Off-Label Use of Prescription Medication: a Literature Review
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REVIEW Off-label Use of Prescription Medication: A Literature Review Robert G. Smith, DPM, MSc, RPh, CPed WOUNDS 2010;22(4):78–86 Abstract: The following review will describe the available literature and outline the concept and practice of off-label prescribing. Phenytoin, From Shoe String Podiatry, misoprostol, and nifedipine will be critically reviewed with emphasis Ormond Beach, Florida on their functional components, mechanisms of action, and patient considerations regarding wound healing. Recipes of off-label medica- tions also will be offered. Address correspondence to: Robert G. Smith, DPM, MSc, RPh, CPed Shoe String Podiatry 723 Lucerne Cir. Ormond Beach, FL 32174 ound management guidelines have been established to assist Phone: 386-673-9933 healthcare professionals in providing the most advantageous Email: [email protected] Wtreatment to promote wound closure. Organized decisions that are often grounded in clinically based evidence from the medical com- pendium are essential tools wound care specialists employ to promote heal- ing. Unfortunately, the multitude of advertisements for wound dressings pos- sibly eclipses the fact that only small, poor-quality trials exist to support the use of manyREPRODUCE products.1 Nonetheless, attempts have been made to provide the educational tools necessary for making informed decisions using evi- dence-based medicine to select wound care products.2 Determining the most appropriate treatment or selection of a wound care product to satisfy a particular patient’s needs requires a delicate balance between knowledge and art. Secundum artem is a Latin phrase meaning “according to the art.” In medicine it is often taken to mean, “use your skill and judgment.” Agents that have been approved by the US Food and Drug Administration (FDA) to treat wounds include anesthetics, antibiotics, anti-infectives, enzymes for debridement, granulation stimulants, growth factors, and mois- ture enhancers. Numerous wound care dressings and topical medications line the shelves of pharmacies and hospitals, which makes the selection NOTprocess even more difficult. Despite the plethora of approved products, some wound care patients have healthcare needs that off-the-shelf prescrip- tion medicines do not meet. Off-label prescribing of customized medicines to help promote dermal wound closure has been employed by wound care specialists to meet these needs. The concept of off-label prescribing of approved pharmaceuticals has cre- ated much attention and led to myths and misconceptions regarding its prac- tice. Case studies exist in the literature regarding the use of topical pheny- 78 DOWOUNDS www.woundsresearch.com Smith toin, misoprostol, and nifedipine to treat wounds. It is for Table 1. Prescription recipes for wound care com- this reason that this review article has been written; to pounds. allow data from previously published literature to be pre- Compounds (Reference) Type sented and evaluated in the context of clinically based evidence to justify the current practice of prescribing of Misprostol 0.0024% Diabetic cream these agents off-label. Phenytoin 5% (42) A review of the available literature outlining the con- Lidocaine HCl 2% Topical powder cept and practice of off-label prescriptions is offered to Misprostol 0.0024%. serve as a foundation. Secondly, specific medications are Phenytoin 2% (43) critically reviewed regarding their mechanisms of action and patient considerations in the context of wound Metronidazole 2% Topical gel healing. Recommended off-label medication compounds Misprostol 0.0024% Phenytoin 5% (44) are presented for the treatment of cutaneous wounds (Table 1). Lidocaine HCl 2% Topical gel Misprostol 0.003% Off-label Prescribing Phenytoin 2.5% (45) Healthcare providers do not all fully understand the Gentamicin sulfate 0.2% Topical gel drug development and regulatory issues that exist. Two Misprostol 0.0024% factors that motivate a wound care specialist to choose Phenytoin 5% (46) one therapy over another when attempting to close a particular wound are: 1) an understanding of the scien- Misprostol 0.0024% Topical formula tific basis for a drug’s activity in a given disease state, and Phenytoin 5% Lidocaine HCl 4% (48) 2) the belief in the drug’s efficacy in achieving wound closure. It is currently illegal for pharmaceutical manu- Misprostol 0.0024% Topical formula facturers to promote their approved drugs for unap- Phenytoin 5% proved conditions.3 Off-label or unapproved prescribing Lidocaine HCl 4% refers to a registered medicine being prescribed for a use Metronidazole 2% (48) that is not included or disclaimed in the product infor- mation.4 Sufficient evidence exists in the medical litera- port of safety and efficacy for drugs, biological products, ture to justify some off-label practices. LiteratureREPRODUCE cita- and medical devices. The FDA will accept a foreign clini- tions are identified and explored so that the misconcep- cal study involving a drug or biological product not con- tion that off-label use of an approved medication is itself ducted under an investigational new drug (IND) applica- an illegal or risky endeavor for the clinicians can be tion only if the study conforms to the ethical principles addressed and any myths or misconceptions may be contained in the 1989 version of the Declaration of debunked.3–8 Helsinki. Another consideration regarding off-label pre- First, the decision of whether to use a drug for an off- scribing is that many wound care products are consid- label purpose is a matter of medical judgment and not ered medical devices. The FDA was prohibited from one of regulatory approval. The FDA has never had the intruding into medical practice with respect to off-label authority to regulate the practice of medicine.5 To build use of medical devices when Congress enacted section on this, a policy statement was issued in the December 214 of the Food and Drug Administration Modernization 1982 FDA Drug Bulletin specific to the use of approved Act (FDAMA).5 Finally, a review of the Medicare Benefit drugs for unlabeled indications: “The Federal Food, Drug, Policy Manual, chapter 15, section 50.42 endorses the NOT 8 and Cosmetic [FD&C] Act does not, however, limit the practice of off-label prescribing. Approved drugs used manner in which a physician may use an approved drug.” for indications other than what is identified on the offi- Additionally, once approved for marketing, a physician cial label may be covered under Medicare if the insur- may prescribe a drug product for uses or in treatment ance carrier determines the use to be medically accept- regimens or patient populations that are not included in able and that its use is consistent with the drug com- the approved labeling. Further, the FDA may accept clin- pendia, authoritative medical literature, and accepted ical studies conducted outside the United States in sup- standards of medical practice.8 DO Vol. 22, No. 4 April 2010 79 Smith The practice of off-label prescribing of drugs and federal laws designed to regulate mass-produced drugs. medical devices plays an important therapeutic role in Therefore, pharmacists should observe the same princi- many disease states, including psychiatric disorders, ples and levels of evidence when dispensing off-label human immunodeficiency virus (HIV), and diseases in medications that a physician applies when prescribing children and other patient populations that are under- off-label drugs. served by approved medicines. When medications and devices are used off-label for medical treatment, their pri- Medication Classes and Wound Healing mary purpose is to benefit the individual patient. Within Medications may exert their effects by either assisting the scope of medical practice, the clinician’s primary or interfering with the specific phases of wound healing. purpose and intention when using a product off-label is The effect of a particular medication on the wound heal- to enhance the wellbeing of the patient with an expec- ing process may depend on its mechanism of action, tation of success. It is clear that rapid developments in dosage, and route of administration in relation to the spe- medical science often outpace the speed with which reg- cific phase of the wound healing process.10 Specific med- ulatory authorities like the FDA can move to implement ications of interest to the wound care specialists include new legislation.5 Physicians may safely prescribe any misprostol, nifedipine, and phenytoin. drug off-label provided he or she practices a standard of A search profile was compiled using key terms to per- care based on sound evidence.6,7 Williams8 states that off- form Boolean logic electronic searches to identify rela- label drug use may constitute the current standard of tive primary literature citations from 1967 to 2009 care, and failure to provide or discuss off-label therapy (Figure 1). Further, a manual review of citations’ refer- with patients may be considered malpractice. ences lists and bibliographies was undertaken to gather Uniformly accepted specific guidance to assist clini- any additional information that might have led to further cians attempting to make decisions about the appropri- material for this review. Citations (n = 317) were ateness of such prescriptions does not exist. Given the reviewed and evaluated as defined by the search limita- lack of FDA approval for off-label uses, many off-label uses of drugs are published in the literature as case reports, which allows other clinicians the opportunity to learn and use these