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FAQ: Off-label prescribing

General information

Common off-label prescribing practices

Definition of off-label prescribing.

Off-label use is the prescribing of a medication in a different dose, for a longer duration of time, or for a different medical indication than recommended in the prescribing information. Although the Food and Drug Administration (FDA) approves a drug for a specific indication, the physician has discretion to prescribe it as indicated above, or in combination with other medications in the treatment of patients.

In 1998, the agency proposed an amendment to the FDA Modernization Act that allows dissemination of information by manufacturers about unapproved uses of drugs and medical devices. The act allows a firm to disseminate peer-reviewed journal articles about an off-label indication of its product, provided the company files a supplemental application based on appropriate research to establish the safety and effectiveness of the unapproved use.

See the following FDA documents on the practice of off-label prescriptions


Liabilities of off-label prescribing

Although physicians may prescribe any drug off-label, many are reluctant to do so. The reason for this is that they put themselves at more risk for a malpractice law suit. Physicians make decisions to prescribe off-label based on clinical experience and clinical studies. Some off-label practices are all but routine, such as prescribing two blood-pressure medications to a patient, or blood-pressure medication in combination with a diuretic. Other off-label practices are life-saving. Almost all cancer chemotherapy and AIDS medication protocols are off-label.

However, clinical studies may not reveal medication complications. Rare complications can arise, and result in law suits. This is what happened with phen/fen, the combination of phentermine and fenfluramine. While pulmonary hypertension was a known side-effect of fenfluramine, heart valve damage was not. And because both diseases are so rare among patients taking fenfluramine, no cases of either were found in long term phen/fen studies by Michael Weintraub and Thomas A. Wadden. The phen/fen fiasco has made many physicians more conservative about off-label prescribing of weight loss medications.

For more on the pitfalls of off-label prescribing and other perspectives, see the articles below.


Drug approvals for new indications.

You may wonder why pharmaceutical companies don't just get FDA approval for weight loss drug combinations, like phentermine and Prozac (phen/pro), or to increase the recommended prescription duration of some of the older, but very effective weight loss drugs. The answer is simple, economics.

Sometimes it is worth getting a drug approved for a new indication, if there is a market base. This occurred with the drug bupropion, which is marketed as Wellbutrin for depression and Zyban for smoking cessation. There is no chemical difference between the two drugs. When the little purple pills come off the conveyor belt, half go one way and are stamped Zyban, and the others are stamped Wellbutrin. And for the $350 million or so that GlaxoWellcome (now GlaxoSmithKline) spent in getting Zyban approved, it received a shiny new 17-year patent. But the market for an effective smoking cessation drug is huge, and therefore worth the investment.

On the other hand, spending money for clinical trials which would not expand a drug's market base, makes very little sense from an economic standpoint even if a new patent was granted. At least this is how Eli Lilly felt when Michael Anchors approached the company in an effort to get the "phen/pro" combination approved. However, this is not the case with every pharmaceutical company. Currently the antidepressants Wellbutrin (bupropion) and Zoloft (sertraline), and Topamax (topiramate), an anti-seizure medication, are in clinical trials for weight loss.

For more information on weight loss trials on medications currently approved for other uses, see the articles below, and the Obesity-news article index:

Off-label prescription of older anti-obesity drugs.

The prescription weight loss drugs phentermine (Adipex-P, fastin, Ionamin), phendimetrazine (Bontril), diethylpropion (Tenuate), mazindol (Sanorex) and benzphetamine (Didrex), have been on the market for many years, and are no longer under patent. The prescribing information on each of them recommends prescription for only a few weeks use, however any of these medications can be and are prescribed long term, either continuously or intermittently.

A major reason why these drugs were not approved for longer periods of time is that obesity was not looked at as a chronic condition back in the 1970s when the new drug applications were filed with the FDA. Few if any health care providers saw weight loss drugs as anything other than a "jump start" for a long term commitment to a diet and exercise program, and most studies on anorexiants only ran for 20 weeks. Obesity medications were not a profit center for drug companies, and as a result, they were not willing to invest the funds for long-term clinical trials

However, in clinical practice these drugs have been shown to be effective over the long term, and there are several small longer term studies on phentermine, the most commonly prescribed stimulant weight loss drug. In addition, these medications are commonly used in combination with other medications and in varying doses.

See also:


Stimulants and SSRIs.

Since the withdrawal of fenfluramine and dexfenfluramine from the market in September in 1997, physicians have been trying to find a replacement. Despite the US approval of Xenical in 1998 and Meridia in 1997, the old combination of phentermine and fenfluramine (phen/fen) has been the most effective weight loss medication ever, in terms of percentage of body weight lost (15.9%).

Since that time, physicians have prescribed a number of specific serotonin reuptake inhibitors (SSRIs) in combination with phentermine or other stimulant weight-loss drugs, but there are no studies to date showing efficacy. Probably the most commonly prescribed, and most publicized combination, is that of phentermine and fluoxetine (Prozac) as popularized by Dr. Michael Anchors. In his book, Safer than Phen/fen, Anchors chronicles the stories of several of his patients who succeeded in losing weight using phen/pro, and other SSRI/stimulant combinations. Although Anchors was not able to convince Eli Lilly to get the phen/pro combination FDA approved, Lilly did fund a small study on patients in his office. According to Anchors, the results showed that 117 patients who took phentermine alone did not lose weight whereas 711 patients on phen-pro lost about 15% (average) of their total body weight in 9 months. This was an open-label study, but if the results could be replicated in a double-blind trial, this would indicate that phen/pro is as effective as phen/fen was.

While norepinephrine, the primary neurotransmitter on which phentermine acts, excites β-adrenoceptors, which decrease appetite, it also works on α-receptors which serve to increase appetite. Anchors hypothesizes that Prozac in the "phen/pro" combination serves to extend the action of phentermine, block phentermine's actions on alpha-1 and alpha-1 receptors, and work with the 5-HT2c receptor to reduce hunger.

In his book, Anchors did note that some of his male patients had unacceptable sexual side effects, and for that reason he tried other SSRI/stimulant combinations on them, including phentermine and Zoloft (sertraline). Other combinations include phentermine and Paxil (paroxetine), Celexa (citalopram) and even Serzone (nefazodone). Like with the combination of phentermine and Prozac, there are no clinical studies on efficacy, and sometimes several combinations need to be tested in different dosage strengths before good weight loss results are achieved.

For more information on SSRIs, stimulants and weight loss see:

From Obesity 101

From Obesity-news


Stimulant combinations.

Even before the withdrawal of fenfluramine, many physicians were hesitant to prescribe it, and some of them prescribed, and still prescribe, phentermine and phendimetrazine. The purpose of prescribing the combination is to avoid the tolerance problems that sometimes occur with a single agent. Other physicians will prescribe the combination of phentermine and Wellbutrin (bupropion), although this is less common.

For more information see the following article from Obesity-news:


Xenical and other weight loss drugs.

Because Xenical is a nonsystemic drug, it is safe to take with either stimulants or anti-depressants. There are no drug interactions between Xenical and centrally acting medications. This would seem to make it a likely candidate for use with existing medications to potentiate the weight loss effects. Unfortunately, studies conducted so far do not indicate that Xenical has an additive effect on weight loss when combined with other drugs. The combinations of phentermine and Xenical, and Meridia and Xenical have both been tested in pilot clinical trials with minimal results. But larger studies need to be conducted on these combinations before any definitive conclusions can be made.

For more information see the following articles from Obesity-news:

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