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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?
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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 - Federal
Food, Drug,
and Cosmetic
Act (FDCA) - 60
day approval
process
1912 – Sherley
Amendment –
prohibits
labeling
medicines with
false therapeutic
claims
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
1969 – Adverse Event
Reporting System
established
1970 – 1st
patient
package insert
(oral
contraceptives)
1979 - 21 CFR §201.56,
§201.57 - Regulation of
format and content of
prescription drug
labeling
Boxed Warning Facts
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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
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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?
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“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
Boxed Warning Limitations
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Criteria and steps for BW placement not welldefined
Compliance with BW Requirements
Study Overview
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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
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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
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Definition of non-compliant prescribing; noncompliance 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
Study Results: Potentially Relevant BW
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
BW Drugs Prescribed without Baseline Lab Tests
► No
claims for baseline tests noted
49.6% prescribed in violation
of BW recommendation!
Results: Other Findings
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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
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contraindication
Warnings listing contraindicated drug coadministration
Concise and focused wording = better
compliance
Potential Barriers of Compliance with BW
Recommendations
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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
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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
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>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
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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
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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