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ABSTRACT Background. Rapid progress in dental pharmacotherapeutics requires that clinicians constantly update their knowledge of new drugs, drug interactions and useful therapeutic trends. This article is the first in a five-part series based on a 1998 International Association for Dental Research symposium entitled Adverse Drug Interactions in Dentistry: Separating the Myths From the Facts. The goal of the series is to identify specific adverse drug interactions that are relevant to the therapeutic agents commonly used in general dental practice: analgesics, antibiotics, sedatives, local anesthetics and vasoconstrictors. Methods. A group of dentist/clinical pharmacologists, with documented expertise in specific areas of dental therapeutics, reviewed the current literature regarding adverse drug interactions in dentistry. This expert panel evaluated the quality of information used to document these drug interactions and assess the severity of these drug reactions with respect to the drugs use in dental practice. Results. On the basis of the quality and severity of each reported interaction, the authors summarized the clinical importance of these drug interactions using a Significance Rating for Dental Drug Interactions. The participants presented their recommendations at the above-mentioned IADR symposium. Conclusions. Although thousands of drug interactions are described in the literature, the authors found many to be poorly documented or of minor importance to dental practitioners. For interactions that they determined to be relevant, the participants provided recommendations and precautions for preventing these potential complications. This article discusses the professional impact of drug interactions on dental practice; the classification and documentation of drug interactions; the determination of causality between drug interactions and adverse effects; risk factors; and unique characteristics of dental therapeutics. Subsequent articles will present specific summary recommendations for drug interactions associated with the use of antibiotics, analgesics, sedatives, and local anesthetics and vasoconstrictors. Clinical Implications. Although thousands of drug interactions have been reported in the literature, only a few are significantly associated with dental therapeutic agents. Avoiding these drug interactions will prevent potentially severe reactions in dental practice.

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ARTICLE 1
COVER STORY

ADVERSE DRUG INTERACTIONS IN DENTAL PRACTICE

PROFESSIONAL AND EDUCATIONAL IMPLICATIONS
Editors note. This article introduces a new department in The Journal of the American Dental Association called Pharmacology. Edited by JADA Associate Editor Paul A. Moore, D.M.D., Ph.D., the department is slated to appear in JADA at least every other month.

PART I OF A SERIES xpected changes in the nations demographics, patient populations and drug consumption make a comprehensive review and evaluation of drug interactions in dental practice particularly timely. The number and proportion of elderly dental patients in the United States continue to grow. The prevalence of edentulism and tooth loss among geriatric patients has decreased in the last decade, and subsequently the need for restorative dentistry and periodontal therapy will continue.1-3 Elderly patients tend to have more chronic health problems and take more medications. The recording of complex medical and drug histories has become the norm for many dental practitioners. The risks associated with new drugs and the implications of multiple-drug therapy challenge our understanding of clinical pharmacology and adverse drug interactions.

PAUL A. MOORE, D.M.D., PH.D.; TOMMY W. GAGE, D.D.S., PH.D.; ELLIOT V. HERSH, D.M.D., M.S., PH.D.; JOHN A. YAGIELA, D.D.S., PH.D.; DANIEL A. HAAS, D.D.S., PH.D.

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All marketed prescription drugs have undergone extensive human safety and efficacy evaluations (Phase II and III clinical trials) before being approved by the U.S. Food and Drug Administration, or FDA. This premarketing research and evaluation usually is performed for short periods on no more than several thousand healthy patients, and it rarely involves patients who are seriously ill or who are receiving concomitant drug therapy. fundamentals of basic science to quality patient care. As recommended in the 1993 Institute of Medicine publication on the future of dental education,5 a greater emphasis should be placed on case-oriented and problem-based learning that integrates basic and clinical science curricula. The inclusion in dental school curricula of information specific to drug interactions provides opportunities for clinically relevant instruction in the basic sciences and scientifically based instruction in the of an integrated dental curriculum. Equally challenging for dental educators is meeting practitioners needs for up-to-date continuing education. Continual learning is a lifetime enterprise for anyone in a health-related profession, and information transfer regarding current drug therapy is demanding because of the rapid changes in drug use that have occurred in the last few decades. For example, of the 20 drugs most frequently prescribed in 1997, only 10 existed in 1987.6 Additionally, 39 new drug entities were marketed by the pharmaceutical industry in 1997 in the United States.7 The knowledge of safe and effective drug therapy learned during dental school rapidly becomes irrelevant, and the need to obtain reliable new information is a constant challenge for practicing dentists. One of the most effective means of preventing adverse drug interactions is rapidly and clearly informing practitioners of the existence of these potential complications and recommending alternative therapeutic strategies. Patients who have chronic diseases, receive prescriptions from a number of physicians, and take many different types of drugs reinforce the need for a thorough patient evaluation. Dentists are expected to use reasonable prudence in taking a patients medical and drug history. The old axiom of First, know your patient is well-applied in these circumstances, enabling the practitioner to design a treatment plan that avoids potential adverse drug interactions. However, many obstacles exist to obtaining an accurate

ew newly approved drugs are required to undergo Phase IV studies, which monitor postmarketing adverse drug reactions, or ADRs, and interactions in the general population. However, as we will report in this series of articles, unsuspected drug interactions often are not elucidated until larger numbers of patientswho may have significant health problems and complex drug historieshave taken these new drugs. The recent withdrawal of mibefradil (Posicor, Roche Laboratories) after only one year of marketing because of reports of unexpected drug interactions is an excellent example of the need for careful monitoring of newly marketed drugs. By competing for drug-metabolizing liver enzymes, mibefradil therapy was found to increase the plasma concentrations of as many as 25 other coadministered medications, including erythromycin, an antibiotic commonly used in dentistry.4 An understanding of ADRs is important in dental education. For dental educators, case studies in dental therapeutics provide prime examples of the application of the relevant

The knowledge of safe and effective drug therapy learned during dental school rapidly becomes irrelevant, and the need to obtain reliable new information is a constant challenge for practicing dentists.
clinical sciences. Safe and effective drug administration requires a comprehensive understanding of pharmacology, human anatomy, physiology, biochemistry, microbiology, immunology and pathology that are affected by a drugs action. When more than one drug is administered, drug interactions can result that lead to unexpected and serious adverse effects. Knowledge of the basic mechanisms associated with clinically significant drug interactions is a valuable component

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medical and drug history. Patients cannot always remember the names and the dosages of the drugs they are taking, and many forget to include over-the-counter, or OTC, drugs in their histories. Older patients may have limited recall abilities. It is important to know not only which drugs a patient is taking, but also the dosage and duration of use. Patients taking higher dosages of drugs for longer periods could be at higher risk of experiencing a drug interaction. Consultation with prescribing physicians, the patients pharmacist and family members might be required in some circumstances. The dentist might need to order laboratory data to ensure a complete patient evaluation. ll drugs the patient is takingincluding prescription medications, OTC drugs, drugs of abuse and herbal remediesas well as compliance with drug regimens should be documented in the patients dental record. One should have a working knowledge of how these drugs act, how the body handles them, what dosing restrictions they have and any potential drug interactions associated with them. Selecting dental therapeutic agents with proven records of clinical efficacy and minimal risks is also recommended. Caution is particularly necessary when treating a high-risk patient. Because of the abundance of newly marketed drugs and drug combinations, one should be alert to possible unreported drug interactions until he or she gains experience with new drug entities.8 As health care providers, dental practitioners are responsible for monitoring potential interactions with medical drugs the patient might be taking at the time of dental treatment. It is possible for either the prescribing physician or pharmacist, or both, to miss a potential interaction that the dental practitioner can recognize while taking the patients history. Various electronic and printed resources are available to the dentist to check for these possible medical drug interactions. The Physicians Desk
CLASSIFICATION OF ADVERSE DRUG INTERACTIONS

It is possible for either the prescribing physician or pharmacist, or both, to miss a potential interaction that the dental practitioner can recognize while taking the patients history.
Reference, or PDR,9 provides complete product information for currently marketed drugs. Quick drug references such as Lexi-Comps Drug Information Handbook for Dentistry, Mosbys Dental Drug Reference and The Medical Letter Handbook of Adverse Drug Interactions are extremely useful guides.10-12 Additionally, the Internet has many Web sites that offer rapid access to drug information. A valuable review of electronic drug databases useful for dental practitioners recently was published.13

Not all drug interactions result in untoward effects. Many of the prescription analgesics used for postoperative pain management are formulated as combinations of peripherally acting analgesics and centrally acting opioids. Examples include acetaminophen and codeine (Tylenol with Codeine No. 3, McNeil Pharmaceuticals), ibuprofen and hydrocodone (Vicoprofen, Knoll Laboratories) and acetaminophen and oxycodone (Percocet, Endo Pharmaceuticals). Another example of advantageous multidrug therapy is intravenous sedation, using various combinations of a benzodiazepine, a short-acting opioid and methohexital. These combinations were developed to minimize the dosages of the individual drugs and optimize either the safety or efficacy of therapy. Although the drug interactions addressed in this series are limited to adverse reactions, beneficial interactions often have similar mechanisms. Various nomenclatures can be used to characterize drug interactions. Yagiela and Picozzi14 classified drug interactions into five categories: antagonism, potentiation, unexpected, summation and synergism. Application of these categories depends on whether the interaction is specific to a pharmacological effect of one of the drugs and whether the result is a decreased or an increased drug response. An increased response for a sedative drug might result in serious central nervous system, or CNS, toxicity, while a decreased response to an antibiotic might result in prolifera49

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TABLE

SIGNIFICANCE RATINGS FOR DENTAL DRUG INTERACTIONS.

SEVERITY RATING Major Potentially life threatening or capable of causing permanent damage Could cause deterioration of patients clinical status; additional treatment or hospitalization might be necessary Mild effects that are bothersome or unnoticed; should not significantly affect therapeutic outcome DOCUMENTATION RATING Established Probable Moderate Suspected Proved to occur in well-controlled clinical studies Very likely, but not proved clinically Could occur; some good data exist, but more study is needed Could occur; data are very limited Doubtful; there is no consistent and reliable evidence of an altered clinical effect

Minor

Possible Unlikely

CUMULATIVE RATING* Rating 1 2 3 4 5 Definition Major reactions that are established, probable or suspected Moderate reactions that are established, probable or suspected Minor reactions that are established, probable or suspected Major or moderate reactions that are possible Minor reactions that are possible; all reactions that are unlikely

* These cumulative ratings, which are based on the reactions severity and the strength of documentation regarding the interaction, have been modified for dental therapeutics from ratings of medical therapeutic agents by Tatro.21

tion of a serious orofacial infection. The categories are defined as follows: dantagonism indicates an interaction that decreases the clinical response of one drug when a second drug is administered; dpotentiation occurs when the combination of two drugs that do not share a common pharmacological activity results in a response that is greater than normal; dan unexpected drug interac50

tion is an adverse response that has not been observed for either of the drugs when they are administered alone; dsummation is the increased response that occurs when drugs with similar effects are administered together; dsynergism is the special situation in which the combination produces an exaggerated response that is greater than could be achieved by either drug administered alone at its maximally effective dose.

REPORTING ADVERSE DRUG INTERACTIONS IN DENTISTRY

Reliable information regarding adverse drug interactions specific to dental therapy can be difficult to obtain. Because the practice of dental medicine often is isolated within a community, an unusual or severe drug response that occurs in a dental office might not be welldocumented. Loss of a dentists professional reputation within the community and subsequent

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loss of patient referrals could be reasons for the underreporting of adverse reactions in dentistry. These problems could be overcome through greater access to malpractice insurance databases, encouragement of the publication of case reports and comprehensive use of the FDA-sponsored MEDWatch Medical Product Reporting Program.

RISK FACTORS FOR ADVERSE DRUG INTERACTIONS.

dUse of drugs that are highly bound to plasma proteins dUse of orally administered agents that have low bioavailability because of first-pass effect dAdministration to very young and elderly patients dAdministration to medically compromised patients dUse of drugs with small margins of safety (such as digoxin, warfarin, opioids) dUse of chronic drug therapies involving drugs that are excreted slowly

he MEDWatch program provides a database into which health care providers can place reports of adverse events and problems associated with drugs, biological agents and medical devices.15 Spontaneous reporting of ADRs by dental and medical practitioners through the MEDWatch program frequently provides the first information about such an interaction. Placing a report in the MEDWatch system requires only that a practitioner suspect that a reaction is related to an administered drug. A serious eventdefined as life-threatening and requiring hospitalization or some medical intervention to prevent permanent impairmentdefinitely should be reported to MEDWatch. The FDA acknowledges that dentists and physicians have justified concerns regarding their own and their patients privacy and therefore provides substantial protection against releasing to the public the identities of the prescribers and patients involved in these reports.16 ADRs can be reported to the MEDWatch program by calling 1-800-FDA-1088. There are many limitations to the information acquired through spontaneous reporting systems such as published case

reports, case series and the MEDWatch program. The most significant is that the actual incidence of a particular reaction is unknown. The rate and, therefore, the estimate of risk of a reported ADR could be one per 1,000 or one per 10,000,000, depending on the number of patients actually exposed to a particular drug or drug combination. Even when an estimate of the overall drug use can be made, the ADR rate is almost always less than the true incidence rate because of underreporting by prescribers. In the MEDWatch program, the number of ADR reports usually is higher for newly marketed drugs and for drug reactions that have received publicity in the media. The reports vary in quality and frequently are incomplete or inadequate for determining causal relationships.17
DETERMINING CAUSALITY

ADRs rarely occur in healthy patients or during simple dental procedures. The actual cause of a drug reaction often is multifaceted and results from a sequence of events or circumstances that increase the risk of a drug interaction. Consider a recently reported case involving

the antihistamine antagonist terfenadine (Seldane, Marion Merrell Dow Inc. [no longer marketed in the United States]), used to manage allergic rhinitis.18 Macrolide antibiotics such as erythromycin may inhibit certain metabolic isoenzymes located in the liver and gut wall (CYP3A4s), and subsequently increase the bioavailability of orally administered terfenadine.19 If bioavailability is improved, there is a significant increase in the systemic uptake of the parent drug, with subsequent elevation of its blood concentrations. Fatal cardiac arrhythmias associated with high terfenadine blood concentrations have been reported.20 In fact, recent evidence also has implicated a component of grapefruit juice in inhibition of these gut-wall enzymes.18 A 29-year-old Michigan man had been taking terfenadine twice daily for more than a year for allergic rhinitis. He had been in the habit of drinking grapefruit juice two to three times per week, and sometimes more often. One day after consuming two glasses of grapefruit juice, he was mowing the lawn. He became ill, stumbled into the house, collapsed and
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RESPONSE (PERCENTAGE)

100
Drugs A and B Toxicity

Drug A Efficacy 50

Drug A Toxicity

Shift to the left owing to a drug interaction

0 5 10 15 20 25 30 35 40 45 50 55 60

ED50 = 10 mg

LD50 = 50 mg

DOSE (MILLIGRAMS)
Figure. A shift in the therapeutic index of Drug A when administered in combination with Drug B. When administered alone, Drug A has a therapeutic index of 5.0 (50 milligrams/10 mg). In combination with Drug B, the therapeutic index has shifted to 4.0 (40 mg/10 mg). ED50: median effective dose. LD50: median lethal dose.

died. The postmortem plasma terfenadine blood concentration was extremely high. He also had an ethanol blood concentration exceeding the legal limit for driving and was found to have had cardiomegaly and hepatomegaly, although there was no indication that he had significant impairment of hepatic function.10

in the fatality? In establishing the significance of a case report and making recommendations for prescribing drugs, one needs to determine causality. As illustrated in this case, a reported adverse drug interaction can be causal, co-causal or only incidental.8
SIGNIFICANCE RATINGS FOR DENTAL DRUG INTERACTIONS

as the grapefruit juice-terfenadine drug interaction the cause of death? It is nearly impossible to confirm the mans compliance with the terfenadine dosing and, conceivably, he had taken additional doses before mowing the grass. To what extent did the existing cardiac and hepatic disease contribute to the outcome? Was the elevated alcohol level involved with the cardiac sensitivity? Although not reported, was cigarette smoking involved

The certainty of a true drug interaction, therefore, is based in part on the quality and quantity of documentation. Some reactions have been known for years and are well-documented, whereas others have been established through extrapolation from limited clinical information. Some suggested interactions are, in fact, theoretically based on our understanding of drug mechanisms but have never been reported in a clinical situation. Many reactions in-

volve dental therapeutic agents but occur in circumstances that are not common to dental practice. For example, a drug interaction reported after the intravenous infusion of lidocaine for treatment of cardiac arrythmias in a coronary care unit involves high blood concentration steadystate kinetics of lidocaine that is not seen after lidocaines use for dental anesthesia. We have attempted to rate on the basis of quality of documentationthe reactions we will discuss in this series as established, probable, suspected, possible or unlikely.21 Additionally, because of the importance of a reactions potential severity, three degrees of severity (major, moderate and minor) are included in the classification. The table provides definitions for both of these ratings as well as a composite score: Significance Ratings for Dental Drug Interactions. This rating

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system assigns higher clinical importance to well-documented severe reactions and less importance to poorly documented minor interactions. Additionally, these ratings of significance are made in the context of basic dental therapeutics: local anesthetics are administered for regional anesthesia during one setting and at accepted doses,22 analgesics are administered orally for less than two weeks, and CNS depressants and anxiolytics are administered orally on the day of (or possibly the day before) dental treatment. In creating this rating system, we did not consider intravenous drug use and dental therapies lasting longer than a few weeks to be common dental therapies, and we did not include them in establishing the significance ratings of ADRs that should be important for general practitioners.
RISK FACTORS FOR DRUG INTERACTIONS

UNIQUE CHARACTERISTICS OF DENTAL PHARMACOTHERAPEUTICS.

dTherapy usually is in single-dose or short-term form dMost dental drugs have large margins of safety dUse of intravenously administered drugs is limited dDental procedures frequently are elective dNumber of agents in a practitioners armamentarium is limited dDrugs often administered as a single dose dTherapies are limited to five to 10 days

A number of risk factors can contribute to the significance of a drug interaction (Box, Risk Factors for Adverse Drug Interactions). Drugs that are highly bound to plasma proteins (that is, 99 percent bound) can attach to a common binding site on the plasma proteins. Dramatic increases of unbound drug concentrations could occur if such drugs are administered concurrently. An orally administered drug that has a low bioavailability because of metabolism before systemic absorption (in other words, the first-pass effect) could demonstrate enormous changes in blood concentrations if the enzymes in the liver or gut are inhibited by another drug. Drugs used to treat elderly or medically com-

promised patients might have higher incidences of ADRs because these patients have limited homeostatic reserves and are less able to respond to drug-induced physiological stress. A drug that has a small margin of safety is more prone to ADRs that are caused by modest alterations in pharmacokinetics or shifts in pharmacodynamics. The figure illustrates the dose-response relationship for the hypothetical Drug A. The margin of safety for a drug is estimated by its therapeutic index. A therapeutic index, determined in animal studies, is defined as the median lethal dose, or LD50, of a drug divided by its median effective dose, or ED50.14 When Drug A is given alone, the therapeutic index is calculated to be 5.0in other words, 50 milligrams, the LD50, divided by 10 mg, the ED50. When the interacting hypothetical Drug B is given concurrently, the toxicity response curve of Drug A shifts. If the margin of safety is large, this shift is unlikely to induce a drug interaction, because any significant overlap of effective dosing and toxic dosing is unlikely. Yet, if the therapeutic index of Drug A was 2.0 or 3.0 (as is seen with drugs such as warfarin and digoxin), a similar shift in the toxicity curve would be quite

likely to cause a significant drug interaction. Given all the concerns and complexities of drug interactions, one might expect a relatively high incidence of adverse events in dental practice. Yet, severe adverse reactions in dentistry rarely are reported. Agents used by dental practitioners generally have large margins of safety, and the durations of dental drug therapy are limited. Additionally, there is normally a great deal of variation in the pharmacokinetics (absorption, distribution, metabolism and excretion) and the pharmacodynamics within the general population, owing to health habits, diet and genetics.23,24 Plasma concentrations for a given dose of a drug can normally have a wide range, such that a minor shift in elimination is unlikely to result in an overdose situation. Consider, for example, the plasma concentrations of diazepam reported by Mandelli and colleagues.25 Three hours after a 15-mg oral dose of diazepam was administered, blood concentrations in 18 subjects ranged from 20 to 260 micrograms per milliliter. A drug interaction that caused a 20 percent increase in plasma diazepam levels is unlikely to cause significant toxicity for the majority of patients. Most healthy patients can tolerate small
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variations in a drugs pharmacokinetics.
UNIQUE CHARACTERISTICS OF DENTAL PHARMACOTHERAPEUTICS

Many of the characteristics of drug therapy in dentistry are unique and limit the likelihood of serious drug interactions (Box, Unique Characteristics of Dental Pharmacotherapeutics). Drug therapy in dentistry is administered either as a single dose or only for a short duration. Many drug interactions associated with changes in the rate of drug metabolism and excretion require repeated dosing before blood concentrations are altered significantly. Most of the drugs used in dental therapy have large margins of safety, therefore limiting the likelihood of many drug interactions. Additionally, much of dental therapy is elective and can be postponed if the medical status of a patient is in question or increases the risk of an adverse drug interaction. Finally, there is a limited number of drugs routinely used in dental therapeutics: antibiotics, local anesthetics and vasoconstrictors, analgesics and sedatives/anxiolytics. Consequently, most dental practitioners have a thorough knowledge of the indications for, contraindications of and precautions for the drugs they routinely use. Dental practitioners are able to focus their drug information needs on the clinically significant drug interactions of only a few drugs and drug classes.
CONCLUSION

nation of causality between drug interactions and adverse effects; risk factors; and unique characteristics of dental therapeutics. The significance of many adverse drug interactions associated with each of the common dental therapeutic agents (antibiotics, vasoconstrictors, analgesics, local anesthetics and sedative/anxiolytic agents) will be evaluated in the series of articles to be published in future issues of JADA. The goal of each of these critical reviews is to provide relevant and scientifically based information assessing the mechanisms of these possible reactions, clearing the confusion surrounding many interactions that might not be significant and providing the basis for preventing possible serious drug complications that could arise in dental therapy. s
Dr. Moore is a professor of pharmacology, University of Pittsburgh, School of Dental Medicine, Department of Dental Public Health, 614 Salk Hall, Pittsburgh, Pa. 15261. Address reprint requests to Dr. Moore. Dr. Gage is a professor of pharmacology, Baylor College of Dentistry, Texas A & M University System, Dallas. Dr. Hersh is an associate professor of pharmacology, University of Pennsylvania, School of Dental Medicine, Philadelphia. Dr. Yagiela is a professor and chair, Division of Diagnostic and Surgical Sciences, School of Dentistry, University of California Los Angeles. Dr. Haas is an associate professor and head of anaesthesia, Faculty of Dentistry, University of Toronto, and an associate professor, Department of Pharmacology, Faculty of Medicine, University of Toronto. This article is based on material presented March 4, 1998, in a symposium entitled Adverse Drug Interactions in Dentistry: Separating the Myths From the Facts. Drs. Moore and Hersh organized this symposium, which was presented at the 27th General Session of the American Association for Dental Research in Minneapolis. The symposium was jointly sponsored by the IADR, the American Association of Dental Schools and the American Dental Association. 1. Burt BA, Eklund SA. Dentistry, dental practice, and the community. 4th ed. Philadelphia: Saunders; 1992:11-22. 2. Marcus SE, Drury TF, Brown LJ, Zion GR. Tooth retention and tooth loss in the permanent dentition of adults: United States, 1988-1991.

This article has discussed the professional impact of drug interactions on dental practice; the classification and documentation of drug interactions; the determi54

J Dent Res 1996;75(special issue):684-95. 3. U.S. Public Health Service. Healthy people 2000: National health promotion and disease prevention objectives. Washington, D.C.: U.S. Department of Health and Human Services; 1991. DHHS publication (PHS) 91-50212. 4. Dear health care professional letter. Roche Laboratories, 6/12/98; Internet publication by the FDA. Available at: http://www.fda.gov/medwatch/safety/1998/ posico2.htm. Accessed July 15, 1998. 5. Institute of Medicine Committee on the Future of Dental Education. Dental education at the crossroads: Challenges and changes. In: Field MJ, ed. Washington, D.C.: National Academy Press; 1995. 6. The top 200 drugs. American Druggist 1997; Feb:30-7. 7. Drug topics red book 1998. Montvale, N.J.: Medical Economics Company; 1998:132. 8. Wright JW. Drug interactions. In: Melmon KL, Morrelli HF, Hoffman BB, Nierenberg DW, eds. Clinical pharmacology. 3rd ed. New York: McGraw-Hill; 1992:1012-21. 9. Physicians desk reference. 52nd ed. Montvale, N.J.: Medical Economics Company; 1999. 10. Wynn RL, Meiller TF, Crossley HL. Drug information handbook for dentistry. 4th ed. Hudson, Ohio: Lexi-Comp; 1998. 11. Gage TW, Pickett FA. Dental drug reference. 4th ed. St. Louis: MosbyYear Book; 1999. 12. Rizack MA. The medical letter handbook of adverse drug interactions. New Rochelle, N.Y.: Medical Letter Inc.; 1998. 13. Wynn RL. Internet Web sites for drug information. Gen Dent 1998;46(1):12-8. 14. Yagiela JA, Picozzi A. General mechanisms of drug interactions. In: Yagiela JA, Neidle EA, Dowd FJ, eds. Pharmacology and therapeutics for dentistry. 4th ed. St. Louis: MosbyYear Book; 1998:61-8. 15. Kessler DA. Introducing MEDWatch: a new approach to reporting medication and device adverse effects and product problems. JAMA 1993;269:2765-8. 16. Protecting the identities of reporters of adverse events and patients: preemption of disclosure rules. Fed Regist 1995;60:16961-8. 17. Baum C, Kweder SL, Anello C. The spontaneous reporting system in the United States. In: Strom BL, ed. Pharmacoepidemiology. 2nd ed. New York: Wiley & Sons; 1994. 18. Spence JD. Drug interactions with grapefruit: whose responsibility is it to warn the public? Clin Pharmacol Ther 1997;61:395-400. 19. Amsden GW. Macrolides versus azalides: a drug interaction update. Ann Pharmacother 1995;29(9):906-17. 20. Honig P, Wortham D, Lazarev A, Cantilena LR. Pharmacokinetics and cardiac effects of terfenadine in poor metabolizers receiving concomitant grapefruit juice in humans (abstract). Clin Pharmacol Ther 1995;57:185. 21. Tatro DS, ed. Drug interaction facts. St. Louis: Facts and Comparisons; 1997:xiv-xvii. 22. Ciancio SG, ed. ADA guide to dental therapeutics. Chicago: ADA Publishing Co., Inc.; 1998. 23. Schein JR. Cigarette smoking and clinically significant drug interactions. Ann Pharmacother 1995;29:1139-47. 24. Slavkin HC. Benefits and risks of medications: challenges for the 21st century. JADA 1997;128:1157-60. 25. Mandelli M, Tognoni G, Garattini S. Clinical pharmacokinetics of diazepam. Clin Pharmacokinet 1978;3:72-91.

JADA, Vol. 130, January 1999 Copyright 1998-2001 American Dental Association. All rights reserved.