Off-label use

Off-label use is the practice of prescribing pharmaceuticals for an unapproved indication. 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. 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). 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. 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 is common

Off-label use of medications is very common. Generic drugs generally have no sponsor as their indications and use expands, and incentives are limited to initiate new clinical trials to generate additional data for approval agencies to expand indications of proprietary drugs. Up to one-fifth of all drugs are prescribed off label and amongst psychiatric drugs, off-label use rises to 31 %. 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.

A study published in 2006 found that off-label use was the most common in cardiac medications and anticonvulsants. This study also found that 73% of off-label use had little or no scientific support

By default use of non-approved drugs is common in obstetrics as, by 2010, during almost five decades of activity the FDA had approved only two drugs for obstetrical indications, namely oxytocin and cervidil. A small market and the high risk of medicolegal action, as exemplified by the Bendectin case, may explain the reluctance to develop drugs for approval.

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.. 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.

Regulations of off-label use in different countries

United States

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. The company paid $430 million to the federal government to settle the case.

Access to pharmaceutical industry documents have revealed marketing strategies used to promote drugs for off-label use. 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. 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. 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.

United Kingdom

Physicians in the United Kingdom can prescribe medications off-label. According to the British General Medical Council, off-label prescriptions must better serve patient needs than alternatives and must be supported by evidence or experience to demonstrate safety and efficacy.

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

• Actiq (oral transmucosal fentanyl citrate), a Schedule II controlled substance, is used off-label to treat moderate to severe chronic, non-malignant pain even though it is FDA-approved solely for breakthrough pain in cancer patients.
• Avastin has been currently been used for wet AMD, age-related macular degeneration.
• Bevacizumab has been used against wet age-related macular degeneration, as well as macular edema from diseases such as diabetic retinopathy and central retinal vein occlusion.
• Buprenorphine has been shown experimentally (1982-1995) to be effective against severe, refractory depression.
• Bupropion, when sold under the brand name Wellbutrin is indicated for depression. However, it is also sold under the name Zyban as a smoking cessation drug. In Ontario, Canada, smoking cessation drugs are not covered by provincial drug plans. Thus, a physician can write a prescription for Wellbutrin to assist with giving up the habit of smoking.
• Carbamazepine, or Tegretol, has been used as a mood stabilizer and is accepted treatment for bipolar disorder.
• Dexamethasone and Betamethasone in premature labor, to enhance pulmonary maturation of the fetus.
• Doxepin, has been used to treat Angiodema and severe allergic reactions due to its strong anti histamine properties.
• Gabapentin, approved for treatment of seizures and postherpetic neuralgia in adults, is used off-label for a variety of conditions including bipolar disorder, essential tremor, hot flashes, migraine prophylaxis, neuropathic pain syndromes, phantom limb syndrome, and restless leg syndrome.
• Magnesium sulfate in obstetrics for premature labor and preeclampsia.
• Methotrexate (MTX), approved for the treatment of choriocarcinoma, is frequently used for the medical treatment of an unruptured ectopic pregnancy. There is no FDA-approved drug for this purpose and there is little incentive to sponsor an unpatented drug such as MTX for FDA-approval.
• The SSRI medication sertraline is approved as an anti-depressant. It is also commonly prescribed off-label to help men suffering from premature ejaculation.
• Stimulants such as Amphetamine (Adderall) and Methylphenidate (Ritalin) are indicated for childhood attention deficit disorder Benzphetamine (Didrex)(ADD/ADHD), but are often prescribed to treat this condition in adults, as well. Atomoxetine (Strattera), a non-stimulant norepinephrine reuptake inhibitor is currently the only drug (In the United States) indicated for adult ADD. In Australia dextroamphetamine is indicated for adult ADHD treatment. While Atomoxetine is also indicated for the treatment in Australia, it represents only a minor percentage of the drugs prescribed for the condition, due to its prohibitively high price, and it not being currently subsidised by the Government's Pharmaceutical Benefits Scheme. By contrast, the stimulant medications methylphenidate and dextroamphetamine are. Stimulants are also used off-label to treat depression, usually in conjunction with a standard antidepressant drug.

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.

Research relating to off-label use

• Tabarrok A. Assessing the FDA via the anomaly of off-label drug prescribing. Independent Review. 2000. V;1:25-53.
• Walton SM, Schumock GT, Lee KV, Alexander GC, Melzter DO, Stafford RS. Prioritizing medications for policy and research initiatives examining off-label prescribing. Pharmocotherapy. 2008;28:1443-1452.
• Chen DT, Wynia MK, Moloney RM, Alexander GC. Physician knowledge of the FDA-approved indications of commonly prescribed drugs: results of a national survey Pharmacoepidemiology and Drug Safety. 2009;18:1-7.

See also

• Pharmaceutical marketing
• U.S. Food and Drug Administration

External references

• Article about the Bioethics of off-label prescribing.
• Recent FDA proposal to loosen off-label marketing restrictions.de:Off-Label-Use

fi:Off label -käyttö