Dedication iii
Preface xxv
About the Author xxix
The Contributors xxxi
Part I: The Pharmaceutical Process
Chapter 1: The FDA and the Drug-Approval Process 3
Edited by Justina A. Molzon, M.S. Pharm., J.D.
1.1 Introduction 3
1.2 Clinical Studies (Overview) 4
1.3 Phases of Clinical Studies 5
A. Phase 1 clinical studies 6
B. Phase 2 clinical studies 6
C. Phase 3 clinical studies 6
1.4 Accelerated Development or Review 6
1.5 Treatment IND 6
1.6 Parallel Track 7
1.7 Subpart E 7
1.8 Investigational New Drug (IND) Application 7
1.9 New Drug Application (NDA) 7
1.10 Fundamentals of NDA Submissions 8
1.11 NDA Classifications 8
1.12 Labeling Review 8
1.13 Additional FDA-Approved Patient Labeling 9
1.14 The Generic-Drug-Approval Process 10
A. Abbreviated New Drug Applications (ANDAs) 10
B. Bioequivalence review 10
C. Chemistry or microbiology review 10
D. Labeling review 10
E. ANDA approval 10
1.15 Over-the-Counter Drug Products 10
1.16 Post-Marketing Surveillance 11
1.17 Organizational Changes: Drug Safety 11
A. Division of Drug Risk Evaluation B. Division of Medication Errors and Technical Support (DMETS) 11
C. Division of Surveillance, Research, and Communication Support (DSRCS) 11
D. MedWatch program 12
E. Adverse Events Reporting System (AERS) 12
1.18 Recent FDA Initiatives Related to Drug Safety 12
1.19 Applicable Statutes 13
A. Food and Drug Acts of 1906 13
B. Food, Drug and Cosmetic Act (1938) 13
C. Durham-Humphrey Amendment (1951) 13
D. Drug amendments of 1962 14
E. Orphan Drug Act (1983) 14
F. Drug Price and Competition and Patent Term Restoration Act of 1984 14
G. Revision of New Drug Application regulations (1985) 14
H. Revision of Investigational New 14
I. Treatment Use of Investigational New Drugs (1987) 14
J. FDA Modernization Act of 1997 14
1.20 Controlling Statute 15
1.21 Classification as Food or Drug? 15
Chapter 2: The Dietary Supplement and Health Education Act of 1994 (DSHEA) and Related FDA Activities 17
Justina A. Molzon, M.S. Pharm., J.D.
2.1 Definition of a Dietary Supplement 17
2.2 Overview of DSHEA 18
2.3 The FDA’s Role in Implementation of DSHEA 19
A. Elements of the dietary-supplement
B. Boundaries of regulatory classification 19
C. Labeling of a dietary supplement 20
2.4 Claims Permitted under DSHEA 21
A. Structure/function claims 21
B. The FDA’s dietary-supplement proposal 22
C. Advertising 23
2.5 Monitoring the Safety of Dietary Supplements 23
A. MedWatch 24
B. Good manufacturing practices to assure quality (GMPs) 24
C. Literature guidelines under DSHEA 25
D. Commission on Dietary Supplements 25
E. Office of Dietary Supplements 25
2.6 Growth of Dietary-Supplement Industry 25
2.7 Future FDA Activities Related to DSHEA 26
A. Guidelines for evaluating herbal medicines 26
B. Combination drug rule 27
C. FDA research efforts 27
Appendix A: Regulatory Chronology of Ephedrine Dietary Supplementation 27
Appendix B: HHS Acts to Reduce Potential Risks of Dietary Supplements Containing Ephedra 28
Appendix C: Evidence on the Safety and Effectiveness of Ephedra 31
Chapter 3: The Pharmaceutical Industry 35
James T. O’Donnell, Pharm.D., M.S., FCP, ABCP, FACN, CNS, R.Ph.
3.1 Introduction 35
3.2 Direct-to-Consumer Advertising (DTC) 37
A. GAO investigation and analysis of direct-to-consumer advertising 37
B. The FDA’s requirements for the content of DTC advertisements 39
C. The FDA sends regulatory letters when it identifies a violation 39
3.3 Marketing Abuses, Fines, Government Actions and Litigation 41
A. Tap investigation 41
B. The Centocor controversy 41
3.4 Generic Pharmaceutical Industry 41
A. Imminent loss of patent protection worth billions of dollars leads to panic in the boardroom 42
B. Savings for Medicare beneficairies 42
C. Pharmaceutical industry patent battles 42
3.5 Summary 43
Endnotes 43
References 43
Chapter 4: The Failed System of Drug Warnings in America 45
Kip A. Petroff, Esq.
4.1 Introduction 45
A. Overview of “the system” 45
B. Overview of the problem 46
4.2 Underreporting of ADEs 47
A. Adverse drug events 47
B. The underreporting problem 48
C. Solutions to the problem 49
4.3 Problems at the FDA 50
A. The FDA in the 1990s 50
B. The current and future FDA 52
4.4 Conclusion 54
Endnotes 54
Chapter 5: Clinical Research: Testing Treatments in Humans 59
Lori A. Nesbitt, Pharm.D., MBA and Karen L. Pellegrin, Ph.D., MBA
5.1 Introduction 59
5.2 Testing Drugs in Humans 59
A. Phase 1 60
B. Phase 2 60
C. Phase 3 60
D. Phase 4 60
5.3 Clinical Research: Not an Exact Science 61
5.4 Study Design 62
A. Control groups 63
B. Random assignment 65
C. Double-blind 65
D. Crossover design 66
E. Historical control 66
5.5 Elements of the Clinical-Trial Protocol 66
A. Background and significance 66
B. Specific aims or endpoints 66
C. Inclusion and exclusion criteria 66
D. Study procedures 67
E. Statistical design 67
5.6 Clinical-Trial Service Providers 68
A. The Food and Drug Administration 68
B. Clinical-trial sponsor 68
C. Contract research organizations 69
D. Study monitors 69
E. Clinical-trial site 70
F. Site-management organizations 71
G. Institutional review board 72
H. Research participants 72
5.7 Industry Trade Organizations and Support Services 72
Endnotes 73
Recommended Reading 73
Chapter 6: FDA Compliance and Inspection Programs Governing Clinical Investigations 75
James P. Walters, J.D., M.S.
6.1 Introduction 75
6.2 FDA Regulations for Clinical Investigators 76
A. 21 C.F.R. Part 312: Investigator Regulations 76
B. 21 C.F.R. Part 312: Sponsor Regulations 77
C. 21 C.F.R. Part 50: Informed Consent 79
D. 21 C.F.R. Part 56: Institutional Review Board 81
6.3 Guidance for FDA Compliance Programs 83
A. Compliance Program 7348.811: Clinical Investigators 84
B. Compliance Program 7348.810: Sponsors 85
C. Compliance Program 7348.809: Institutional Review Boards 85
6.4 FDA Inspection Procedures 86
6.5 Warning Letters to Clinical Investigators 86
A. FDA warning letters 86
B. Analysis of FDA warning letters from 1996 to 2002 86
C. FDA’s apparent trend toward an
D. Regulations most often cited in warning letters 87
E. Comments on warning letters 88
References 89
Endnotes 91
Chapter 7: The Protection of Subjects in Clinical Research 95
Gopi Doctor Ahuja, MPH and David C. Clark, Ph.D.
7.1 The Safety Net: The Web of Responsibilities that Minimizes Human Subjects’ Risks 95
7.2 Evolution of Ethics 95
7.3 Violations of the Rights of Human Subjects 96
A. Tuskegee syphilis study: 1932-1972 96
B. Radiation experiments: 1940s-1950s 96
7.4 Violations of the Rights of Human Subjects: Drug Studies 97
A. Thalidomide use: 1956-1961 97
B. Willowbrook State School study: 1960s 97
C. Hexamethonium: 2001 97
D. Dangers of off-label therapy 98
7.5 Preventive Measures: Protecting Human Subjects 99
A. Why do we need research oversight?
B. Federal agencies 99
C. Institutional Review Board 100
D. Informed consent 101
E. Investigators’ responsibilities 101
F. Serious and unexpected adverse events 102
G. Subjects’ responsibilities 104
H. Sponsors’ responsibilities 104
I. Institutional responsibilities 105
J. Subjects’ safety 105
Endnotes 106
Appendix A: Resources for Further Reading 107
Appendix B: Examples of the Types of Questions that a Subject Should Ask the Investigator or Research Coordinator 107
Appendix C: Comparison of FDA and HHS Human-Subject Protection Regulations 108
Chapter 8: Identification of Regulated Solid-Dosage Forms 115
Francis J. Muno, Jr., B.S. Pharm., R.Ph., MBA
8.1 Introduction 115
8.2 Physical Chemical Analysis 115
8.3 Accompanying Documents 116
8.4 Imprints and Appearance 117
8.5 Conceptually, Imprints are Unique 122
8.6 Conclusion 123
Endnotes 123
Part II: High-Risk Drug Therapies Resulting in Injury and Litigation
Chapter 9: Adverse Drug Reactions: The Extent of the Problem 127
James T. O’Donnell, Pharm.D., M.S., FCP, ABCP, FACN, CNS, R.Ph.
9.1 Adverse Drug Reactions (ADRs): How Large is the Problem? What Drugs are Involved? What are the Injuries? 127
A. Historical perspective 127
B. ADR incidence 128
C. FDA reporting requirements 128
D. The “seven deadly sins": why doctors fail to report ADRs 129
E. Attitudes toward ADRs 130
F. Investigator fraud 131
9.2 Classification of ADRs 131
A. Categories of ADRs 132
B. Which drugs are the most dangerous? 132
C. Claimants 133
D. Complications and injuries 133
E. Identification of the ADR 133
9.3 The Assessment of ADRs 133
A. Documentation 133
B. Selection 134
C. Administration 134
D. Medication errors 135
9.4 Adverse Reactions Manifest in the Skin 135
A. Alopecia 136
B. Exfoliative dermatitis 136
C. Photosensitivity reactions 136
D. Lupus erythematosus-like eruptions 136
E. Erythema multiforme and Stevens-Johnson syndrome 136
F. Toxic epidermal necrolysis (TEN) 136
G. Skin changes induced by systematically and locally administered corticosteroids 137
9.5 Drug-Induced Hepatic Injury 137
9.6 Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) 137
A. “The Seven Pillars of Foolishness” 137
B. Ketorolac: The latest NSAID in the news 138
C. Other side effects 138
D. Litigation report 139
E. Aspirin-sensitive rhinosinusitis or asthma 140
F. Adverse gastrointestinal effects of aspirin and other NSAIDs 140
G. Liver: Reye’s syndrome 140
9.7 Summary and Conclusions 141
Endnotes 141
References 142
Chapter 10: Evaluation of Medical Causation 143
Donald H. Marks, M.D., Ph.D.
10.1 Definitions in Medical Causation 143
10.2 The Importance of Establishing Causation 143
10.3 Definition of an Adverse Effect 144
10.4 Degree Adverse Effects Relate to Intervention 144
A. Unrelated cause of adverse effect 144
B. Unlikely cause of adverse effect 144
C. Possible cause of adverse effect 145
D. Probable cause of adverse effect 145
E. Definite cause of adverse effect 145
10.5 Methods of Investigating Causation 145
A. Randomized clinical trials 145
B. Epidemiological studies 145
C. Case-controlled studies 145
D. Individual case reports or series 145
10.6 Structured Algorithms for Determining Causation 145
A. Koch’s postulates 146
B. Riddell’s criteria 146
10.7 Daubert v. Merrell Dow Pharmaceuticals, Inc., and the Evolution of Causation 147
A. Cases and controls 147
B. Clinical trials 147
C. Scientific evidence 148
D. Challenge, de-challenge, and re-challenge studies 148
E. Epidemiological studies 148
F. Theories and methods 148
G. Alternative explanations 148
H. Scientific testimony 148
I. Effects and causes 148
10.8 Conclusion 148
Endnotes 148
Chapter
11: The Role of Pharmacoepidemiology and Expert Testimony 151
William N. Kelly, Pharm.D., FISPE
11.1 Introduction 151
11.2 Drug “Misadventures” 152
A. Adverse drug reactions 152
B. Allergic drug reactions 152
C. Drug interactions 153
D. Medication errors 153
11.3 Did the Drug Cause the Adverse Event? 154
11.4 Patient Risk Factors for ADEs 154
11.5 Preventability 156
11.6 Cost 156
11.7 Supporting Evidence 156
A. Pre-FDA approval studies 156
B. Drug labeling 156
C. Post-marketing surveillance 156
11.8 Grading the Strength of the Evidence 159
11.9 Risk Communication and Possible Actions by the FDA 160
11.10 Communicating Drug Risks to Patients 160
A. Doctors’ duties 160
B. Pharmacists’ duties 160
C. Patients’ duties 161
11.11 Human Error and Disciplinary Decision Making 161
11.12 Drug-Injury Testimony 161
A. Can it occur? 161
B. Did it occur? 161
C. How did it occur? 162
D. Why did it occur? 162
11.12 Summary 162
Endnotes 162
Chapter
12: Medications Errors and Adverse Drug Reactions in Hospitalized Patients: How Common are They, and Why do They Occur? 165
James T. O’Donnell, Pharm.D., M.S., FCP, ABCP, FACN, CNS, R.Ph., Larry Cohen, M.D., FCCP and Patricia Iyer, M.S.N., RN, LNCC
12.1 Introduction 165
12.2 What is a Medication Error? 165
12.3 Medication Error Rates 166
12.4 The Dimensions of the Problem 166
12.5 Understanding the Normal Process for Medication Management 167
A. The order-entry process 167
B. Signing off the order 167
C. Name of the drug 168
D. Dosage of the drug 168
E. Route of the drug: Intravenous (IV),
F. Frequency of the drug 169
G. Medication-administration record 170
H. Twenty-four-hour check 170
I. If the pharmacist is unavailable 170
12.6 Why Do Errors Occur? A Statistical Explanation 170
12.7 Broad Classification of Medication Errors into Four Categories 171
A. Prescriptive errors 171
B. Transcriptive errors 171
C. Preparative errors 172
D. Administrative errors 172
12.8 Selected Types of Medication Errors 172
A. Omitted dose 173
B. Duplicate dose 173
C. Unordered-drug error 173
12.9 Error Categorization by Severity 173
A. Category-I incidents (least significant) 173
B. Category-II incidents (moderate clinical significance) 173
C. Category-III incidents (serious clinical significance) 173
12.10 Those Patients at Increased Risk for Medication Errors 174
12.11 Adverse Drug Reactions (ADR) 174
12.12 Summary 175
Endnotes 176
Chapter 13: Medical-Legal Aspects of Medication Errors 177
Patricia Iyer, M.S.N, RN, LNCC, I. Larry Cohen, M.D., FCCP and James T. O’Donnell, Pharm.D., M.S., FCP, ABCP, FACN, CNS, R.Ph.
13.1 Introduction 177
13.2 Detection of Medication Errors 177
13.3 Nursing Responsibilities Following a Medication Error 178
13.4 Reporting Medication Errors to the Patient or Family 178
13.5 Determining Damages 178
13.6 Determining Culpability 179
13.7 When the Five Rights Go Wrong 180
A. Unordered drug error 180
B. Wrong drug 180
C. Wrong dose 180
D. Dosing errors and children 181
E. Wrong dose of intravenous medication 182
F. Wrong rate 182
G. Wrong route 183
H. Wrong time 183
I. Omitted dose 183
J. Wrong site 184
13.8 Intravenous-Related Injuries 184
13.9 High-Risk Medications 186
A. Anticoagulants 186
B. Caustic chemicals 187
C. Chemotherapy medication errors 188
D. Electrolyte solutions: Potassium chloride 190
E. Insulin 191
F. Opioids 191
G. Inducing addiction 192
H Respiratory depressants 192
13.10 Treatment Errors and Adverse Drug Reactions 194
A. Allergic reactions 194
B. Adverse drug reactions 195
C. Negligent prescription 196
D. Failure to diagnose 196
E. Failure to monitor 197
Endnotes 197
Appendix A: Estate of G.V. v. Community Hospital, et al. 200
Appendix B: B.L. v. Dr. R., et al. 203
Chapter 14: Preventing Medication Errors 207
I. Larry Cohen, M.D., FCCP, Patricia Iyer, M.S.N, RN, LNCC and James T. O’Donnell, Pharm.D., M.S., FCP, ABCP, FACN, CNS, R.Ph.
14.1 Introduction 207
14.2 A Primer on Strategic Management of the Problem 20
A. Measurement and tracking 208
B. Analysis 208
C. Variation 208
D. Process improvement and process re-design 209
E. Questioning the basis for the policies 209
F. Supply-chain management (SCM) and barcode-enabled point-of-care (BPOC) 209
G. Six-Sigma processes and what purchasers of health care know 210
H. KISS (keep it simply simple) 210
I. Murphy’s law 210
14.3 Examples of Strategies for Preventing Errors 210
A. Manufacturers 211
B. Healthcare systems 213
C. Physician and physician extenders 216
D. Pharmacists 217
E. Nursing responsibilities 218
14.4 Summary 221
Endnotes 221
References 222
Chapter 15: Pharmacists’ Errors 223
Dennis Miller, B.S. Pharm.
15.1 Filling Prescriptions at Warp Speed 223
15.2 Why are Errors so Common? 224
15.3 Memorable Misfills 225
15.4 Lawsuits and Liability 226
15.5 Error Stories 227
15.6 How Widespread is this Problem? 229
15.7 The “Confidence Interval” 233
15.8 Employers Attempt Action 234
15.9 Inexperienced Technicians Fill Prescriptions 235
15.10 Doctors’ Errors 237
15.11 Fed Up with Doctors’ Handwriting 240
15.12 Calling Doctors about Drug Interactions 244
15.13 A Pharmacist Who has “Had Enough” and “Will No Longer Practice Pharmacy” 245
15.14 Pharmacy: A “Horrible” Profession 245
Endnotes 247
Chapter
16: Danger at the Drugstore: Some Practical Comments on Pondimin and Redux Litigation 249
Kip Petroff, Esq. and James A. Morris, Jr., J.D.
16.1 Introduction 249
16.2 How Did We Get to Where We are Today? 249
A. The medical issues 249
B. The legal issues 240
16.3 Overview of the Issues 251
A. The drugs involved 251
B. Medical issues: What damages did these drugs cause? 251
C. Liability issues: Were the fenfluramines more harmful than helpful? 252
16.4 Round Two: Litigating PPH, Intermediate, and Back-End Opt-Out Cases 253
A. Initial opt-out 253
B. Intermediate opt-out 253
C. “Back-end” opt-out 253
D. PPH cases: No opt-out needed 254
16.5 Major Contested Issues in Fen-Phen Litigation 254
16.6 Issues Particular to Litigation of Future Second-Round Fen-Phen Cases 254
A. Proving your right to opt out 254
B. Removal to federal court 254
C. Limitations on damages and the right to recover 256
D. No punitive damages 256
E. Multiple-plaintiff trials 257
16.7 Conclusion 257
Endnotes 257
Chapter 17: Diet-Pill Litigation: The Fen-Phen-Redux Debacle: A Medical-Legal Perspective 259
John M. Restaino, D.P.M., J.D.
17.1 Introduction 259
17.2 Fenfluramine and Dexfenfluramine 260
A. General characteristics 260
B. Dosage and duration of therapy 261
17.3 Phentermine 261
A. General characteristics 261
B. Dosage and duration of therapy 262
17.4 Primary Pulmonary Hypertension (PPH) 262
A. Diet drugs and PPH: Establishing the connection 262
B. Pathological findings 265
C. Natural history 266
D. Diagnostic studies 267
E. Prognosis 267
17.5 Cardiac Valvulopathy 268
A. Diet drugs and VHD: Establishing the connection 269
B. Pathological findings 269
C. Mitral-valve regurgitation 270
D. Aortic-valve regurgitation 270
E. Tricuspid-valve regurgitation 270
F. Pulmonic-valve regurgitation 270
G. Natural history and symptoms 270
H. Echocardiography 271
I. Cardiac catheterization 271
J. Prognosis 271
17.6 Cardiac Epidemiology 272
17.7 Neurotoxicity 273
A. Fen-phen and serotonin: Establishing the connection 273
B. Species generality 275
C. Animal studies and humans “neurotoxicity” 275
D. Clinical experience 276
17.8 Conclusion 276
Endnotes 278
Appendix A: Morbidity and Mortality Weekly Report on Cardiac Valvulopathy Associated with Exposure to Fenfluramine or Dexfenfluramine 285
Appendix B: Statement of the American College of Cardiology on Recommendations for Patients Who have Used Anorectic Drugs 291
Chapter 18: Diet Drugs: Pharmacology/Interactions/ Cautions 293
James T. O’Donnell, Pharm.D., M.S., FCP, ABCP, FACN, CNS, R.Ph.
18.1 Introduction 293
18.2 Pharmacology 294
A. Indicated usage 294
B. Other uses: As an aid in cessation of smoking and drinking 294
18.3 Mechanism of Action 294
18.4 Effectiveness 294
A. Generally 294
B. Effectiveness in diabetic patients 295
18.5 Adverse Effects 295
A. Listed adverse effects: Primary pulmonary hypertension 295
B. Other adverse effects 295
18.6 Drug Interactions: Metabolism; Cytochrome P450 296
18.7 Early Warnings of Heart Valvulopathy 296
18.8 The Pharmacology of Serotonin-Neurotransmission 297
18.9 Serotonin 297
A. Effects on the cardiovascular B. Sleep 298
C. Disease states with excessive serotonin 298
18.10 Ergotamine 298
18.11 Prescription Drug Treatment of Obesity 298
18.12 Fen-Phen Diet 299
A. Drugs used in obesity 299
B. Actions and uses 299
C. Fenfluramine hydrochloride (Pondimin): Actions and uses 299
18.13 Phentermine Resin (Ionamin) 300
18.14 Receptors 300
18.15 Central Nervous System 300
18.16 Behavior 301
A. Sleep-wakefulness cycle 301
B. Aggression and impulsivity 301
C. Anxiety and depression 301
18.17 Pharmacological Manipulation of the Amount of 5-HT in Tissues 301
18.18 MAO Inhibitors 301
18.19 Tricyclic Antidepressants 302
18.20 Features of Second-Generation Antidepressants 302
18.21 Bupropion 302
18.22 Trazodone 302
18.23 Selective Serotonin Inhibitors 325
A. Fluoxetine 303
B. Paroxetine 303
C. Sertraline 303
18.24 Serotonin Syndrome 303
18.25 5-HT Receptor Agonists and Antagonists 304
A. The 5-HT receptor agonists 304
B. The 5-HT receptor antagonists 304
C. Ketanserin 304
D. Clozapine 304
E. Risperidone 304
F. Methysergide 304
18.26 Summary 306
Endnotes 307
Recommended Reading 308
Chapter 19: The Story of E-Ferol: Adding Insult to Injury 309
Kathleen M. Dahle, RN, B.S.N.
19.1 Introduction 309
19.2 E-Ferol Beginnings 309
19.3 The Fruition of E-Ferol 311
19.4 Final Exposure 312
19.5 FDA Alert 312
19.6 The Recall of E-Ferol 312
19.7 Congressional Hearing 312
19.8 Criminal Ramifications 313
19.9 Hospital Policy and Procedure 314
19.10 Morbidity and Mortality Untold 314
19.11 Long-Term Aftermath 316
19.12 Implicit Duty 316
19.13 The Exposure of Duty (and Ethics) through Litigation 317
19.14 The Revelations from Litigation 320
References 323
Cases 323
Appendix: A Plaintiff’s Expert Report on the Duty of the Pharmacist in the Recall of E-Ferol 324
Endnotes for Appendix 331
Chapter 20: Accutane: Focus on Psychiatric Toxicity and Suicide 333
Donald H. Marks, M.D., Ph.D. and Tzarina Middlekoop, Ph.D.
20.1 Introduction 333
20.2 Mechanism of Action 334
20.3 Metabolism 334
20.4 Adverse Effects of Accutane 334
A. Hypervitaminosis A 334
B. Psychiatric adverse events 335
C. Pseudotumor cerebri 335
20.5 Accutane and Depression 336
A. Literature reports 336
B. Media reports 336
20.6 Accutane and Suicide in Adolescents 337
A. Case studies 337
B. Methods 337
C. Substance-induced mood disorder 338
D. Clinical summaries 338
E. Results 339
F. Discussion 339
20.7 Neuropsychiatric Adverse Effects of Accutane 339
20.8 OPDRA Study 342
20.9 FDA Postmarketing Study 342
A. Dr. Wysowski (FDA, Postmarketing Experience Suicide and Depression) 342
B. Dr. O’Connell (FDA, Biological Plausibility and Risk Management) 342
C. Dr. Branch 344
20.10 Selected Abstracts from Accutane 2002 Prescribing Information 345
A. Indications and usage 345
B. Warnings 345
C. Adverse reactions: Clinical trials and postmarketing surveillance 345
20.11 Selections from Accutane Informed Consent/Patient Agreement 346
20.12 Medication Guide: Accutane Capsules 346
20.13 Adverse Drug-Reaction Reports 347
20.14 Submission of ADR Reports 348
20.15 Revised Label Warning 348
20.16 Defense of Accutane 349
20.17 Lawsuits 349
20.18 Case Reports 349
A. Jones/106079, filed August 8, 1997 349
B. Owensby, filed March 10, 1998 349
C. Balsham, filed March 10, 1998 349
D. Kenny Spaeth, filed June 30, 1998 349
20.19 Retinoids Implicated in Schizophrenia 350
20.20 Teratogenesis of the Retinoids 350
20.21 Isotretinoin: When Warnings are Not Enough 351
20.22 Dermatological Advisory Committee 351
20.23 The FDA’s Battle with Accutane 351
20.24 RTE-PrimeTime 352
20.25 Inadequate Testing 352
20.26 Prescribing Patterns: Failure to Comply 352
20.27 License Indications: Failure to Comply 353
20.28 Etretinate and Acitretin 353
A. Metabolism 353
B. Therapeutic use 354
C. Toxicities and adverse reactions 354
20.29 Topical Retinoids 354
20.30 Future of Retinoids 354
20.31 Conclusion 355
Endnotes 355
Appendix A: Bishop v. Hoffman-LaRoche, Inc. 359
Appendix B: Memorandum on Adverse Event Report for Roaccutane 373
Appendix C: Review of Adverse Events Reported for Roaccutane for Children and Adolescents Aged Under 18 Years of Age 374
Chapter 21: Antidepressants: Clinical Use and Litigation 379
Henry Cohen, B.S., M.S., Pharm.D., BCPP, CGP and Antonia Alafris, B.S., Pharm.D., CGP
21.1 Major Depressive Disorders 379
21.2 Antidepressant Pharmacology 379
21.3 Antidepressant Overdose 380
21.4 Antidepressants and the Patient with Suicidal Ideation 380
A. Prozac and suicidal ideation 381
B. Paxil and suicide risk in children 382
21.5 The Adverse Effects of Antidepressants and the Duty to Warn 382
A. Docken v. Ciba-Geigy 382
B. Stebbins v. Concord Wrigley Drugs, Inc., et al. 383
C. Morgan et al. v. Wal-Mart Stores, Inc. 383
D. Penelope A. Carafelle et al. v. Brockton Oaks CVS, Inc. 384
21.6 Antidepressants and Alcohol 384
A. Kirk v. Michael Reese Hospital 385
B. Hand v. Krakowski 385
21.7 Selective Serotonin Reuptake Inhibitors and the Serotonin Syndrome 386
21.8 Hepatic Cytochrome P450 Drug Interactions and SSRIs 387
21.9 Serzone and Liver Disease 387
21.10 The Pharmacist’s Role 387
21.11 The Omnibus Budget Reconciliation Act 388
21.12 In a Perfect World 388
21.13 Conclusion 388
Endnotes 389
Chapter 22: Drugs for Asthma, Allergies, and Anaphylaxis: Harm from Use, Misuse, and Non-Use 391
Constantine John Falliers, M.D.
22.1 Introduction: Care and Harm 391
A. Young boy attacks brother after taking theophylline 392
B. Nurse disrupts home and work with steroid psychosis 392
22.2 Information, Interpretations, Attitudes 392
A. Life-threatening sulfonamide B. Sudden death after intravenous Primaxin 393
C. Fatal anaphylactic shock after multiple fire ant bites 393
D. Blood clots and amputation after EACA for angioedema 393
22.3 Vehicles, Propellants, Other “Inert” Ingredients 394
22.4 Adrenergic Agonists 394
A. Anaphylactic death in a medical office 396
B. Death from asthma in the emergency room 396
C. Death from asthma after leaving the doctor’s office 396
22.5 Methylxanthines 397
A. Convulsive seizure from intravenous aminophylline 397
B. Permanent brain damage from double theophylline doses 398
22.6 Mast-Cell Stabilizers and Anti-IgE 398
22.7 Histamine and Leukotriene Antagonists 398
22.8 Anticholinergics 399
22.9 Corticosteroids 399
A. Diabetes after a short course of oral prednisone 401
B. AVN after dexamethasone for the prevention of postoperative scars 401
C. High-dose prednisone for contact dermatitis 401
D. Wheezing pneumonitis treated as severe asthma 401
E. Massive steroids for refractory bronchitis complicating asthma 402
F. Overtreatment with steroids prescribed by telephone 402
22.10 Antitussives and Expectorants 403
22.11 Herbal and “Recreational” Drugs 403
A. Anaphylaxis from herbal “bee pollen” ingestion 403
B. Worsening of asthma perceived as a cure with marijuana 404
22.12 Communications and Monitoring 404
A. Three steroids taken together for orthopedic inflammation 404
B. Liver failure due to phenytoin hypersensitivity 404
C. Unanticipated death of an asthmatic child 404
D. Missed diagnosis of pulmonary carcinoma 404
E. Inappropriate attribution of blame 405
F. Exacerbation of asthma after a riot-control spray 405
22.13 Conclusion 405
Endnotes 405
Chapter 23: Corticosteroids 409
James T. O’Donnell, Pharm.D., M.S.,FCP, ABCP, FACN, CNS, R.Ph., and Linda S. Robinson, Esq.
23.1 Introduction 409
23.2 Specific Side Effects 409
23.3 Mechanism of the Toxicity 410
23.4 Sample Case Discussion 410
23.5 Specific Monitoring and Prevention Functions 410
23.6 General Precautions 410
23.7 Sample Case Discussion Regarding Withdrawal of Corticosteroids 411
A. Playing “Telephone” and “Transcription” with Crucial Information: Transcription Errors Lead to Addisonian Crises and Whopping Lawsuits 411
B. Teaching Tips 412
23.8 Drug Interactions 412
A. Nonsteroidal Anti-Inflammatory Drugs and Other Agents 412
B. Macrolide Antibiotics: Corticosteroid Interaction with Macrolide Antibiotics, Including Erythromycin, Clarithromycin, Azithromycin, and Others 412
C. Topical Steroids 413
D. Case Illustration 413
E. Case Illustration 414
23.9 The Skin-Cap Case: Fraud and Injury of the Public 414
A. Opinions 414
B. Summary 415
23.10 Contraindications and Precautions 415
23.11 Steroid Psychosis and Psychoactive Effects 416
23.12 Intralesional Steroids 416
23.13 Warnings 417
23.14 Adrenal Suppression 418
23.15 Avascular (Aseptic) Necrosis/Osteonecrosis 418
23.16 Steroid-Induced Avascular Necrosis 419
A. Fat embolus 420
B. Alcoholism 420
C. High-dose corticosteroids and avascular necrosis 420
D. Animal experiments 420
23.17 An Unusual Case of Steroid-Induced Avascular Necrosis 421
23.18 Orthopedic Surgical Experience 421
23.19 Cushing’s Syndrome 422
23.20 Ophthalmologic Steroid Injury 422
A. Glaucoma 422
B. Cataracts 422
23.21 Summary 423
Endnotes 423
Recommended Reading 424
Chapter 24: Adverse Effects of Diabetic Drugs 425
James T. O’Donnell, Pharm.D., M.S., FCP, ABCP, FACN, CNS, R.Ph.
24.1 Diabetes Demographics and Epidemiology 425
24.2 Insulin 425
24.3 Insulin Preparations 425
24.4 Clinical Use of Insulin 425
24.5 Hypoglycemia (Low Blood Sugar) 426
A. Etiologies of hypoglycemia 427
B. Insulin-induced hypoglycemia 427
24.6 Pathophysiology and Clinical Symptoms of Hypoglycemia 427
24.7 Incidence 428
24.8 Pathophysiology and Biochemistry of Hypoglycemia 428
24.9 Adverse Experiences with Hypoglycemia 428
A. Case report: Insulin-related malpractice-sliding scale and urine sugars result in cardiac arrest 428
B. Insulin damages baby’s brain; pharmacist error suggested 429
C. Another interloper? 430
24.10 End Product Testing Recommended 431
24.11 Insulin Murders 431
24.12 Hypoglycemia from the Sulfonylurea Derivatives 431
24.13 Adverse Effects of the Sulfonylureas 431
24.14 Drug Interactions with Sulfonylureas 433
24.15 Rezulin for Type-II Diabetes 433
24.16 Summary and Conclusions 433
Endnotes 433
Chapter 25: Nephrotoxic Drugs 437
Domenic A. Sica, M.D. and Todd W.B. Gehr, M.D.
25.1 Introduction 437
25.2 Framework of the Problem 437
25.3 Basis for the Kidney being Susceptible to Damage 437
25.4 Patient Groups Most Susceptible to Nephrotoxicity 438
25.5 Demographics of Chronic Kidney Disease 439
25.6 Methods to Assess Renal Function and Damage 439
25.7 Level of Renal Function at Which Drug Accumulation Occurs 439
25.8 Nephrotoxic Drugs 440
25.9 Nephrotoxicity Scenarios 440
A. Lithium toxicity 440
B. Gentamicin toxicity 440
C. Dialysis-related issues 441
D. Drug clearance in relationship to renal failure 441
E. Angioedema with an ACE inhibitor 442
F. Fatal hyperkalemia with medications 443
G. Statin therapy and the development of myopathy 443
25.10 Conclusions 444
Endnotes 444
Chapter 26: Drug-Induced Hepatotoxicity 445
James T. O’Donnell, Pharm.D., M.S., FCP, ABCP, FACN, CNS, R.Ph.
26.1 Introduction 445
A. Hepatitis 446
B. Cirrhosis 446
26.2 The Problem of Drug-Induced Liver Toxicity 446
26.3 Hepatic Drug Metabolism 447
A. Cytochrome P450 447
B. Induction processes increasing hepatotoxicity in humans 447
C. Nutritional effects on drug metabolism 447
26.4 Biochemical Mechanisms 447
26.5 History of Adverse Drug Reactions 447
26.6 NSAID Use and Hepatotoxicity 448
26.7 Bromfenac Hepatotoxicity 448
A. FDA review of bromfenac 448
B. Review of Duract labeling revision, July 31, 1996 (Widmark letter) 449
C. Reviewer’s annotations for labeling 449
D. Medical officer review 449
E. Bromfenac safety summary by John Hyde, Ph.D., M.D., December 19, 1995 450
26.8 Isoniazid-Induced Hepatotoxicity 450
A. Introduction 450
B. Clinical features and laboratory findings 451
C. Mechanism 451
26.9 Acetaminophen-Phenytoin Interaction Leading to Fulminant Liver Failure 451
26.10 Pharmacologist’s Report: Acetaminophen-Phenytoin Interaction 452
A. Case summary 452
B. Opinions 452
C. Bases for opinions 453
D. Summary 454
26.11 Acetaminophen Toxicity 454
A. Facts of the case 455
B. Opinions 455
C. Bases for opinions 455
26.12 Other Acetaminophen Cases 457
26.13 Biaxin (Clarithromycin)-Induced Fulminant Hepatic Failure 457
26.14 Rezulin Hepatotoxicity 459
A. Case report 459
B. Discussion 459
26.15 Methotrexate-Induced Hepatotoxicity 460
A. Introduction 460
B. Clinical features and laboratory findings 461
C. Liver function tests 462
D. Mechanism of damage 462
26.16 Iron Supplement Hepatotoxicity 462
A. Case report 462
B. The literature 463
C. Opinions 464
26.17 Thalassemias 464
26.18 Dangers of Iron 464
26.19 Liability and Warning 465
26.20 Summary and Conclusions 465
Endnotes 465
Chapter 27: Statins Including Baycol: Questionable Cholesterol Control 469
John Lehmann, Ph.D. and Joel M. Kauffman, Ph.D.
27.1 Introduction 469
27.2 Statins are HMG-CoA Reductase Inhibitors 469
27.3 Doubts about Benefits of Cholesterol Reduction 470
27.4 Adverse Reactions to Statins 472
A. Myalgia 472
B. Myopathy 472
C. Rhabdomyolysis 473
D. Neuropathy 473
E. Cognitive impairment 473
F. Cancer 474
27.5 Drug Interactions with Statins 474
A. Fibrates 474
B. Cytochrome P450 interactions 474
27.6 Baycol in Brief (Cerivastatin) 474
27.7 Legal Complaints 475
A. Failure to warn 475
B. Defective product 475
C. Medical malpractice 476
27.8 Politics and the Economics of Cholesterol 476
27.9 Cholesterol Activists 476
27.10 Conclusions 476
Endnotes 477
Chapter 28: The Rezulin Litigation 479
Zoe Littlepage, J.D. and Rainey C. Booth, J.D.
28.1 Identifying and Understanding a Rezulin Injury 479
A. The medicine 479
B. Rezulin: A breakthrough drug for type-II diabetes? 480
C. Rezulin poisons the mitochondria D. The range of Rezulin injuries 482
28.2 What Warner Lambert Knew (and When) about Rezulin’s Liver Toxicity 482
A. Class effect 483
B. Cell testing 483
C. Animal studies 483
D. Human testing 483
28.3 Warner Lambert’s Reaction 485
Endnotes 485
Chapter 29: Drug-Induced Movement Disorders 489
Jadwiga S. Najib, Pharm.D., B.S.
29.1 Introduction 489
29.2 Akathisia 489
29.3 Neuroleptics 491
29.4 Metoclopramide 492
29.5 Selective Serotonin Re-Uptake Inhibitors (SSRIs) 492
29.6 Other Drugs 492
29.7 Chronic, Tardive, and Withdrawal Akathisia 493
29.8 Dystonias 493
29.9 Neuroleptics 494
29.10 Other Agents 494
29.11 Parkinsonism 495
29.12 Neuroleptics and Other Agents 496
29.13 Tardive Dyskinesia 498
29.14 Neuroleptics and Other Agents 500
29.15 Neuroleptic Malignant Syndrome 501
29.16 Diagnostic Terminology 502
29.17 Theories of Causation 503
29.18 Clinical and Legal Issues in Psychiatry 504
29.19 Conclusion 507
Endnotes 507
Recommended Reading 516
Chapter 30: Pain Medications and OxyContin 517
James T. O’Donnell, Pharm.D., M.S., FCP, ABCP, FACN, CNS, R.Ph.
30.1 Treatment of Chronic Nonmalignant Pain 517
A. Diagnostic evaluation of pain 518
B. Evaluation of chronic pain 518
C. Neuropathic pain 518
D. Suffering and pain behavior 518
E. The chronic pain patient 519
F. Analgesics 520
G. Peripherally acting analgesics 520
H. Equipotency of analgesics 521
I. Hepatic side effects 522
J. Cognitive-behavioral strategies 522
K. Pain management centers 522
L. Goal of treatment 523
M. Dosing 523
30.2 Case Evaluation of Pharmacotherapy for Chronic Nonmalignant Pain: Case Summary of Chronic Low Back Pain 523
A. Opinions 524
B. The drugs 525
30.3 Case Reports: Opiate Toxicity Causing Respiratory Arrest, Brain Damage, and Death 525
30.4 Respiratory Arrest and Brain Damage Following Morphine Overdose in the Hospital 525
A. Opinions 525
B. Bases for opinions 526
C. Case discussion/facts 526
D. Case report: Fentanyl epidural respiratory arrest 526
E. Facts of the case and summary of testimony 527
F. Opinions 528
G. The drugs: Opioids (fentanyl) and respiratory depression, with and without additional central nervous system (CNS) depressants 529
H. Obesity-hypoventilation syndrome 530
I. Case summary 530
30.5 Case Report: Duragesic (Fentanyl) Death Discharged Patient 531
A. Fentanyl (Duragesic) 531
B. Dosage and administration 531
C. Dose selection 531
D. Opinions 532
E. Patient controlled analgesia (PCA) errors and injuries 532
30.6 Pain Equilibration 533
A. Introduction 533
B. Experimental and clinical pain C. Clinical pain 535
D. Pain studies 535
E. Therapeutic trials 535
F. Treatment of pain 535
G. Goodman and Gilman discussion of morphine 536
H. Types of pain 536
I. Sample report 538
J. Oral analgesic medication studies 539
K. Dental extraction pain equivalence 540
L. Conclusion 541
30.7 OxyContin 541
A. Qualifications 541
B. Background 541
C. Summary of opinion 542
D. Opinions and bases of opinions 542
E. Materials reviewed 544
Endnotes 545
Appendix 547
Chapter 31: Performance-Enhancing Substances: Ephedrine, Anabolic Steroids, Herbals and Dietary Supplements 549
John Salemi, B.S. and James T. O’Donnell, Pharm.D., M.S., FCP, ABCP, FACN, CNS, R.Ph.
31.1 Performance-Enhancing Drug Use in Athletes 549
A. Ergogenic drugs 549
B. Performance enhancement and testing 551
C. Anti-doping code 552
31.2 Anabolic Steroids 553
A. Introduction 553
B. Erythropoiesis 553
C. Other uses 553
D. Side effects 554
E. Psychological effects 555
F. Habituation and addiction 555
G. Nontherapeutic usage 555
H. Case illustration 556
I. Regulation of anabolic steroid use 556
31.3 Non-Athletic Performance-Enhancing Substances 559
A. Steriods for non-athletes: Steroid chewing gum? 559
B. DHEA 559
31.4 Herbal Products Get AMA Attention 559
31.5 Amended CGMP for Dietary Supplements, March 2003 561
A. Background 561
B. Why are CGMPs needed? 563
C. Benefits and costs 563
31.6 Summary and Conclusions 563
Endnotes 563
Chapter 32: Ephedra 565
James T. O’Donnell, Pharm.D., M.S., FCP, ABCP, FACN, CNS, R.Ph.
32.1 Adverse Effects of Ephedrine Stimulants 565
A. Ephedrine and primary pulmonary hypertension 565
B. Hearing loss 566
C. Incidence of ephedra toxicity in herbal products 566
D. Ephedra alkaloids combined with botanical caffeine 566
32.2 Ephedra Alkaloids as Dietary Supplements 567
32.3 United States Armed Forces Ban on Sale of Ephedra Products 567
32.4 Ephedra as an Alternative to Illegal Substance Abuse 568
32.5 Chronology of Ephedra Use in Dietary Supplements after Passage of DSHEA 568
32.6 The RAND Report on Ephedra, 2003 569
A. Main results: Weight loss 570
B. Athletic performance 570
C. Safety issues 570
D. Conclusions 570
32.7 The Agency for Healthcare Research and Quality and the RAND Report 571
A. Findings: Efficacy for weight loss 571
B. Efficacy for physical performance enhancement 571
C. Safety issues 571
D. Future research 572
32.8 FDA Comments on the RAND Report on Ephedra, March 2004 572
32.9 Ellis and Metabolife Company Indicted for Obstruction of Justice 575
Endnotes 576
Appendix A: Expert Report 576
Appendix B: Expert Report 587
Endnotes for Appendix B 592
Chapter 33: Recreational Drugs: Alcohol, Cocaine and Marijuana: Forensic Issues 595
James T. O’Donnell, Pharm.D., M.S., FCP, ABCP, FACN, CNS, R.Ph.
33.1 Introduction 595
33.2 Alcohol: A Major Contributor to Injury 596
33.3 Impairment and Intoxication by Alcohol 596
33.4 Motor Vehicles 596
33.5 Other Non-Motor Vehicle Injuries Related to Alcohol 597
33.6 Reaction Time, Impairments and Tolerance; Effect of Alcohol/Contribution 599
33.7 Adaptation Effects of Alcohol in the Central Nervous System-Tolerance 601
33.8 Sample Report: Extreme Alcohol Levels/Tolerance 602
33.9 Sample Expert Reports: Alcohol 604
33.10 An Unusual Case of Alcohol Hypersensitivity Reaction, in Combination with Marijuana, Leads to Apparent Psychotic Reaction 606
33.11 Sample Case Report: Alcohol Metabolism and Kinetics in a Malnourished Bulemic Woman Charged with the Reckless Homicide of Her Infant 609
33.12 Testing: Alcohol and Recreational Drugs 612
A. Urine testing 612
B. Confirmation testing of urine samples 612
C. Sample case report: Urine drug testing 613
D. “Poppy seed” opiate false positives 614
33.13 Cocaine 615
A. Blood concentrations 615
B. Metabolism and excretion 616
C. Toxicity 616
D. Analysis 617
E. Cocaine psychoses 617
F. Cocaine dysphoria 617
G. Violent behavior 617
H. Cocaine use as a cause of death 618
I. Effect of cocaine on driving 618
J. Testing reckless drivers for cocaine and marijuana 618
33.14 Marijuana 619
A. Effects of cannabis 620
B. Marijuana in combination with alcohol and other drugs 621
C. Clinical diagnosis 622
D. Passive exposure: I never smoked it! 622
E. Testing 622
33.15 Phencyclidine (PCP) 622
33.16 Heroin and Other Opiates 624
33.17 Sample Case Report: Methadone Arrest with Brain Damage/Differentiation from Cocaine; Criminal Defendant 626
33.18 Prescription Drugs and Driving 627
33.19 Conclusion 628
Endnotes 628
References 631
Chapter 34: Hemophilia Holocaust Litigation Related to Blood Factor VIII and IX Products and AIDS Transmission 633
Charles R. Kozak, J.D.
34.1 Introduction 633
34.2 Challenges of Factor VIII and IX Litigation 634
34.3 Development of Factor VIII and IX 635
34.4 Sources of Plasma Donors and Transmission of Hepatitis C 635
34.5 Response to Reported Side Effects of Factor VIII and IX 636
34.6 Identifying Hepatitis 637
34.7 AIDS Epidemic and Treatment of Hemophilia 638
34.8 Litigation Strategies 642
34.9 Viral Inactivation 642
34.10 History of Hepatitis Regulation 645
34.11 Defending Factor VIII and IX 646
Endnotes 646
Part III: Pharmacists, Pharmacy, and Pharmacy Practice
Chapter 35: Regulation of Pharmacy Practice 651
Ronald W. Gottrich, R.Ph., M.S.
35.1 Introduction 651
35.2 Regulatory Overview 651
A. OBRA 190 recognized as standard of care by appellate courts 652
B. Death from multiple medications 653
C. Duty transcends dispensing 653
35.3 Prescriptions 654
35.4 Reference Sources 655
35.5 The Pharmacist as a Health Professional 655
Chapter 36: Pharmacist Malpractice and the Infamous Courtney Case 657
James T. O’Donnell, Pharm.D., M.S., FCP, ABCP, FACN, CNS, R.Ph.
36.1 Pharmacist Malpractice Overview 657
A. Wrong drug 658
B. Wrong strength of the drug 659
C. Wrong directions 659
D. Drug review 660
E. Counseling 661
F. Non-bodily injury 661
G. Others 662
36.2 Hospital and Home-Care Pharmacy 662
A. Specialty compounding 662
B. Cardioplegia 662
C. Pediatrics 662
D. Pharmacokinetics: Aminoglycoside nephrotoxicity and ototoxicity 663
E. Anticoagulation 663
F. Managed care 663
36.3 Criminal Activity (The Robert Courtney Case) 664
A. Vigilance 665
B. Privacy issues 665
C. Greed as a motive 665
D. Guilty plea 665
E. Courtney case resolution 666
F. Restitution 666
G. Partners in crime 666
H. Population at risk 666
I. Regulation of compounding 667
36.4 The Courtney Criminal Case 668
A. Illegal manufacturing 668
B. Dilution and counterfeiting 668
C. FDA oversight 668
36.5 Conclusion 669
Endnotes 669
Recommended Reading 669
Citations and Case Summaries 669
Chapter 37: Guidelines for Injectable Medications: 2004 671
Saifi Vohra, Pharm.D., R.Ph., MBA, FASHP, FASCP
37.1 Introduction 671
Endnotes 672
Chapter 38: Specialized Services: A Full-Service Community Pharmacy Practice: Is this Feasible, Beneficial, and Risk-Free? 703
Roger S. Klotz, R.Ph., BCNSP, FASCP, FACA, CDM
38.1 Is There a Need for Community Pharmacy Practice? 703
38.2 Collaborative Practice 705
38.3 Centralization 705
38.4 What is a Full-Service Community Pharmacy? 706
38.5 Drug Information 707
38.6 Clinical Laboratory Services 708
38.7 Home Medical Equipment 709
38.8 Herbal and OTC Medications 710
38.9 Risks and Benefits 7