8. Angiosarcoma when dosage does not exceed 20 mg/meter squared.

9. Metastatic dermatofibrosarcoma protuberans (DFSP) when dosage does not exceed 50 mg/meter squared.

10. Non-Hodgkin’s lymphoma (including all subtypes such as multicentric Castleman’s disease, diffuse large B-cell lymphoma, Mycosis Fungoides, Sézary Syndrome, MALT lymphomas, etc.) when dosage does not exceed 30 mg/meter squared.

11. Hodgkin’s lymphoma when dosage does not exceed 20 mg/meter squared.

12. Uterine neoplasm (i.e., endometrial carcinoma, uterine sarcoma) when dosage does not exceed 50 mg/meter squared.

13. First-line treatment of multiple myeloma when dosage does not exceed 40 mg/meter squared.

14. Refractory, previously-treated multiple myeloma in combination with bortezomib when dosage does not exceed 30 mg/meter squared.

Approval duration: 1 year

DOSAGE/ADMINISTRATION:

THIS INFORMATION IS PROVIDED FOR INFORMATIONAL PURPOSES ONLY AND SHOULD NOT BE USED AS A SOURCE FOR MAKING PRESCRIBING OR OTHER MEDICAL DETERMINATIONS. PROVIDERS SHOULD REFER TO THE MANUFACTURER’S FULL PRESCRIBING INFORMATION FOR DOSAGE GUIDELINES AND OTHER INFORMATION RELATED TO THIS MEDICATION BEFORE MAKING ANY CLINICAL DECISIONS REGARDING ITS USAGE.

FDA-approved: doxorubicin liposome injection is indicated for the treatment of ovarian cancer after failure of platinum-based chemotherapy, AIDS-related Kaposi’s sarcoma after failure or intolerance of prior systemic chemotherapy, and in the treatment of multiple myeloma in combination with bortezomib in persons who have not previously received bortezomib and have received at least one prior therapy. Doxorubicin liposomal injection should be administered at an initial rate of 1 mg/min to minimize the risk of infusion reactions. If no infusion related reactions occur, the rate of infusion should be increased to complete the infusion administration over 1 hour. Do NOT use with in-line filters or mix with other medications. Table 1 lists the FDA-approved indications and recommended dosage regimens. The maximum lifetime cumulative dose is 550 mg/m2 in most persons; for those having received mediastinal radiation or other cardiotoxic drugs, the maximum lifetime cumulative dose is 400 mg/m2.

Table 1

FDA-approved indications and dosage regimens

Indication

Dose

AIDS-related Kaposi’s sarcoma

20 mg/m2 IV every 3 weeks until disease progression or unacceptable toxicity.

Multiple Myeloma

Following bortezomib administration, 30 mg/m2 IV on day 4 every 3 weeks for eight cycles or until disease progression or unacceptable toxicity.

(bortezomib: 1.3 mg/m2 bolus on days 1, 4, 8 and 11)

Ovarian Cancer

50 mg/m2 every 4 weeks until disease progression or unacceptable toxicity.

IV, intravenous

Dose Adjustment

Hepatic Impairment: the dose should be reduced if the bilirubin level is 1.2 mg/dL or greater. Specific dosage recommendations are not given in the package insert; however, the following can be used as a general guideline.

• Serum bilirubin 1.2 to 3 mg/dL: give ½ the normal dose

• Serum bilirubin greater than 3 mg/dL: give ¼ the normal dose.

• Toxicity: adverse reactions, such as hand-foot syndrome, hematologic toxicities, and stomatitis may be managed by dose delay and adjustments. Following the first appearance of a Grade 2 or higher adverse reaction, the dosing should be adjusted or delayed as described in the package insert. Once the dose has been reduced, it should not be increased at a later time.

Drug Availability: doxorubicin liposomal injection is supplied as a 20 mg/10mL and 50 mg/25 mL single-use vial.

PRECAUTIONS:

Boxed Warning

1. Cardiotoxicity including myocardial damage that may lead to congestive heart failure may occur. Please refer to dosage and administration section for maximum lifetime cumulative dose recommendations.

2. Acute infusion reactions have been reported in up to 10% of persons administered doxorubicin liposomal. Medications/emergency equipment to treat such reactions should be available for immediate use. The reactions are sometimes reversible upon terminating the infusion or slowing the infusion rate.

Contraindications

• Members who have a history of severe hypersensitivity reactions, including anaphylaxis, to doxorubicin HCl.

Warnings

1. Do NOT substitute liposomal doxorubicin (Doxil) on a mg per mg basis with doxorubicin hydrochloride (Adriamycin).

2. Do NOT administer as an undiluted suspension or as an intravenous bolus.

3. Reduce the dose in members with hepatic dysfunction. Refer to dosage and administration section for additional information.

4. Hand-Foot Syndrome: may require dose modification or discontinuation.

5. Radiation recall reaction may occur.

6. Doxorubicin can cause fetal harm when administered to pregnant women. Advise females and males of reproductive potential to use effective contraception during and for 6 months after treatment.

7. Doxorubicin may potentiate the toxicity of other anticancer therapies.

8. Complete blood counts, including platelet counts should be obtained frequently and at a minimum prior to each dose of doxorubicin.

9. Secondary oral cancers, primarily squamous cell carcinoma, have been reported from post-marketing experience in patients with long-term (more than one year) exposure. Examine patients at regular intervals for the presence of oral ulceration or with any oral discomfort that may be indicative of secondary oral cancer.

BILLING/CODING INFORMATION:

The following codes may be used to describe:

HCPCS Coding:

Q2049

Injection, doxorubicin hydrochloride, liposomal, imported Lipodox, 10 mg

Q2050

Injection, doxorubicin hydrochloride, liposomal, not otherwise specified, 10 mg

ICD-10 Diagnoses Codes That Support Medical Necessity: (Effective 10/01/15)

C44.99

Other specified malignant neoplasm of skin, unspecified

C46.0 – C46.9

Kaposi’s sarcoma

C47.8

Malignant neoplasm of overlapping sites of peripheral nerves and autonomic nervous system

C48.0 – C49.9

Malignant neoplasm of retroperitoneum and peritoneum and other connective and soft tissue

C50.011 – 50.929

Malignant neoplasm of breast

C53.0

Malignant neoplasm of endocervix

C54.0 – C54.9

Malignant neoplasm of body of uterus

C55

Malignant neoplasm of uterus, part unspecified

C56.0 – C57.4

Malignant neoplasm of ovary, fallopian tube, broad ligament, round ligament, parametrium and uterine adnexa, unspecified

C78.00

Secondary malignant neoplasm of unspecified lung

C81.00 – C81.99

Hodgkin lymphoma

C83.00 – C83.99

Non follicular lymphoma

C84.00 – C84.09

Mycosis fungoides; unspecified site; lymph nodes of head, face, and neck; intrathoracic lymph nodes; intra-abdominal lymph nodes; lymph nodes of axilla and upper limb; lymph nodes of inguinal region and lower limb; intrapelvic lymph nodes; spleen; lymph nodes of multiple sites; extranodal and solid organ sites.

C84.1-C84.19

Sézary disease, unspecified site; lymph nodes of head, face, and neck; intrathoracic lymph nodes; intra-abdominal lymph nodes; lymph nodes of axilla and upper limb; lymph nodes of inguinal region and lower limb; intrapelvic lymph nodes; spleen; lymph nodes of multiple sites; extranodal and solid organ sites.

C88.8

Other malignant immunoproliferative diseases

C88.9

Malignant immunoproliferative disease, unspecified

C90.00 – C90.12

Multiple myeloma and plasma cell leukemia

D47.Z2

Castleman disease

D47.Z9

Other specified neoplasms of uncertain behavior of lymphoid, hematopoietic and related tissue

D48.1

Neoplasm of uncertain behavior of connective and other soft tissue

REIMBURSEMENT INFORMATION:

Refer to section entitled POSITION STATEMENT.

PROGRAM EXCEPTIONS:

Federal Employee Program (FEP): Follow FEP guidelines.

State Account Organization (SAO): Follow SAO guidelines.

Medicare Advantage Products: No National Coverage Determination (NCD) was found at the time of the last guideline revised date. The following Local Coverage Determination (LCD) was reviewed on the last guideline revised date: Doxorubicin, Liposomal (Doxil/Lipodox), (L33722) located at fcso.com

DEFINITIONS:

No guideline specific definitions apply.

RELATED GUIDELINES:

Bortezomib (Velcade®) IV, 09-J0000-92
Carboplatin (Paraplatin®) IV, 09-J0000-93

Erythropoiesis Stimulating Agents, 09-J0000-31

Gemcitabine (Gemzar®), 09-J0000-96

Granulocyte Colony Stimulating Factors, 09-J0000-62

Interferon alfa-n3 (Alferon N Injection®), 09-J0000-33

Lenalidomide (Revlimid®), 09-J0000-80

Oprelvekin; Interleukin II (Neumega®), 09-J0000-63

Paclitaxel and Paclitaxel (protein-bound) IV, 09-J1000-05

Rituximab (Rituxan®), 09-J0000-59

Topotecan HCl (Hycamtin®) IV, 09-J1000-02

Trastuzumab (Herceptin®) Injection, 09-J0000-86

Vinorelbine Tartrate (Navelbine®) IV, 09-J1000-03

Zoledronic Acid IV, 09-J0000-72

OTHER:

None applicable.

REFERENCES:

  1. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2015. URL www.clinicalpharmacilogy-ip.com Accessed 3/19/15.
  2. Doxil (doxorubicin liposomal) [package insert]. Janssen Products, LP. Horsham (PA): January 2015.
  3. Doxorubicin liposomal injection. In: McEvoy GK, editor. AHFS drug information 2015 [monograph on the Internet]. Bethesda (MD): American Society of Health-System Pharmacists; 2015 [cited 2015 Mar 19]. Available from: http://online.statref.com. Subscription required to view.
  4. Micromedex Healthcare Series [Internet Database]. Greenwood Village, Colo: Thomson Healthcare. Updated periodically. Accessed 3/19/2015.
  5. National Comprehensive Cancer Network. Cancer Guidelines. Cancer Guidelines and Drugs and Biologics Compendium. Accessed 3/19/2015.
  6. URGENT – Doxil (Doxorubicin Hydrochloride Liposome Injection) Shortage Update. Sun Pharma Global FZE. January 27, 2012. Accessed 3/19/2015 at: http://www.fda.gov/downloads/Drugs/DrugSafety/DrugShortages/UCM292634.pdf.

COMMITTEE APPROVAL:

This Medical Coverage Guideline (MCG) was approved by the BCBSF Pharmacy Policy Committee on 04/08/15.

GUIDELINE UPDATE INFORMATION:

04/15/09

New Medical Coverage Guideline.

10/15/09

Revision to guideline; consisting of clarifying dosage and updating coding.

04/15/10

Review and revision to guideline; consisting of updating codes and references.

08/01/10

Revision to guideline; consisting of updating coding.

05/15/11

Review and revision to guideline; consisting of updating dosage section and references.

05/15/12

Review and revision to guideline; consisting of updating precautions, coding and references.

10/15/12

Revision to guideline; consisting of removing cervical cancer indication and updating coding.

01/01/13

Annual HCPCS Update; added J9002, removed J9001 and Q2048.

02/15/13

Revision to guideline; consisting of updating coding.

05/15/13

Review and revision to guideline; consisting of revising position statement to remove treatment of uterine sarcoma and adding endometrial carcinoma; revising and reformatting dosage/administration, precautions, and description sections; updating references and coding.

07/01/13

Revision to guideline; consisting of updating coding and Program Exceptions section.

12/15/13

Revision to guideline; consisting of adding new indication and updating coding.

01/01/14

Revision to guideline; consisting of code update.

05/15/14

Review and revision to guideline; consisting of updating position statement, references, and coding.

05/15/15

Review and revision to guideline; consisting of updating description, position statement and decision tree, dosage/administration, precautions, references, and coding.

10/01/15

Revision consisting of update to Program Exceptions section.

11/01/15

Revision: ICD-9 Codes deleted.

10/01/16

Revision: ICD-10 code updates.

Date Printed: August 22, 2017: 06:54 AM