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

Boxed Warning Limitations

Criteria and steps for BW placement not well-defined

Compliance with BW Requirements

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

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

► 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