"Off-Label"

Questions and Answers About "Off-Label" Use of Prescription Drugs

The following is a general summary of issues surrounding the "off-label" use of prescription drugs, and applications to potential Parkinson’s Disease treatments.

Q. What is "off-label" use of a drug?

A. "Off-label" (or "unapproved") use refers to the use of a drug for a disease not listed on the label, or in a dose or by a route not listed on the label.

Q. Is this legal?

A. Yes. Physicians, based on their knowledge and on available current information, may use a drug for a use not indicated in the "approved" labeling if it seems reasonable or appropriate.

Q. How common is this practice?

A. A sampling of prescriptions in 2001, found “21 percent were intended to treat medical conditions for which the drugs lacked specific approval from the U.S. Food and Drug Administration (FDA), though other published research suggested possible benefits. … about three of every four of those prescriptions were for conditions for which there were little or no evidence of the drugs' effectiveness.” (“Medications widely prescribed…”)

Q. Why does FDA permit this?

A. Since the early 1960s, the Food, Drug and Cosmetic Act has required that drugs used in the United States be both safe and effective. The label information, whether on the container, in the package insert, in the Physicians Desk Reference (PDR), or in any advertising, can indicate a drug's use only in certain "approved" doses and routes of administration for a particular condition. The Food and Drug Administration (in the U.S.; there are other similar agencies in other countries) has no authority over the practice of medicine. Their major responsibility is to assure that the evidence from clinical trials shows that the drug is safe and effective for use as indicated. They also have the authority to regulate the commercial promotion of approved drug products, which extends to prohibiting a company from promoting unapproved uses of its drugs.

Q What are some of the benefits and risks of off-label use?

It may offer flexibility and innovation in treatments.

Patients may be able to try an off-label prescription if FDA-approved drugs haven't worked for them.

Patients who are not eligible or able to participate in clinical trials may be offered possibly useful treatments.

It may help build individual knowledge bases of treatments that work best for specific patients.

Risks include:

Off-label uses are not given the same degree of scientific scrutiny for safety or efficacy as labeled indications.

A potential for dangerous interactions with other medications.

Possible denial of coverage under health insurance plans.

But for patients with serious and life-threatening medical conditions, the potential benefits of treatment might outweigh the increased risk associated with off-label use.

Q. Are FDA-approved drugs being researched and developed for other conditions?

A. Yes, due to escalating costs and long time frames of new drug development, some researchers and pharmaceutical companies are looking again at drugs that have already been approved by the FDA and combinations of these drugs that might be utilized for other conditions. In such cases, the clinical trial and FDA approval process could be significantly faster. Phase I trials might be waived if drug safety in humans has already been proven at the dose strength, frequency and duration stated in the label.

However, there are problems financing such trials. Due to economic concerns, most pharma companies may be hesitant to fund research on new indications for their products that are now available as generics. Another possibility is that the company may have carried out some studies on the off-label use as part of its initial application for marketing approval, but the FDA did not find that the studies met the required high standards for approval. For example, a drug may be labeled for use in a certain population (e.g., age) merely because there were too few patients in another population for the clinical trial to be statistically valid.

Q. Are any treatments in development for PD available to patients off-label?

A. Yes. Several potential new Parkinson’s treatments have been approved and/or are in use for other conditions. Among those being tracked in the Parkinson Pipeline Project database (www.pdpipeline.org), as of July 2007, are:

Abilify (aripiprazole) – Currently in use as an antipsychotic. In phase IV trial for treating psychosis associated with Parkinson’s.

Keppra (levetiracetam) – Currently in use as an antiepileptic. In phase IV clinical trial for treatment of levodopa-induced dyskinesia.

Zonegran (zonisamide) – Also in use as an antiepileptic. A phase III study in Japan of its use in Parkinson’s found it improved all main Parkinson disease symptoms including tremor and dyskinesias. Approval as a PD treatment is being applied for in Japan.

Namenda (memantine hydrochloride) - Currently used for moderate to severe Alzheimer's. In phase IV trial for treatment of cognitive impairment and dementia in Parkinson's Disease.

DynaCirc (isradipine) - Currently prescribed for high blood pressure and stroke. Pre-clinical research with mice found it might offer neuroprotection for dopamine neurons. Currently in a phase I trial to determine safety of higher doses.

Minocycline – Currently in use as an antibiotic. A phase II futility trial for possible neuroprotective benefits (NET-PD) concluded that further study would be worthwhile.

PD-02 (Creatine) – A dietary supplement used by athletes to improve performance. Since it plays a role in mitochondrial energy production, and there is evidence of mitochondrial dysfunction in Parkinson's Disease, it is thought creatine might provide neuroprotection. Currently in an NINDS phase III trial.

NOTE: The Parkinson Pipeline Project does not promote or recommend medications – either FDA approved or those in clinical development, labeled or off-label. These decisions should be made in consultation with patients’ doctors and pharmacists. The PPP believes that it is important for PWP to have information about all treatment options, so that they can make informed decisions.

Resources:

Bright, JL. Positive outcomes through the appropriate use of off-label Prescribing (letter). Archives of Internal Medicine, 2006: 166, 2555

Medications widely prescribed without scientific evidence, study finds. Stanford Univ. Center for Health Policy, CHP/PCOR News, May 8, 2006. Accessed at: http://healthpolicy.stanford.edu/news/medications_widely_prescribed_without_scientific_evidence_study_finds_20060508/#

Nightingale, Stuart L., Editorial, American Family Physician, August 1, 2003.

Off-label use of prescription drugs (NLM Bibliography, Dec. 1996) Accessed at: http://www.nlm.nih.gov/archive/20040830/pubs/cbm/offlabel.html

Radley, DC , Finklestein SN, Stafford R. Off-label prescribing among office based physicians. Archives of Internal Medicine, 2006: 166. 1021-6

Tiwary, A. Devesh, "Off-Label Use of Prescription Drugs should be Regulated by the FDA", accessed at http://leda.law.harvard.edu/leda/search/toc.php3?handle=HLS.Library.Leda/tiwarya-off_label_use

Authors of this article:

W. H. DeCamp, Parkinson Pipeline Project

L. Herman, Parkinson Pipeline Project, Therapies Coordinator

July 24, 2007f