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With Precautions, Psychiatrists Need Not Shun off-Label Prescribing

Fear of lawsuits should not stop psychiatrists from prescribing medications for off-label indications as long as they make patient-centered decisions based on evidence and talk to patients about risks and benefits.

By focusing on patient care and providing appropriate informed consent, consultation-liaison psychiatrists can protect themselves from liability lawsuits regarding the use of antipsychotics and other medications for indications not approved by the Food and Drug Administratio (FDA). So said experts who led a workshop for consultation-liaison (C-L) psychiatrists at APA's 2008 annual meeting in Washington, D.C., in May.

Off-label use includes prescribing medications not only for unapproved indications, but also for unapproved dosages and patient populations, some of which may be subject to specific warnings by the FDA, said Ramaswamy Viswanathan, M.D. He is the director of the C-L Psychiatry Department at the State University of New York Downstate Medical Center in Brooklyn, N.Y. Intravenous infusion of haloperidol and the use of antipsychotics to treat dementia-related agitation are only two notable examples.

Off-label prescribing is also an integral part of medical practice, all presenters emphasized, because the FDA's authority is to regulate manufacturers' marketing of drug products, not how drugs should be prescribed. FDA-approved indications and labeling information do not dictate medical practice. If a drug company does not file an application with the FDA for a particular indication, this indication will not be approved regardless of whether clinical research supports this use.

In addition, safety warnings in the package insert are not consistently proportional to the actual risks among all drugs. For example, in the treatment for agitation in dementia, "benzodiazepines carry the indication for treating anxiety and no black-box warnings in the labeling [like atypical antipsychotics do], but they may be more problematic than atypical antipsychotics," said Viswanathan. "Haloperidol also has no black-box warning for this treatment, but it is not necessarily safer."

The criteria for approving a drug and requiring safety warnings are not based strictly on clinical evidence. Some of the older drugs carry more approved indications because the costs and standards of obtaining FDA approvals were different from those today. One example given by James Levenson, M.D., a professor of psychiatry and chair of the Division of Consultation-Liaison Psychiatry at the Virginia Commonwealth University School of Medicine in Richmond, was that chlorpromazine carries approved indications for schizophrenia, nausea and vomiting, restlessness and apprehension prior to surgery, acute intermittent porphyria, adjunct treatment for tetanus, manic-depressive-like illness, and intractable hiccups.

In contrast, many well-established indications have not been approved by the FDA, often because the drug is off patent or the cost of conducting clinical trials and seeking approval are deemed too high by the manufacturer. Lithium, for example, is approved only for bipolar mania and not bipolar depression. Most psychotropic drugs widely prescribed for children and adolescents have been approved only for adults.

Legal Risk for Off-Label Prescribing

"Like other aspects of practice, physicians may face civil liability related to medication prescription," Rebecca Brendel, M.D., J.D., a psychiatrist at the Law and Psychiatry Service and Consultation Psychiatry Service at Massachusetts General Hospital, pointed out. (She was not at the session, but her slides were presented by Levenson.) However, the FDA explicitly acknowledges that "off-label uses by prescribers may represent the standard of practice." The agency has proposed guidelines to allow drug companies to distribute journal article reprints discussing off-label use of their products to health care professionals (Psychiatric News, March 21).

State and local governments may establish regulations that influence medical practice. Viswanathan cited a recent law passed in the District of Columbia that requires physicians to tell patients when they are prescribing a drug off label and "provide the patient with information regarding the potential risks and side effects associated with using the medication for off-label use." In addition, lack of FDA approval is often used by third-party payers as an excuse to deny reimbursement for treatment.

Brendel noted that in court psychiatrists would have a strong defense if they base their decision on benefiting patients. It also helps if psychiatrists can show that their off-label prescribing is consistent with the local standard of practice, such as practice guidelines issued by APA and other specialty associations. These guidelines almost always contain evidence-based unapproved use for certain medications.

Informed Consent Is Key

The increased scrutiny for safety risks has led to the addition of a number of black-box warnings to the labeling of antipsychotics, antidepressants, and other medications for off-label uses that are common in practice. What should psychiatrists do if they believe prescribing an antipsychotic is appropriate for a particular dementia patient with severe agitation or an antidepressant other than the approved fluoxetine is appropriate for an adolescent?

The standard of practice is informed consent if there is substantial risk involved in prescribing a medication or a procedure, the presenters emphasized.

The essential elements of informed consent are diagnosis, the nature and purpose of the proposed treatment, risks and benefits of the treatment, and alternatives to proposed treatment and their risks and benefits, according to Paul Appelbaum, M.D., the Elizabeth K. Dollard Professor of Psychiatry, Medicine, and Law and director of the Division of Psychiatry, Law, and Ethics at Columbia University. Physicians' responsibility is to give patients appropriate information so that patients can make their own decision.

The standard for patient disclosure differs by state. In slightly more than half of all states, a physician is obligated to follow the professional standard, which requires giving patients as much information as a reasonable physician would. In other states, including New York and California, the patient-oriented standard is adopted, meaning that the physician should provide information that a reasonable patient would want.

"The rule of thumb is to disclose major risks even if they are not terribly frequent and frequent risks even if they are not terribly major," Appelbaum recommended. Priapism due to trazodone, for example, has been a reason for many liability lawsuits against psychiatrists because of alleged lack of warning and clearly falls into the rare but major category, Appelbaum and Levenson agreed.

Further complicating the informed consent practice is the question of the competence of patients with psychosis or dementia. Appelbaum suggested that psychiatrists apply the same judgment when informing a patient's family as they would when informing a competent patient.

Appelbaum suggested the following wording as one of many effective ways to begin a discussion with patients about off-label prescriptions: "You should know that this medication hasn't been approved by the FDA for this purpose. We don't think of that as a major issue. Several studies have shown it's effective, and it's commonly used in these situations. But if you have any questions about that, I'd be happy to answer them."

Communicate and Document

C-L psychiatrists may face additional challenges, the presenters and attendees at the workshop agreed. In some settings, psychiatrists often have to recommend off-label use of psychoactive drugs to their medical/surgical colleagues without direct communication with the patient, and nontreatment may carry serious risks that outweigh the risks of treatment. Viswanathan recommended basing one's decision on sound medical evidence, peer consultation, and local practice, as well as developing standard protocols for frequent off-label use for certain indications. Communicating with medical/surgical colleagues about the risks and benefits of a drug is the C-L psychiatrist's responsibility. In addition, psychiatrists should consistently document the reasons for off-label prescribing.

Most important, all presenters stressed that prescribing decisions should be made with a focus on patients' well-being. The fear of malpractice suits should not cause a physician to avoid prescribing a drug that is appropriate for an individual patient, Levenson commented. "You should never make a decision based on whether you might get sued."

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