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From Wikipedia, the free encyclopedia

Off-label use is the practice of prescribing pharmaceuticals for an unapproved indication.[1] In the United States, the Food and Drug Administration Center for Drug Evaluation and Research (CDER) reviews a company's New Drug Application (NDA) for data from clinical trials to see if the results support the drug for a specific use or indication.[2] If satisfied that the drug is safe and effective, the drug's manufacturer and the FDA agree on specific language describing dosage, route of administration, and other information to be included on the drug's label. More detail is included in the drug's package insert.

The FDA approves a drug for prescription use, and will continue to regulate the pharmaceutical industry through the work of the Division for Drug Marketing, Advertisement and Communication (DDMAC).[3] The FDA does not have the legal authority to regulate the practice of the medicine, and the physician may prescribe a drug off label. Contrary to popular notion, it is legal in the United States and in many other countries to use drugs off label, including controlled substances such as opiates. Actiq, for example, is commonly prescribed off label even though it is a Schedule II controlled substance. While it would be legal for a physician to independently decide to prescribe a drug such as Actiq off-label, it is illegal for the company to promote off-label uses to prescribers. In fact, Cephalon, the maker of Actiq, was fined for illegal promotion of the drug in September 2008.[4] Under the Food, Drug, and Cosmetic Act (FDAC) at U.S.C. 21 §§301-97, manufacturers are prohibited from directly marketing a drug for a use other than the FDA approved indication. The Food and Drug Administration Modernization Act of 1997 created an exception to the prohibition of off-label marketing. Manufacturers are now able to provide medical practitioners with off-label information in response to an unsolicited request. 21 U.S.C. §360aaa-6.

Off-label use of medications is very common. Up to one-fifth of all drugs are prescribed off label and amongst psychiatric drugs, off-label use rises to 31% (Radley, et al. 2006).[5] New drugs are often not tested for safety and efficacy specifically in children. Therefore, it is believed that 50-75% of all medications prescribed by pediatricians in the U.S. are for off-label indications.[6]

Some drugs are used more frequently off label than for their original, FDA-approved indications. A 1991 study by the U.S. General Accounting Office found that one-third of all drug administrations to cancer patients were off label, and more than half of cancer patients received at least one drug for an off-label indication. A 1997 survey of 200 cancer doctors by the American Enterprise Institute and the American Cancer Society found that 60% of them prescribed drugs off label.[7]. Frequently, the standard of care for a particular type or stage of cancer involves the off-label use of one or more drugs. An example is the use of tricyclic antidepressants to treat neuropathic pain. This old class of antidepressants is now rarely used for clinical depression due to side effects, but the tricyclics are often effective for treating pain.


Research relating to off-label use

United States law

In the United States, FDA regulations permit physicians and other healthcare practitioners to prescribe approved medications for other than their approved indications. Marketing information for the drug will list one or more indications, that is, illnesses or medical conditions for which the drug has been shown to be both safe and effective. Pharmaceutical companies are not allowed to promote a drug for any other purpose without formal FDA approval.

However, once a drug has been approved for sale for one purpose, physicians are free to prescribe it for any other purpose that in their professional judgment is both safe and effective, and are not limited to official, FDA-approved indications. This off-label prescribing is most commonly done with older, generic medications that have found new uses but have not had the formal (and often costly) applications and studies required by the FDA to formally approve the drug for these new indications. However, there is usually extensive medical literature to support the off-label use.

In 1993, the US FDA approved gabapentin, marked by Pfizer under the name "Neurontin", only for treatment of seizures. Pfizer subsidiary Warner-Lambert used activities not usually associated with sales promotion, including continuing medical education and research, to promote gabapentin, so that within 5 years the drug was being widely used for the off-label treatment of pain and psychiatric conditions. In 2004, Warner-Lambert admitted to charges that it violated FDA regulations by promoting the drug for pain, psychiatric conditions, migraine, and other unapproved uses.[8] The company paid $430 million to the federal government to settle the case.[9]

Access to pharmaceutical industry documents have revealed marketing strategies used to promote drugs for off-label use.[10] The United States federal government is aggressively pursuing criminal and civil cases against pharmaceutical companies and their employees for promoting off-label uses of prescription drugs.[11] Between 2003 and 2008, U.S. federal prosecutors and state attorneys general brought more than a dozen cases against drug makers for off-label marketing and won more than $6 billion in criminal and civil settlements.[12] In September 2009, Pfizer paid $1.3 billion, the largest criminal fine ever imposed in the United States, for the off-label marketing of Bextra and three other drugs. Pfizer paid an additional $1 billion in civil penalties resulting from the same illegal activities.[13]

The position of the British General Medical Council on off-label prescribing may be found here.

Veterinary medicine

The veterinarian has a much smaller pharmacopeia available than does the human practitioner. Therefore, drugs are more likely to be used "off-label"—typically, this involves the use of a human medication in an animal, where there is no corresponding medication licenced for that species. This problem is compounded in "exotic" species (such as reptiles and rodents) where there are very few, if any licenced medications. In addition, especially in Europe, equine veterinarians are forced to use many drugs off-label, as the horse is classified as a "food-producing animal" and many veterinary drugs are labeled specifically not for use in animals intended for human consumption.

This practice is permitted by the Animal Medicinal Drug Use Clarification Act of 1994 (P.L. 103-396). FDA specifically prohibits extralabel use of a number of antibiotics, anti-inflammatory drugs and hormones in food producing animals. FDA also tightly controls the use of certain veterinary-prescribed drugs when administered in the feed of food-producing animals.[14]

Examples of off-label use (and non-use)

See also


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  7. ^ "Why is off-label use of drugs so common in cancer treatment?". National Cancer Institute. Retrieved 2009-07-12.  
  8. ^ Jane E. Henney, MD (15 August 2006). "Editorial: Safeguarding Patient Welfare: Who's In Charge?". Annals of Internal Medicine 145 (4): 305–307. PMID 16908923. Retrieved 2006-08-14.  
  9. ^ US Department of Justice Press Release: Warner-Lambert to Pay $430 Million to Resolve Criminal & Civil Health Care Liability Relating to Off-Label Promotion, retrieved 14 August 2006
  10. ^ Michael A. Steinman, MD; Lisa A. Bero, PhD; Mary-Margaret Chren, MD; and C. Seth Landefeld, MD (15 August 2006). "Narrative Review: The Promotion of Gabapentin: An Analysis of Internal Industry Documents" (abstract). Annals of Internal Medicine 145 (4): 284–293. PMID 16908919. Retrieved 2006-08-14.  
  11. ^ Erika Kelton, "Sales tactics, whistleblowers and qui tam lawsuits in the pharmaceutical industry"
  12. ^ Chris Adams (February 1, 2009). "Late move on drugs by Bush FDA could be dangerous". McClatchy Newspapers.  
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  14. ^ CRS Report for Congress: Agriculture: A Glossary of Terms, Programs, and Laws, 2005 Edition - Order Code 97-905
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  16. ^,,1799772,00.html
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  18. ^ Bodkin JA. et al. (1995): "Buprenorphine Treatment of Refractory Depression", Journal of Clinical Psychopharmacology 15:49-57. PMID 7714228
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External references

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