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Cardiovascular disease (CVD) is the most common cause of death in American women and accounts for a full one-third of all deaths.1 Although the common perception may be that CVD affects mainly men, there is equal prevalence of this disease between the genders by the age of 40, and by the age of 60 more women than men are affected. More women than men have died from CVD causes on a yearly basis since the mid 1980s, and whereas the CVD mortality has steadily declined in men over the past 30 years, it has remained steady in women until very recently when CVD mortality was noted to decrease for both genders.2 See accompanying article on page 277 The impact of cardiovascular disease (CVD) on the health status of American women is gaining more recognition and has become the focus of public education efforts such as the “Go Red for Women” campaign sponsored by the American Heart Association and the “Red Dress” project sponsored by the Department of Health and Human Services, the National Institutes of Health (NIH), and the National Heart Lung and Blood Institute (NHLBI). These programs are, in part, a response to the increasing awareness of cardiovascular disease as a major source of morbidity and mortality in U.S. women. The importance of CVD as a major source of mortality in women was recognized early on by federally funded institutes including the Public Health Service Task Force, which brought attention to concerns about the health information available to women and the historical lack of research focus on women’s health in its 1985 Report of the Public Health Service Task Force on Women’s Health Issues .3 In response to this report, the National Institutes of Health adopted a policy for the inclusion of women in clinical research …

DRUG labeling is of vital importance in guiding the safe and effective use of approved drugs. Drug labels represent the most visible expression of months or years of scientific review by physicians and scientists at the U.S. Food and Drug Administration (FDA), and they are also fundamental to the purpose and mission of the FDA. Creation of the FDA dates to the 1906 passage of the Food and Drugs Act, which prohibited the manufacture and interstate shipment of adulterated and misbranded foods and drugs.†A 1937 disaster, in which more than 100 people died after ingestion of Elixir Sulfanilamide, precipitated the Federal Food, Drug, and Cosmetic Act of 1938, which, for the first time in U.S. history, required demonstration of safety before marketing new drugs. Elixir Sulfanilamide contained diethylene glycol and had never been tested for safety. In 1960, a marketing application for the drug thalidomide was submitted to the FDA. Withstanding enormous pressure from the applicant, FDA reviewers, including Frances Kelsey, M.D., Ph.D., a medical officer at the Center for Drug Evaluation and Research at the FDA (Washington D.C.),‡determined that inadequate data were available to support the safety of the drug product despite its already widespread use throughout the rest of the world. The application was not approved. After thousands of children in 46 countries were born with deformities as a consequence of thalidomide use, leaving the United States relatively unscathed, a political movement for tighter drug controls in the United States gained popular support. The Drug Amendments of 1962 were the first to require demonstration of effectiveness before marketing, recognizing that the assessment of safety must also consider benefit. Since 1962, more than a thousand prescription drugs have had their labeling changed or have been taken off the market to reflect the scientific evidence (or lack thereof) documenting their safety and/or effectiveness.§Section 505 of the Federal Food, Drug, and Cosmetic Act (21 USC 355)∥currently specifies that approved drugs must be safe and effective for use under the conditions prescribed, recommended, or suggested in the labeling.Current regulations stipulate the following labeling requirements1:The Code of Federal Regulations provides the basic skeleton for drug labels,#specifying the section headings and content, as well as the order in which these sections should appear. Regulations have been proposed to improve on the current system of labeling by changing the format of drug labeling to make the information more useful and accessible to practitioners.2This proposal would partition the label into three parts: a Highlights section, an Index, and Comprehensive Prescribing Information.Most typically, the drug manufacturer drafts proposed labeling based on relevant available data. This includes data acquired during drug development, as well as publicly available data on the drug and other related drugs. FDA reviewers carefully scrutinize every phrase in the proposed label for completeness and fair balance and also to ensure that all statements are adequately supported by data.**Scientific experts outside of the FDA and the general public may also be consulted for advice on labeling, particularly in the case of difficult or controversial issues. Commonly, labels undergo one or more rounds of revisions before final approval.Generally, new indications for a drug require evidence of effectiveness based on data submitted from adequate and well-controlled studies (i.e. , generally more than one) conducted in humans under an Investigational New Drug application, under defined standards for data quality and integrity and the reporting of adverse events.††All relevant data must be submitted to a new drug application (NDA), including data from failed trials, along with complete protocols and protocol revisions. Supporting chemistry, pharmacokinetic, and preclinical (in vitro and animal) data are usually required as well. FDA grants indications only after its own internal review and analyses of these data by physicians, statisticians, chemists, clinical pharmacologists, toxicologists, and other relevant scientific and regulatory disciplines within the FDA. In addition, experts external to the FDA, including members of FDA advisory committees, may be consulted as needed. Medical literature, on which much off-label use is based, is usually not accepted as the sole basis for approval of a new drug indication. There are several reasons for this. First, the raw data, along with complete protocols and revisions, are usually unavailable for review. Second, the standards for data quality, integrity, monitoring, and adverse events reporting are often unknown. Last, the study sites are unavailable for inspection. The FDA must also consider the possibility that published literature may present a skewed or incomplete profile of the efficacy and safety of a drug for human use.This regulatory process can be illustrated using the examples of levobupivacaine (Chirocaine; Purdue Pharma LP, Stamford, CT) and of dexmedetomidine hydrochloride (Precedex; Hospira, Lake Forest, IL).‡‡Levobupivacaine (Chirocaine) was approved in 1999 for adult patients for the production of local or regional anesthesia for surgery and obstetrics, and for postoperative pain management. The NDA applicant studied more than 1,400 patients in a total of 27 clinical studies in the United States and Europe. These included 2 pharmacokinetic studies, 4 phase I pharmacodynamic studies examining neurologic and cardiovascular endpoints, 2 studies of epidural administration for cesarean delivery, 2 studies of epidural administration for labor analgesia, 2 studies of epidural infusion for operative procedures, 1 study of intrathecal injection for lower limb surgery, 4 studies of epidural infusion for postoperative pain, 7 studies of peripheral nerve blocks, and 3 pediatric studies, 2 of which were still ongoing at the time of NDA submission. Much of the preclinical support for this application was in the form of animal studies of levobupivacaine and bupivacaine (approved in 1972) that were available in the published literature. Before its approval, the FDA consulted the Anesthetic and Life Support Drugs Advisory Committee, which included a guest cardiac electrophysiology consultant, to discuss the relative safety of levobupivacaine compared with bupivacaine and how the product should be labeled with respect to cardiotoxicity. In addition, FDA chemists and microbiologists reviewed data and information related to the product chemistry, manufacturing, and quality before approval.Dexmedetomidine hydrochloride (Precedex), an α2-adrenoceptor agonist, was approved in 1999 for sedation of initially intubated and mechanically ventilated patients during treatment in an intensive care setting. It is to be administered by continuous infusion for not more than 24 h. The NDA applicant submitted full reports of animal pharmacokinetic, toxicology, and teratogenicity studies; two placebo-controlled human studies demonstrating the efficacy of dexmedetomidine; and a total human safety database of more than 3,038 subjects, of whom 1,473 were intensive care unit patients who received the drug by continuous infusion. Only 78 patients received dexmedetomidine for longer than 24 h, and no patient received the drug for longer than 40 h. No safety data in pediatric patients were submitted, and more than 500 patients older than 65 yr were studied, 129 of whom were aged 75 yr or older. Human pharmacokinetic data included evaluation in patients with renal failure after single administration and evaluation of pharmacokinetics with hepatic impairment, as well as analysis of the effects of age on pharmacokinetics in adults. In addition, the FDA inspected clinical trial sites and reviewed information related to the product chemistry, manufacturing, and quality before approval. The NDA applicant also agreed to seven phase IV commitments to address areas in which the FDA desired additional information that might be used to inform future labeling. These included (1) dog studies to evaluate general toxicology, effects on the hypothalamic-pituitary axis, and changes in drug metabolism after 2 weeks of drug infusion; (2) an animal study to evaluate the effects of the three major human metabolites of dexmedetomidine that are absent in rats and dogs; (3) preclinical mutagenicity studies to elucidate findings from studies submitted before approval; and (4) long-term continuous infusion studies in patients to evaluate the pharmacokinetics, safety, and extended effectiveness of dexmedetomidine in the intensive care unit setting and to evaluate the use of long-term infusions in patients with renal failure. To date, these commitments have not been deemed fulfilled in their entirety, and there have not been any labeling changes for dexmedetomidine (Precedex) that are based on these postmarketing commitments.After a drug has been approved for marketing, a supplemental application to the FDA is required to change the labeling to reflect a new indication. The supplemental application must present data to support the safety and effectiveness of the new indication. The data requirements for a supplemental application might not be as extensive as would be expected for a novel NDA application, depending on the nature of the supplement and the indication sought.For example, a supplemental application for ropivacaine (Naropin; AstraZeneca, Wilmington, DE) was approved in 2000 for changes in the labeling, including (1) use of the 0.75% concentration for major nerve block and for epidural administration for cesarean delivery (previously approved concentrations for these indications were 0.2% and 0.5%, respectively); (2) use of 0.2% ropivacaine (Naropin) for up to 72 h for postoperative pain (previously approved for up to 24 h only); and (3) a change in the recommended infusion range for thoracic epidural administration for postoperative pain from 4–8 ml/h of 0.2% ropivacaine (Naropin) to 6–14 ml/h. To support the new labeling recommendations, the NDA sponsor submitted the results of clinical trials in which 324 women received 0.75% ropivacaine by the lumbar epidural route for cesarean delivery, 119 patients received 0.75% ropivacaine for brachial plexus block, and 441 patients received epidural infusions of 0.2% ropivacaine for postoperative pain. Pharmacokinetic data were obtained in 8 of the 20 submitted clinical studies. The FDA also reviewed preclinical (in vitro and animal) studies investigating acute, subchronic, and chronic toxicity; pharmacokinetics; cardiovascular toxicity; reproductive toxicology; and genotoxicology before approval of the supplement.Generally, the FDA requires that indications reflect the likely clinical use of a drug to ensure that a drug is not approved for unrealistically narrow indications. For example, drug company XYZ might propose to develop a novel general anesthetic agent only for "general anesthesia for left foot bunionectomies" and submit data supporting only this indication. In such a case, the company might be asked for more data to support a broader indication that would realistically reflect the likely clinical use, or they would be asked to provide adequate justification that such a limited indication is appropriate. As a corollary, a very broad indication for "maintenance of general anesthesia" would not be supportable by submission of data only from healthy patients undergoing bunionectomy procedures.Food and Drug Administration guidance to industry states that "in general, drugs should be studied prior to approval in subjects representing a full range of patients likely to receive the drug once it is marketed. …"3Therefore, to the extent possible, sponsors are expected to study the full range of patients likely to receive drug for the desired indications. Further, recent legislation stipulates that new drug applications are specifically required to contain an assessment of the safety and effectiveness of the product in pediatric patients unless this requirement is waived or deferred.4In addition, drug product sponsors are generally expected to study elderly patients, and to investigate the effects of metabolic and renal impairment and drug–drug interactions when relevant.5–7In a new drug application, sponsors are also required to present effectiveness and safety data for important demographic subgroups, specifically sex, age, and racial subgroups.Current regulations also require specific labeling in the following subpopulations as applicable: pregnant women (including use during labor and delivery), nursing mothers, pediatric patients, and elderly patients.8However, with the exception of those few special populations defined by regulation or guidance, unless there are data to indicate a need for special study or labeling, it is generally not required, feasible, or even scientifically meaningful, to discuss all potential subpopulations in the label.Therefore, industry is encouraged to study drugs in the range of settings and populations reflecting their likely clinical use, including the range of likely comedications and comorbidities. Labels, in turn, are written to reflect the clinical trials that were performed to support them. However, these clinical trials cannot anticipate or thoroughly study all of the ways that a drug may be used after it is approved. Because every patient and clinical situation is unique in some way, this would truly be an impossible task. In spite of the best efforts of the FDA and the drug industry, neither labels nor the supporting clinical trials can comprehensively describe all potential labeled or off-label uses.What exactly is off-label use, and what are the implications for the anesthesia practitioner? Any use of a drug for a condition or in a manner not appearing in the drug's approved label is considered off-label. This lack of approval is most commonly because data have not been submitted to the FDA to support the safety and efficacy of that use, not necessarily because there has been an adverse finding with respect to safety or efficacy. Off-label use most often describes a deviation from the labeled indication, dosage form, dose regimen, or patient population. However, any significant departure from the approved labeling or any use that is not described in the approved label may be considered to be off-label. When off-label uses are associated with a particular safety hazard, they may be described in the Contraindications, Warnings, or Precautions sections of the label. However, although all contraindicated uses are off-label uses, the Warnings and Precautions sections may discuss both labeled and off-label uses.For example, dexmedetomidine (Precedex) is indicated for sedation of initially intubated and mechanically ventilated patients during treatment in an intensive care setting. It is to be administered by continuous infusion for not more than 24 h. In this case, the use of dexmedetomidine outside an intensive care setting or in non–mechanically ventilated patients, such as for monitored anesthesia care sedation in the operating room, would be considered off-label. Similarly, infusions of dexmedetomidine lasting longer than 24 h are also off-label, as noted in the Indications and Usage, Precautions, and Dosage and Administration sections of the label. Data have not been submitted to the FDA to support the safe and effective use of dexmedetomidine outside the labeled indications, and for monitored anesthesia care sedation or long-term infusions to be reflected in the FDA-approved labeling, an application would need to be submitted to the FDA with adequate supporting data.The following are additional examples of off-label uses in anesthesiology:Where does that leave the individual anesthesiologist who, based on his or her own knowledge of the medical literature, medical judgment, and experience, believes that a particular off-label use would be safe and effective for the patient at hand? Anesthesiology is unique among medical specialties in the methods by which practitioners administer drugs that they prescribe. Anesthesiologists administer drugs with their own hands and often do not conform to a fixed algorithm. Instead, drug use is tailored to effect and to the individual needs of the patient, as well as to surgical and medical conditions. Anesthesiology is a specialty that prides itself on innovation and resourcefulness. New routes and modes of administration, mixes, doses, and applications for medications are commonly used to solve complex problems.The FDA does not restrict a physician's discretionary use of an approved drug, which is considered the practice of medicine. In fact, it is recognized that off-label use can be essential to medical care, that it is not always investigational or experimental, and that there is no legal or ethical obligation for physicians to discuss FDA regulatory status issues with their patients.9For example, many drugs used in anesthesia have never been approved for use in children. Restricting anesthesiologists only to labeled uses would have a devastating effect on the practice of pediatric anesthesia, and indeed, practitioners restricting their practice in such a way might well be accused of engaging in poor medical practice. It is the physician's prerogative to use legally marketed drugs in a way that he or she believes is best for the individual patient, according to his or her medical judgment (outside of medical research).However, in this context, perhaps understandably, physicians are often unfamiliar with information available in drug labels and even are unaware of basic information the labeling for drugs that they use, such as indications, dosage and administration and are many other reasons that physicians might not have many on their medical practice is and labels may be as to and often cannot the information they are in the label. practitioners may the information contained in the label with and of the for use in drug labeling and practice is illustrated by the drug In 2 yr after it was approved for marketing, a was to the label because of the of related to The label contraindicated use in patients drugs that and the labeling change was by the of a After the of these contraindicated use of in a of practice sites was to in of In the was to other patient at This change was by the of a and of these the of contraindicated use recent history, several effective drugs such as have been from the market because labeling has been in and adverse are very reasons for anesthesiologists to and the of drug labels and to carefully off-label The label much important information that can inform such are the and should what these are and the for in order to inform on when a particular patient may despite an is as important to the label is a particular use is not because data demonstrating safety and effectiveness do not or have never been submitted to the there is no of in the label of a general anesthetic drug, is use in this For the individual who is not to or a drug, the of use in is off-label may be The more relevant is can the drug be used and in and use a of for which the FDA has a that the the in the labeled populations and for individual patients within that the range of and may be even to the extent that some individual patients within the indicated may adverse events that are not by individual benefit. Off-label uses represent a of and unless as would be reflected in a specific labeled or the FDA has not been with adequate data to make a of safety and efficacy for the indication. The label is a to present those conditions in which safety and efficacy have been and to the trials and data that were used to support these As required by regulation and as labeling describes specific and that may for special use is contraindicated in this might be considered a of the adult that was studied to support the drug's indication. However, are not in the it is also likely that they not represent a of the total clinical database to make use of the drug in this should from the adult population. The label describes the important clinical trials and available information on pharmacokinetic, and safety and special this the is expected to clinical judgment in the best use of the drug in the individual patient at may require of dose based on from the general in and of renal and of older drugs for which are available have limited to develop new drug indications. as the clinical use of these drugs clinical use may from the approved labeling, and clinical judgment and ongoing medical may on an important in guiding their of this is the NDA for which was submitted to the FDA in the is approved only for and injection in patients aged 2 yr and older. the widespread use of by intrathecal and epidural and the use of this drug in pediatric patients than 2 data demonstrating the safety and efficacy of these uses have never been submitted to the FDA to support the of these indications to the anesthesiologist should consider several other when off-label use of a data and pharmacokinetic data usually inform labeled Off-label populations and indications have data to indications for new routes of administration and new populations are generally supported by studies in animal In these it is to more the potential profile for drugs in ways that are not in such as by of at the proposed human and data are often unavailable to support the safety of off-label routes of administration or of of or longer than approved and routes of who to administer a drug that is labeled only for use by the or intrathecal route should that the potential for local may not have been thoroughly in those for that Drugs that are used by routes may also have very of than by the approved a situation that may in very drug efficacy and safety for of are often defined by the clinical and preclinical trials from which safety and efficacy data are available only for a limited of may also be limited by specific related to safety or in which case these are usually in the label. may also into For example, assessment of safety for labeling into the potential to drug, and drugs that are approved only for use may in to patients For example, is approved only for of general anesthesia and for of anesthesia during operative infusion of is off-label and has been associated with In addition, many drugs used by pain and or with use of these drugs is not in clinical trials, the may not have adequate information to with use and may not even be of the efficacy of the are also a of and issues of particular to anesthesia For example, drugs approved for epidural or intrathecal use may be to standards than medications with respect to potential to and (including This is a Anesthesiologists commonly use drugs by routes that are not approved for such The and concentrations of and are generally not in the product labeling may the drug is anesthesiologists may to for epidural or intrathecal use, they may not always which drug contain For example, the labels to some of not the of these The had to the to that In addition, drugs can from the product in the of and that the applicant and the and provides information that the do not the safety or efficacy of the drug product for the labeled although the product may contain a or no a of that product may or may not contain that and it may or may not contain a are often in the ways that they and drugs for these are not specifically in the these may be considered off-label The Dosage and Administration section of the label information and administration of the dosage These are supported by data demonstrating and of the drug in the final In addition, drugs are tested for and with with which they into Anesthesiologists and drugs off-label should be of the of and After the FDA received reports of of with FDA a label to Before this the label was on of these drugs. drug labels do not anticipate the range of clinical is the practice of to that contain is a that has been associated with adverse events in particularly to reproductive in in have concentrations under use and conditions. However, is to in into that contain The extent and time for the of of into which is and the potential for to humans related to such have not been Anesthesiologists should be and of drugs outside their not described in the label. When or drugs off-label, practitioners should be in for and for drug When these events do practitioners should are the best of for an individual However, information from trials, the individual may be at a in this Drug effects from patient to patient and from situation to situation in the In addition, relatively adverse events may not be as potential events in clinical practice. This potential is particularly in the and surgical an in which adverse events are and in which there are usually potential for adverse is on individual physicians to be of off-label use and to adverse events when they in the of both labeled and use of adverse reporting is a major by which the FDA can and safety information off-label use of drugs. information the patient, the clinical and the clinical supporting data the are to the effective analysis and of these adverse data. on how to adverse product or can be on the FDA may be submitted or by or after which they are into a database they undergo FDA labeling has implications for and marketing of drugs. Drug generally must conform to labeling and contain information and effectiveness as in the drug label. Drug sponsors are not to off-label uses of although they may medical literature relevant to such uses under some usually submission or a to submit an application for the off-label that the use is not FDA along with the approved labeling for the drug, must also such FDA itself has that a product has been approved for marketing, a may it for uses or in treatment or patient populations that are not included in approved labeling. new uses for drugs already on the market are often first and regulatory with respect to off-label uses of medications may be a of in the literature and in the However, it is that (1) the associated with off-label use represent a broad (2) the of off-label uses may the associated in patients, and (3) off-label use a vital in the practice and of have the to be well the drugs they are and to off-label use on scientific or on medical To best and consider the potential implications and of off-label use, it is that anesthesia practitioners be with the labels for the drugs that they use and the and of these

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