Define Boxed Warning (BW) Legislature behind Boxed Warnings Describe and give examples of BW...
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Transcript of Define Boxed Warning (BW) Legislature behind Boxed Warnings Describe and give examples of BW...
Define Boxed Warning (BW) Legislature behind Boxed Warnings Describe and give examples of BW addition process Consequences of BW addition Provide list of top prescribed medications that have
Boxed Warnings Evaluate frequency of physicians prescribing
medications with BW and compliance with warnings List alert systems that notify prescribers and
consumers of newly issued warnings List sources of information regarding medication
alerts
What is Boxed Warning?
Boxed Warning – strongest warning that FDA requires on labeling of prescription medication
Boxed Warning – brief summary of information critical for prescriber to be aware of, including restrictions on distribution or use► Risk of serious adverse reaction► Proper administration and monitoring requirements
that can prevent or diminish serious adverse reaction
► Information on restriction of distribution and use of drug
► Important risk/benefit information unique to drug Only FDA can mandate addition of BW to labeling
§ 21 CFR 201.57(c)(1)
Boxed Warnings in History
1938 - FederalFood, Drug, and Cosmetic Act (FDCA) - 60 day approval process
1948 – Administrative Procedures Act – enforcement of labeling compliance
1962 - Kefauver-Harris Amendments to FDCA – drug has effects claimed by manufacturer; greater safety proof; FDA, not FTC regulates drug advertisement
1912 – Sherley Amendment – prohibits labeling medicines with false therapeutic claims
1979 - 21 CFR §201.56, §201.57 - Regulation of format and content of prescription drug labeling
1969 – Adverse Event Reporting System established
1970 – 1st patient package insert (oral contraceptives)
Boxed Warning Facts
Nomenclature - “Boxed Warning”, sometimes referred to as ► “Black Box Warning”► “Black Label Warning”► Warning information displayed in box “black box”
Boxed warning placement dictated by FDA► Usually – at beginning of label
Boxed warning information availability► Post-marketing or at marketing
FDCA – “drug is misbranded if it lacks adequate warning of possible danger”
Adequate warning must appear on all drug labeling
Results of Survey of 206 Drugs: Categories
Identification and avoidance of high risk patients – 25% (95/375)► E.g., PO contraceptives in smokers
Important drug dosing and drug interactions – 20% (74/375)► E.g., ketorolac
Need for special training or special setting for drug administration – 18% (66/375)► E.g., chemotherapeutic agents
Drug administration information – 15% (57/375) Early detection of reversible condition – 12% (47/375) Benefits > Risks in certain situations – 10% (47/375)
Beach JE et al. Food and Drug Law Journal 1998;53:403-411
What are BW Based on?
“Ordinarily based on clinical data”► Trials that were part of new drug application (NDA)
– 28.7% (73/206)−E.g., zalcitabine
► Postmarketing reports – 52.4% (133/206)−E.g., felbamate
► Epidemiological surveys – 9.4% (24/206)−E.g., PO contraceptives in smokers
Serious animal toxicity data in absence of clinical evidence
Other miscellaneous sources – 9.4% (24/206)► E.g., potential for abuse, not studied in certain
patient groups (e.g., children)
Beach JE et al. Food and Drug Law Journal 1998;53:403-411
Process of Boxed Warning Addition
1. Clinical data from post-marketing surveillance reported to MEDWATCH
2. FDA may refer ADE reports to Center for Drug Evaluation and Research (CDER)
3. CDER may refer information to FDA Advisory Committee for drug under evaluation
4. FDA Commissioner makes final decision ► Note: FDA Commissioner not obligated to follow
FDA Advisory Committee− E.g., droperidol case – 2001 BW added− Anesthetic and Life Support Drugs Advisory
Committee within the Center for Drug Evaluation and Research not consulted
Dershwitz M. Journal of Clinical Anesthesia 2002;14(8):598-603
Repercussions of BW Addition
Prescriber ► Ensure to follow BW advisory to avoid patient harm► May lead to significant reduction of drug use for
approved indications► May lead to prejudice against drug► Increased potential for litigation
Pharmacist► Ensure adequate counseling► Perform adequate “checks and balances”► Dispense medication guide (in some cases)
Repercussions of BW Addition
Pharmaceutical manufacturer► Restricted advertisement (e.g., no “reminder ads”)► Negative effects on drug sales
−Seldane® sales dropped from $700 $450 million
► Decrease in prescribing ► Protects from product liability
Patient ► Decreased compliance due to fear
Study Overview
Objective► To assess frequency of use of medications
containing boxed warnings in ambulatory care and prescribing compliance with BW recommendations
Design► Retrospective study► Data drawn from automated clams of members of
HMO Research Network’s Center for Education and Research on Therapeutics
► 10 geographically diverse plans in US► Data collection 01.01.1999 – 31.06.2001
Study Methods …cont’d
Assessment of prevalence of dispensing BW medications► N = 929,958 health plan members
−Continuously enrolled−Had ongoing drug benefits
Assessment of prescribing compliance with BW► N = 216,694► Received 1 of 19 selected BW medications or
groups of medications Sources of BW information
► Physician’s Drug Reference 1999 – 2001► Published lists of BW medications from Hosp Pharm
2002;37 issue
BW Definition and Inclusion
Drugs grouped by pharmacologic class if they all carried same BW
BW classification► Applies to all patients► Applies to children (0 – 14 y/o) only► Applies to women only► Applies to women of childbearing age (15 – 44 y/o)
only Other BW included
► Drugs requiring laboratory monitoring► Contraindications of coadministration ► Specified pregnancy as contraindication
Study Definitions …cont’d
Definition of non-compliant prescribing; non-compliance with:► BW requiring laboratory monitoring before therapy
initiation or during continued therapy► BW listing contraindicated co-medications► BW with pregnancy as contraindication
Drugs with BW excluded from study if► BW pertained to storage, handling, distribution,
compounding directions, administration, or dosing guidelines
Results: 11 Most Common Drugs with BW
► BW warning against abrupt discontinuation−Atenolol−Metoprolol
► BW warning for restricted use for specific indications−Clindamycin−Levothyroxine−Metronidazole
► BW indicating drugs not to be used in some cases−Propoxyphene−Medroxyprogesterone
► No claims for baseline tests noted
BW Drugs Prescribed without Baseline Lab Tests
49.6% prescribed in violation of BW recommendation!
Results: Other Findings
Missing claims for recommended laboratory tests with continuous therapy – 6,605 (12.8%)► Valproic acid (29.5%)► Isoniazid (25.2%)► Various diuretics
Dispensing drugs with BW against coadministration – 5,199 (9.3%)► Methotrexate + NSAIDs► Ketorolac + NSAIDs
Drugs with BW contraindicated in pregnancy – 95 (0.3%)
BW Drugs with Excellent Compliance
Warning explicitly states pregnancy as contraindication
Warnings listing contraindicated drug co-administration
Concise and focused wording = better compliance
Potential Barriers of Compliance with BW Recommendations
Poor lay public education regarding boxed warning meaning and implications
Inconsistent format of BW text Unclear message and/or non-specific
requirements ► E.g., not listing specific contraindicated medication ► E.g., not specifying how often laboratory test should
be done Criteria for BW to be added
Timing of New BW Addition and Drug Withdrawal from Market
Objective► To determine frequency and timing of new BW
addition or withdrawal of prescription medications PDR review 1975-1999
► 548 new drugs approved► 56 (10.2%) new Boxed Warning added or withdrawn
−45 (8.2%) 1 Boxed Warning−16 (2.9%) withdrawn (5 with new BW)
Lesser KE et al. JAMA 2002;287(17):2215-2219.
BW Addition or Market Withdrawal …cont’d
Kaplan-Meier analysis ► 20% chance for withdrawal or new BW for drug
over 25 years► ½ package insert changes within 7 years of
approval► ½ withdrawals within 2 years of approval
Boxed Warnings inconsistencies noted► Asynchronous appearances of BW among drugs in
same class► Not all drugs in same class have BW
−E.g., Beta blockers (atenolol vs. bisoprolol)► Asynchronous appearances of BW among
interacting medications
Lesser KE et al. JAMA 2002;287(17):2215-2219.
U.S. Drugs on Market
>4,300 drugs on U.S. market 428 drugs have Boxed Warning
► ~ 10% drugs carry Boxed Warnings Top prescribed drugs with BW from 2007
1. Fluticasone+salmeterol (Advair® Diskus)2. Quetiapine (Seroquel®)3. Venlafaxine (Effexor XR®)4. Escitalopram (Lexapro®)5. Pioglitazone (Actos®)6. Risperidone (Risperdal®)7. Aripiprazole (Abilify®)8. Duloxetine (Cymbalta®)9. Lamotrigine (Lamictal®)10. Olanzapine (Zyprexa®)
www.drugs.com/top200.html
New Boxed Warnings
02/26/2009 – new BW for metoclopramide December 2008
► Avandamet► Avandaryl► Myozyme
November 2008► Premarin vaginal cream► Truvada► Viread► Fluoroquinolone antibiotics ► Ontak IV► Raptiva for injection► Regranex gel
Self Assessment Question
Which statement is true regarding Boxed Warnings?
A. 17% of approved medications on US market have boxed warning
B. Boxed warning can only be placed in package insert
C. Boxed warning labeling does not always apply to all patients
D. If manufacturer is aware of severe adverse drug event of their medication, it may place Boxed Warning initially, but FDA may recommend deleting it later on