PRESENTED BY: Christine M. Cheng, PharmD, Colleen DeLizza, BSPharm, Joan Kapusnik-Uner, PharmD A Survey Of Boxed Warning Adverse Reaction Content From U.S. Prescription Drug Labeling

BACKGROUND RESULTS

• Boxed warnings describe serious, potentially life-threatening adverse reactions associated with use of a drug 1, 2 1 There were a total of 419 boxed warning drug groups. 2 Hierarchical representation of boxed warning adverse reactions 3 The majority (n=387/419, 92%) of the drug groups had a boxed warning that included 25 main categories and > 150 subcategories. described at least one adverse reaction (range 1 to 10 ADR concepts per drug group). • More than 1/3 of drug labels for human prescription drugs 24 3 have a boxed warning 6% Top Boxed Warning Adverse Drug Reaction Categories INGREDIENT EXAMPLES 70% Cardiovascular Main Categories of Adverse Events Warfarin, adalimumab, bupropion NUMBER OF DRUG GROUPS (% OF • Adverse drug reactions (ADRs) described within boxed Disorders (partial listing) CATEGORY EXAMPLE SUBCATEGORIES EXAMPLE DRUG GROUP warnings have not been well characterized 7 DRUG GROUPS WITH BXW ADR) INGREDIENT DOSE FORM EXAMPLES 2% 93 + Hematologic abnormalities 103 (27%) Bone marrow suppression clozapine 22% Testosterone transdermal gel solution Cardiac Rhythm 22% Testosterone undecanoate (intramuscular injection solution) Disorders Thrombotic disorders tamoxifen NUMBER OF Hemolytic anemia fludarabine DRUG CLASS EXAMPLES Dermatologic Psychiatric disorders 72 (19%) Suicidal ideation antidepressants OBJECTIVE GROUPS (%) Systemic fluoroquinolones Disorders Abuse potential amphetamines 295 6% Nonsteroidal anti-inflammatory drugs TO REPORT CATEGORIES OF ADVERSE REACTIONS 70% Cardiovascular disorders 61 (16%) Congestive heart failure thiazolidinediones described within boxed warnings in FDA-approved prescription INGREDIENT + STRENGTH EXAMPLES Endocrine Capillary leak syndrome aldesleukin Mifepristone 200 mg Disorders drug labels available on the National Library of Medicine 2% Mifepristone 300 mg Hepatic disorders 58 (15%) Hepatic failure valproic acid and derivatives DailyMed website and the FDA website between July 2013 ADVERSE Peliosis hepatis danazol and March 2014. Fetal INGREDIENT + DOSE FORM INGREDIENT + STRENGTH Disorders EVENTS Neoplasms 50 (13%) T cell lymphoma metreleptin Medullary thyroid carcinoma liraglutide AVEED (testosterone undecanoate) injection MIFEPREX® (mifepristone) tablet, 200 mg Endo Pharmaceuticals Solutions Inc. Danco Labs LLC Gastrointestinal Respiratory system disorders 42 (11%) Interstitial pneumonitis nilutamide System Disorders Pulmonary oil microembolism reaction testosterone undecanoate METHODS WARNING: SERIOUS PULMONARY OIL MICROEMBOLISM (POME) REACTIONS Serious and sometimes fatal infections and bleeding occur very rarely following AND ANAPHYLAXIS spontaneous, surgical, and medical abortions, including following Mifeprex* use. No Immune system disorders 41 (11%) Anaphylaxis carboplatin causal relationship between the use of Mifeprex and misoprostol and these events • Serious POME reactions, involving urge to cough, dyspnea, throat tightening, chest Hematologic Infusion reactions trastuzumab has been established. Before prescribing Mifeprex, inform the patient about the • Review collection of prescription drug labels with boxed pain, dizziness, and syncope; and episodes of anaphylaxis, including life-threatening Abnormalities reactions, have been reported to occur during or immediately after the administration risk of these serious events and discuss the MEDICATION GUIDE and the PATIENT Infection 37 (10%) Progressive multifocal leukoencephalopathy brentuximab warnings on DailyMed and the FDA websites that were AGREEMENT. Ensure that the patient knows whom to call and what to do, including of testosterone undecanoate injection. These reactions can occur after any injection Opportunistic infection belatacept previously identified 3 of testosterone undecanoate during the course of therapy, including after the first going to an Emergency Room if none of the provided contacts are reachable, if dose [see Warnings and Precautions (5.1)]. she experiences sustained fever, severe abdominal pain, prolonged heavy bleeding, Immune System • Following each injection of Aveed, observe patients in the healthcare setting for 30 or syncope, or if she experiences abdominal pain or discomfort or general malaise Disorders • Assign labels to drug groups based on boxed warning minutes in order to provide appropriate medical treatment in the event of serious (including weakness, nausea, vomiting or diarrhea) more than 24 hours after taking 4 Boxed warnings for 33/387 (9%) of drug groups referenced a POME reactions or anaphylaxis [see Warnings and Precautions (5.1)]. misoprostol. DISCLOSURES: content • Because of the risks of serious POME reactions and anaphylaxis, Aveed is available • Atypical Presentation of Infection. Patients with serious bacterial infections (e.g. restricted distribution program for the drug (e.g., TOUCH prescribing Neurologic Disorders Author(s) of this presentation have the following to disclose concerning possible • Drug groups may be based on drug class or ingredient only through a restricted program under a Risk Evaluation and Mitigation Strategy Clostridium sordellii) and sepsis can present without fever, bacteremia or significant Infection program for natalizumab). financial or personal relationships with commercial entities that may have a direct or (REMS) called the Aveed REMS Program [see Warnings and Precautions (5.2)]. findings on pelvic examination following an abortion. Very rarely, deaths have been Subcategories and further qualified by additional attributes (e.g., dose indirect interest in the subject matter of this presentation: reported in patients who presented without fever, with or without abdominal pain, Christine M. Cheng: Employee, First Databank, Inc. form, strength) if needed but with leukocytosis with a marked left shift, tachycardia, hemoconcentration, and 5 There were 32 drug groups not associated with an adverse reaction. general malaise. A high index of suspicion is needed to rule out serious infection Hepatic Botulinum Toxin Colleen DeLizza: Employee, First Databank, Inc. ANDROGEL (testosterone) gel and sepsis (see WARNINGS). Disorders Spread • Most prevalent clinical issues described were: Joan-Kapusnik Uner: Employee, First Databank, Inc. AbbVie Inc. • Identify subset of drug groups with boxed warnings that • Bleeding. Prolonged heavy bleeding may be a sign of incomplete abortion or other • complications and prompt medical or surgical intervention may be needed. Advise Need for experienced physician supervision during use of describe ≥1 adverse reaction WARNING: SECONDARY EXPOSURE TO TESTOSTERONE REFERENCES: patients to seek immediate medical attention if they experience prolonged heavy Metabolic and Central Nervous Post-injection the drug (n= 16/32, 50% of drug groups). 1. Code of Federal Regulations, Title 21, Part 201, subpart B, section 201.57 (21CFR201.57) • Virilization has been reported in children who were secondarily exposed to vaginal bleeding (see WARNINGS). Nutritional Disorders System Depression Delirium & Sedation 2. Guidance for Industry on Warnings and Precautions, Contraindications, and Boxed Warning Sections of Labeling for Human Prescription Drug and • Precautions surrounding appropriate patient selection Biological Products—Content and Format; October 2011. Accessed 5/19/2014 at http://www.fda.gov/downloads/Drugs/Guidances/ucm075096.pdf. testosterone gel [see Warnings and Precautions (5.2) and Adverse Reactions 6.2)]. Patients should be advised to take their MEDICATION GUIDE with them if they visit  • Categorize boxed warning adverse reactions using • Children should avoid contact with unwashed or unclothed application sites in 3. Cheng CM, DeLizza C, Kapusnik-Uner J. Prevalence and therapeutic classifications of FDA-approved prescription drugs with boxed warnings. an emergency room or another health care provider who did not prescribe Mifeprex, criteria for use of the drug (n= 15/32, 47% of drug groups). Therapeutic Innovation and Regulatory Science, 2014;48:165-172. hierarchical concepts men using testosterone gel [see Dosage and Administration (2.2) Warnings and so that provider will be aware that the patient is undergoing a medical abortion. Chemical 4. Thompson CA. Hospital inspectors eye black-box warnings. American Journal of Health System Pharmacists, 2008;65:890-4.  Precautions (5.2)]. Neoplasms © 2014 First Databank, Inc. Part of the Hearst Health network. All trademarks mentioned herein belong to their respective holders • Healthcare providers should advise patients to strictly adhere to recommended Arachnoiditis instructions for use [see Dosage and Administration (2.2) Warnings and Precautions (5.2) and Patient Counseling Information (17)]. KORLYM (mifepristone) tablet, 300 mg DISCUSSION /CONCLUSION Corcept Therapeutics Inc. Neurologic Intracranial Disorders Hypertension Neuromuscular WARNING: TERMINATION OF PREGNANCY •  DRUG CLASS Blockade Knowledge of boxed warning adverse reaction content can help guide safe and appropriate use of Mifepristone is a potent antagonist of progesterone and cortisol via the progesterone Psychiatric CIPRO (ciprofloxacin hydrochloride) tablet, film coated and glucocorticoid (GR-II) receptors, respectively. The antiprogestational effects will Myasthenia Gravis high-risk drugs CIPRO (ciprofloxacin) kit result in the termination of pregnancy. Pregnancy must therefore be excluded before Disorders Exacerbation Osmotic Demyelination Bayer HealthCare Pharmaceuticals Inc. the initiation of treatment with Korlym and prevented during treatment and for one •  Syndrome Boxed warning adverse reactions are diverse but can be organized into an adverse reaction CIPRO® (ciprofloxacin hydrochloride) TABLETS month after stopping treatment by the use of a non-hormonal medically acceptable method of contraception unless the patient has had a surgical sterilization, in which Respiratory System classification schema CIPRO® (ciprofloxacin) ORAL SUSPENSION Neurotoxicity case no additional contraception is needed. Pregnancy must also be excluded if Disorders WARNING treatment is interrupted for more than 14 days in females of reproductive potential. Peripheral • When integrated within health information systems, hierarchical classification of boxed warning adverse Fluoroquinolones, including CIPRO®, are associated with an increased risk of tendinitis Neuropathy Urinary System reactions may help facilitate and tendon rupture in all ages. This risk is further increased in older patients usually Seizure over 60 years of age, in patients taking corticosteroid drugs, and in patients with Disorders kidney, heart or lung transplants (see WARNINGS). • Tardive Dyskinesia Identification of patients at risk for a serious reaction from a boxed warning drug Fluoroquinolones, including CIPRO, may exacerbate muscle weakness in persons with myasthenia gravis. Avoid CIPRO in patients with known history of myasthenia gravis Vision • Development of specific monitoring/surveillance programs for boxed warning drugs and adverse reactions (see WARNINGS). Disorders • Retrospective evaluation for quality improvement initiatives related to boxed warning drugs • Fulfillment of regulatory requirements for boxed warning drugs 4