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Off-label Drug Use

» Summary» Procedure Codes
» Description» Selected References
» Prior Approval» Policy History
» Policy

Medical Policy: 05.01.09 
Original Effective Date: July 2005 
Reviewed: August 2015 
Revised: August 2014 

Benefit Application
Benefit determinations are based on the applicable contract language in effect at the time the services were rendered. Exclusions, limitations or exceptions may apply. Benefits may vary based on contract, and individual member benefits must be verified. Wellmark determines medical necessity only if the benefit exists and no contract exclusions are applicable. This medical policy may not apply to FEP. Benefits are determined by the Federal Employee Program.

This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.


Off-label drug use is the use of a drug approved by the U.S. Food and Drug Administration (FDA) for other uses or in treatment regimens or patient populations that are not included in approved labeling.


The FDA approves drugs or specific indications that are included in the drug's labeling. When a drug is used for an indication other than those specifically included in the labeling, it is referred to as an off-label use. Many off-label uses are effective, well-documented in the literature, and widely used.


Unapproved uses of drugs include a variety of situations ranging from completely unstudied to thoroughly investigated drug uses where the FDA has not been asked for approval, whereas approved uses of drugs have been proved to be safe and effective by the FDA after the review of adequate and controlled clinical trials that have documented their use.


Prior Approval: 


Not applicable.



The off-label use of a drug may be considered medically necessary when the following criteria are met:


I. The patient has tried and failed established FDA approved and/or clinical guideline recommended therapy unless contraindicated.


II. The requested use is supported by at least one of the following drug compendia:

  • Thomson Micromedex DrugDex (DrugDex®) meeting each of the following:
    • Strength of Recommendation Class I or IIa; and
    • Strength of Evidence Category A or B and
    • Strength of Efficacy Class I or IIa (evidence favors efficacy)
  • Facts & Comparisons® documentation level 1 (good) or 2 (fair)
  • National Comprehensive Cancer Network (NCCN) Drugs and Biologics CompendiumTM Category of Evidence and Consensus 1 or 2A


  •  Scientific evidence demonstrates efficacy and safety for the requested use. The evidence must:
    • Consist of an adequate number of well-designed studies with sufficient numbers of patients in relation to the incidence of the disease.
    • Be published in major peer-reviewed journals that publish original manuscripts only after the manuscripts have been critically reviewed by unbiased independent experts for scientific accuracy, validity, and reliability.
    • Demonstrate consistent results across all studies.
    • Document positive health outcomes and demonstrate that the drug is as effective as or more effective than established alternatives.
    • Document improvements that are attainable outside the investigational setting. 

If criterion I and/or criterion II have not been satisfied, the requirements of the off-label drug use policy have not been met. 




Thomson Micromedex DrugDex® is a drug compendia that includes all FDA approved indications and off-label indications. Off-label indications are identified through routine monitoring of the primary
literature and medical information from the FDA, NIH, and CDC. They may also be identified through the consideration of external requests or suggestions for inclusion in DrugDex and then reviewed and evaluated for validity. DrugDex uses three evidence-based rating types for FDA-labeled and off-label indications that include efficacy, strength of recommendation and strength of evidence. All indications are assigned one rating for each of the three rating types. For the purpose of this policy, indications listed in DrugDex is determined to be medically necessary when the Strength of Recommendation is Class I or IIa and Strength of Evidence is Category A or B and Efficacy is Class I or IIa.


Facts & Comparisons® eAnswers is a drug compendia that provides up-to-date drug information including all FDA approved indications and off-label uses. An editorial review panel consisting of practicing physicians and pharmacists assign a documentation level to each monograph with level 1 being good and level 5 being poor. According to Facts and Comparisons, this panel critically evaluates monograph data and provides an authoritative consensus about whether the reviewed published information is considered sufficient to warrant prescribing in appropriate populations. For the purpose of this policy, indications listed in Facts and Comparisons® eAnswers is determined medically necessary when the documentation level is a 1 (good) or 2 (fair).


The National Comprehensive Cancer Network (NCCN) Drug & Biologics Compendium is a listing of agents with both FDA-approved indications and NCCN designated off-label indications derived from the NCCN Clinical Practice Guidelines in Oncology. As stated by NCCN, these off-label uses are based upon evaluation of evidence from literature combined with expert judgment in an evidence-based method. Each recommendation is designated with a Category of Evidence that reflects the quality of evidence and consensus on which the recommendation is based. For the purpose of this policy, indications listed in NCCN Drug and Biologics Compendium with a Category of Evidence and Consensus 1 or 2A are considered medically necessary.


Procedure Codes and Billing Guidelines: 

  • To report provider services, use appropriate CPT* codes, Alpha Numeric (HCPCS level 2) codes, Revenue codes, and/or diagnosis codes.


Selected References: 

1. U.S. Food and Drug Administration (FDA). Off-label and investigational use of marketed drugs, biologics, and medical devices.External Sitebr />2. DrugDex® SystemExternal Site (database online). Greenwood Village, CO: Thomson Micromedex. 
3. Facts and ComparisonsExternal Site® (database online). St. Louis, MO: Wolters Kluwer Health, Inc.   
4. National Comprehensive Cancer NetworkExternal Site®. NCCN Drugs & Biologic Compendium™ (database online).


Policy History: 

August 2015 - Annual Review, Policy Renewed

August 2014 - Annual Review, Policy Revised

August 2013 - Annual Review, Policy Revised

September 2012 - Annual Review, Policy Renewed

September 2011 - Annual Review, Policy Renewed


Wellmark medical policies address the complex issue of technology assessment of new and emerging treatments, devices, drugs, etc.   They are developed to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. Wellmark medical policies contain only a partial, general description of plan or program benefits and do not constitute a contract. Wellmark does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Wellmark or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. Our medical policies may be updated and therefore are subject to change without notice.

*Current Procedural Terminology © 2012 American Medical Association. All Rights Reserved.

Contact Information
New information or technology that would be relevant for Wellmark to consider when this policy is next reviewed may be submitted to:
  Wellmark Blue Cross and Blue Shield
  Medical Policy Analyst
  P.O. Box 9232
  Des Moines, IA 50306-9232
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