rare & serious events label comprehension ruth s. day duke university [email protected] fda...

RARE & SERIOUS EVENTSLabel Comprehension

Ruth S. Day

Duke [email protected]

FDA Arthritis Advisory Committee March 5, 2003

“COGNITIVE ACCESSIBILITY”

The ease with which

people can

findunderstandrememberuse

drug

information

in a safe and effective manner.

COGNITIVE PRINCIPLES


Information Load

Chunking

Coding

Representation

Location


Information Load

Chunking

Coding

Representation

Location

Readability

Comprehension

Attention

Cognitive Task

Metacognition

LOAD

How much is too much?

LOAD

Information Load


LOAD

Information Cognitive Load Load


POSSIBLE WARNING

POSSIBLE WARNING

“Rare but life-threatening liver toxicity has been reported, including acute liver failure.”

LOCATION ?

LOCATION ?

Black Box Warnings Section

P r e s c r i b i n g I n f o r m a t i o n a s o f A p r i l 2 0 0 0 AA R A V A ™ T a b l e t s( l e f l u n o m i d e )1 0 m g , 2 0 m g , 1 0 0 m g

C O N T R A I N D I C A T I O N S A N D W A R N I N G S

P R E G N A N C Y M U S T B E E X C L U D E D B E F O R E T H E S T A R T O F T R E A T M E N T W I T HA R A V A . A R A V A I S C O N T R A I N D I C A T E D I N P R E G N A N T W O M E N , O R W O M E N O FC H I L D B E A R I N G P O T E N T I A L W H O A R E N O T U S I N G R E L I A B L E C O N T R A C E P T I O N . ( S E EC O N T R A I N D I C A T I O N S A N D W A R N I N G S . ) P R E G N A N C Y M U S T B E A V O I D E D D U R I N GA R A V A T R E A T M E N T O R P R I O R T O T H E C O M P L E T I O N O F T H E D R U G E L I M I N A T I O NP R O C E D U R E A F T E R A R A V A T R E A T M E N T .

D E S C R I P T I O NA R A V A ™ ( l e f l u n o m i d e ) i s a p y r i m i d i n e s y n t h e s i s i n h i b i t o r . T h e c h e m i c a l n a m e f o r l e f l u n o m i d e i sN - ( 4 ´ - t r i f l u o r o m e t h y l p h e n y l ) - 5 - m e t h y l i s o x a z o l e - 4 - c a r b o x a m i d e . I t h a s a n e m p i r i c a l f o r m u l aC 1 2 H 9 F 3 N 2 O 2 , a m o l e c u l a r w e i g h t o f 2 7 0 . 2 a n d t h e f o l l o w i n g s t r u c t u r a l f o r m u l a :

A R A V A i s a v a i l a b l e f o r o r a l a d m i n i s t r a t i o n a s t a b l e t s c o n t a i n i n g 1 0 , 2 0 , o r 1 0 0 m g o f a c t i v e d r u g .C o m b i n e d w i t h l e f l u n o m i d e a r e t h e f o l l o w i n g i n a c t i v e i n g r e d i e n t s : c o l l o i d a l s i l i c o n d i o x i d e ,c r o s p o v i d o n e , h y d r o x y p r o p y l m e t h y l c e l l u l o s e , l a c t o s e m o n o h y d r a t e , m a g n e s i u m s t e a r a t e ,p o l y e t h y l e n e g l y c o l , p o v i d o n e , s t a r c h , t a l c , t i t a n i u m d i o x i d e , a n d y e l l o w f e r r i c o x i d e ( 2 0 m g t a b l e to n l y ) .C L I N I C A L P H A R M A C O L O G YM e c h a n i s m o f A c t i o nL e f l u n o m i d e i s a n i s o x a z o l e i m m u n o m o d u l a t o r y a g e n t w h i c h i n h i b i t s d i h y d r o o r o t a t ed e h y d r o g e n a s e ( a n e n z y m e i n v o l v e d i n d e n o v o p y r i m i d i n e s y n t h e s i s ) a n d h a s a n t i p r o l i f e r a t i v ea c t i v i t y . S e v e r a l i n v i v o a n d i n v i t r o e x p e r i m e n t a l m o d e l s h a v e d e m o n s t r a t e d a n a n t i - i n f l a m m a t o r ye f f e c t .P h a r m a c o k i n e t i c sF o l l o w i n g o r a l a d m i n i s t r a t i o n , l e f l u n o m i d e i s m e t a b o l i z e d t o a n a c t i v e m e t a b o l i t e A 7 7 1 7 2 6( h e r e a f t e r r e f e r r e d t o a s M 1 ) w h i c h i s r e s p o n s i b l e f o r e s s e n t i a l l y a l l o f i t s a c t i v i t y i n v i v o . P l a s m al e v e l s o f l e f l u n o m i d e a r e o c c a s i o n a l l y s e e n , a t v e r y l o w l e v e l s . S t u d i e s o f t h e p h a r m a c o k i n e t i c s o fl e f l u n o m i d e h a v e p r i m a r i l y e x a m i n e d t h e p l a s m a c o n c e n t r a t i o n s o f t h i s a c t i v e m e t a b o l i t e .

A b s o r p t i o nF o l l o w i n g o r a l a d m i n i s t r a t i o n , p e a k l e v e l s o f t h e a c t i v e m e t a b o l i t e , M 1 , o c c u r r e d b e t w e e n 6 - 1 2h o u r s a f t e r d o s i n g . D u e t o t h e v e r y l o n g h a l f - l i f e o f M 1 ( ~ 2 w e e k s ) , a l o a d i n g d o s e o f 1 0 0 m g f o r3 d a y s w a s u s e d i n c l i n i c a l s t u d i e s t o f a c i l i t a t e t h e r a p i d a t t a i n m e n t o f s t e a d y - s t a t e l e v e l s o f M 1 .

BlackBox

When female rats were treated with 1.25 mg/kg of leflunomide beginning 14 days before matingand continuing until the end of lactation, the offspring exhibited marked (greater than 90%)decreases in postnatal survival. The systemic exposure level at 1.25 mg/kg was approximately1/100 the human exposure level based on AUC.ARAVA is contraindicated in women who are or may become pregnant. If this drug is used duringpregnancy, or if the patient becomes pregnant while taking this drug, the patient should beapprised of the potential hazard to the fetus.WARNINGSImmunosuppression PotentialARAVA is not recommended for patients with severe immunodeficiency, bone marrow dysplasia,or severe, uncontrolled infections.There have been rare reports of pancytopenia in patients receiving ARAVA. In most of thesecases, patients received concomitant treatment with methotrexate or other immunosuppressiveagents, or they had recently discontinued these therapies; in some cases, patients had a priorhistory of a significant hematologic abnormality. If ARAVA is used in such patients, it should beadministered with caution and with frequent clinical and hematologic monitoring. The use ofARAVA in combination therapy with methotrexate has not been adequately studied in a controlledsetting.If evidence of bone marrow suppression occurs in a patient taking ARAVA, treatment withARAVA should be stopped, and cholestyramine or charcoal should be used to reduce the plasmaconcentration of leflunomide active metabolite (see PRECAUTIONS – General – Need for DrugElimination).In any situation in which the decision is made to switch from ARAVA to another anti-rheumaticagent with a known potential for hematologic suppression, it would be prudent to monitor forhematologic toxicity, because there will be overlap of systemic exposure to both compounds.ARAVA washout with cholestyramine or charcoal may decrease this risk, but also may inducedisease worsening if the patient had been responding to ARAVA treatment.Skin ReactionsRare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported inpatients receiving ARAVA. If a patient taking ARAVA develops any of these conditions, ARAVAtherapy should be stopped, and a drug elimination procedure is recommended (seePRECAUTIONS - General - Need for Drug Elimination).HepatotoxicityIn clinical trials, ARAVA treatment was associated with elevations of liver enzymes, primarily ALTand AST, in a significant number of patients; these effects were generally reversible. Mosttransaminase elevations were mild (=2-fold ULN) and usually resolved while continuingtreatment. Marked elevations (>3-fold ULN) occurred infrequently and reversed with dosereduction or discontinuation of treatment. The following table shows liver enzyme elevations seenwith monthly monitoring in clinical trials US301 and MN301. It was notable that the absence offolate use in MN302 was associated with a considerably greater incidence of liver enzymeelevation on methotrexate.

Table 4. Liver Enzyme Elevations >3-fold Upper Limits of Normal (ULN)US301 MN301 MN302*

LEF PL MTX LEF PL SSZ LEF MTXALT (SGPT)

>3-fold ULN 8 3 5 2 1 2 13 83(n %) (4.4) (2.5) (2.7) (1.5) (1.1) (1.5) (2.6) (16.7)

Reversed to =2-fold ULN: 8 3 5 2 1 2 12 82

Warnings

Does it matter?

Study CognitiveLabel Tasks

time

PROCEDURE


time

CONTENT

--Indication

--Warnings (liver failure)

PROCEDURE


time

CONTENT

--Indication

--Warnings (liver failure)

TASKS

--Free Recall

--Recognition

PROCEDURE

CONTRAINDICATIONS AND WARNINGS

PREGNANCY MUST BE EXCLUDED BEFORE THESTART OF TREATMENT WITH ARAVA. ARAVA ISCONTRAINDICATED IN PREGNANT WOMEN, ORWOMEN OF CHILDBEARING POTENTIAL WHO ARENOT USING RELIABLE CONTRACEPTION. (SEECONTRAINDICATIONS AND WARNINGS.) PREGNANCYMUST BE AVOIDED DURING ARAVA TREATMENT ORPRIOR TO THE COMPLETION OF THE DRUGELIMINATION PROCEDURE AFTER ARAVATREATMENT. RARE BUT LIFE-THREATENING LIVERTOXICITY HAS BEEN REPORTED, INCLUDING ACUTELIVER FAILURE.

WARNINGSHepatotoxicityRare but life-threatening liver toxicity has been reported,including acute liver failure. In clinical trials, ARAVAtreatment was associated with elevations of liver enzymes,primarily ALT and AST, in a significant number of patients;these effects were generally reversible. Most transaminase

elevations were mild (=2-fold ULN) and usually resolvedwhile continuing treatment. Marked elevations (>3-fold ULN)occurred infrequently and reversed with dose reduction ordiscontinuation of treatment. The following table shows liverenzyme elevations seen with monthly monitoring in clinicaltrials US301 and MN301. It was notable that the absence offolate use in MN302 was associated with a considerablygreater incidence of liver enzyme elevation on methotrexate.

0

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FREE RECALL

“What are the warnings?”

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FREE RECALL


2.5x

0102030405060708090

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FREE RECALL


0102030405060708090

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RECOGNITION

“Is _________ a warning?”

0102030405060708090

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RECOGNITION

“Is liver failure a warning?”

OVERVIEW

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Free Recall Recognition

Does it matter?

YES

Warnings section location increased the ability to --remember the warning --recognize the warning

Why?

1) Location

Why?

1) Location

2) Chunking



CHUNKING1



CHUNKING


PREGNANCY MUST BE EXCLUDED BEFORE THESTART OF TREATMENT WITH ARAVA. ARAVA ISCONTRAINDICATED IN PREGNANT WOMEN, ORWOMEN OF CHILDBEARING POTENTIAL WHO ARENOT USING RELIABLE CONTRACEPTION. (SEECONTRAINDICATIONS AND WARNINGS.) PREGNANCYMUST BE AVOIDED DURING ARAVA TREATMENT ORPRIOR TO THE COMPLETION OF THE DRUGELIMINATION PROCEDURE AFTER ARAVATREATMENT.

RARE BUT LIFE-THREATENING LIVER TOXICITY HASBEEN REPORTED, INCLUDING ACUTE LIVERFAILURE.

1

2

CHUNKING & CODING

CONTRAINDICATIONS AND WARNINGS PREGNANCY PREGNANCY MUST BE EXCLUDED BEFORE THE START OF TREATMENT WITH ARAVA. ARAVA IS CONTRAINDICATED IN PREGNANT WOMEN, OR WOMEN OF CHILDBEARING POTENTIAL WHO ARE NOT USING RELIABLE CONTRACEPTION. (SEE CONTRAINDICATIONS AND WARNINGS.) PREGNANCY MUST BE AVOIDED DURING ARAVA TREATMENT OR PRIOR TO THE COMPLETION OF THE DRUG ELIMINATION PROCEDURE AFTER ARAVA TREATMENT.

LIVER TOXICITY RARE BUT LIFE-THREATENING LIVER TOXICITY HAS BEEN REPORTED, INCLUDING ACUTE LIVER FAILURE.

3

Virazole WARNINGS: USE OF AEROSOLIZED VIRAZOLE IN PATIENTS REQUIRING MECHANICAL VENTILATOR ASSISTANCE SHOULD BE UNDERTAKEN ONLY BY PHYSICIANS AND SUPPORT STAFF FAMILIAR WITH THE SPECIFIC VENTILATOR BEING USED AND THIS MODE OF ADMINISTRATION OF THE DRUG. STRICT ATTENTION MUST BE PAID TO PROCEDURES THAT HAVE BEEN SHOWN TO MINIMIZE THE ACCUMULATION OF DRUG PRECIPITATE, WHICH CAN RESULT IN MECHANICAL VENTILATOR DYSFUNCTION AND ASSOCIATED INCREASED PULMONARY PRESSURES (SEE WARNINGS ). SUDDEN DETERIORATION OF RESPIRATORY FUNCTION HAS BEEN ASSOCIATED WITH INITIATION OF AEROSOLIZED VIRAZOLE USE IN INFANTS. RESPIRATORY FUNCTION SHOULD BE CAREFULLY MONITORED DURING TREATMENT. IF INITIATION OF AEROSOLIZED VIRAZOLE TREATMENT APPEARS TO PRODUCE SUDDEN DETERIORATION OF RESPIRATORY FUNCTION, TREATMENT SHOULD BE STOPPED AND REINSTITUTED ONLY WITH EXTREME CAUTION, CONTINUOUS MONITORING AND CONSIDERATION OF CONCOMITANT ADMINISTRATION OF BRONCHODILATORS (SEE WARNINGS).VIRAZOLE IS NOT INDICATED FOR USE IN ADULTS. PHYSICIANS AND PATIENTS SHOULD BE AWARE THAT RIBAVIRIN HAS BEEN SHOWN TO PRODUCE TESTICULAR LESIONS IN RODENTS AND TO BE TERATOGENIC IN ALL ANIMAL SPECIES IN WHICH ADEQUATE STUDIES HAVE BEEN CONDUCTED (RODENTS AND RABBITS); (SEE CONTRAINDICATIONS ).

DepakeneHEPATOTOXICITY: HEPATIC FAILURE RESULTING IN FATALITIES HAS OCCURRED IN PATIENTS RECEIVING VALPROIC ACID. EXPERIENCE HAS INDICATED THAT CHILDREN UNDER THE AGE OF TWO YEARS ARE AT A CONSIDERABLY INCREASED RISK OF DEVELOPING FATAL HEPATOTOXICITY, ESPECIALLY THOSE ON MULTIPLE ANTICONVULSANTS, THOSE WITH CONGENITAL METABOLIC DISORDERS, THOSE WITH SEVERE SEIZURE DISORDERS ACCOMPANIED BY MENTAL RETARDATION, AND THOSE WITH ORGANIC BRAIN DISEASE. WHEN DEPAKENE PRODUCTS ARE USED IN THIS PATIENT GROUP, THEY SHOULD BE USED WITH EXTREME CAUTION AND AS A SOLE AGENT. THE BENEFITS OF THERAPY SHOULD BE WEIGHED AGAINST THE RISKS. ABOVE THIS AGE GROUP, EXPERIENCE IN EPILEPSY HAS INDICATED THAT THE INCIDENCE OF FATAL HEPATOTOXICITY DECREASES CONSIDERABLY IN PROGRESSIVELY OLDER PATIENT GROUPS. THESE INCIDENTS USUALLY HAVE OCCURRED DURING THE FIRST SIX MONTHS OF TREATMENT. SERIOUS OR FATAL HEPATOTOXICITY MAY BE PRECEDED BY NON-SPECIFIC SYMPTOMS SUCH AS MALAISE, WEAKNESS, LETHARGY, FACIAL EDEMA, ANOREXIA, AND VOMITING. IN PATIENTS WITH EPILEPSY, A LOSS OF SEIZURE CONTROL MAY ALSO OCCUR. PATIENTS SHOULD BE MONITORED CLOSELY FOR APPEARANCE OF THESE SYMPTOMS. LIVER FUNCTION TESTS SHOULD BE PERFORMED PRIOR TO THERAPY AND AT FREQUENT INTERVALS THEREAFTER, ESPECIALLY DURING THE FIRST SIX MONTHS.

TERATOGENICITY: VALPROATE CAN PRODUCE TERATOGENIC EFFECTS SUCH AS NEURAL TUBE DEFECTS (E.G., SPINA BIFIDA). ACCORDINGLY, THE USE OF VALPROATE PRODUCTS IN WOMEN OF CHILDBEARING POTENTIAL REQUIRES THAT THE BENEFITS OF ITS USE BE WEIGHED AGAINST THE RISK OF INJURY TO THE FETUS.

PANCREATITIS: CASES OF LIFE-THREATENING PANCREATITIS HAVE BEEN REPORTED IN BOTH CHILDREN AND ADULTS RECEIVING VALPROATE. SOME OF THE CASES HAVE BEEN DESCRIBED AS HEMORRHAGIC WITH A RAPID PROGRESSION FROM INITIAL SYMPTOMS TO DEATH. CASES HAVE BEEN REPORTED SHORTLY AFTER INITIAL USE AS WELL AS AFTER SEVERAL YEARS OF USE. PATIENTS AND GUARDIANS SHOULD BE WARNED THAT ABDOMINAL PAIN, NAUSEA, VOMITING, AND/OR ANOREXIA CAN BE SYMPTOMS OF PANCREATITIS THAT REQUIRE PROMPT MEDICAL EVALUATION. IF PANCREATITIS IS DIAGNOSED, VALPROATE SHOULD ORDINARILY BE DISCONTINUED. ALTERNATIVE TREATMENT FOR THE UNDERLYING MEDICAL CONDITION SHOULD BE INITIATED AS CLINICALLY INDICATED. (See WARNINGS and PRECAUTIONS ).

Experiments

chunked > unchunked

coded > uncoded

CHUNKING & CODING

LEGIBILITY

LEGIBILITYCONTRAINDICATIONS AND WARNINGS


LEGIBILITYCONTRAINDICATIONS AND WARNINGS



Pregnancy must be excluded before the start of treatment with Arava. ARAVA is contraindicated in pregnant women, or women of childbearing potential who are not using reliable contraception. (See Contraindications and Warnings.) Pregnancy must be avoided during Arava treatment or prior to the completion of the drug elimination procedure after Arava treatment. Rare but life-threatening liver toxicity has been reported, including acute liver failure.

Imuran

WARNING Chronic immunosuppression with this purine antimetabolite increases risk of neoplasia in humans. Physicians using this drug should be very familiar with this risk as well as with the mutagenic potential to both men and women and with possible hematologic toxicities. See WARNINGS.

READABILITY

READABILITYCONTRAINDICATIONS AND WARNINGS

PREGNANCY MUST BE EXCLUDED BEFORE THESTART OF TREATMENT WITH ARAVA. ARAVA ISCONTRAINDICATED IN PREGNANT WOMEN, ORWOMEN OF CHILDBEARING POTENTIAL WHO ARENOT USING RELIABLE CONTRACEPTION.PREGNANCY MUST BE AVOIDED DURING ARAVATREATMENT OR PRIOR TO THE COMPLETION OF THEDRUG ELIMINATION PROCEDURE AFTER ARAVATREATMENT.

# Words = 48# Sentences = 3

READABILITYCONTRAINDICATIONS AND WARNINGS

PREGNANCY MUST BE EXCLUDED BEFORE THESTART OF TREATMENT WITH ARAVA. ARAVA ISCONTRAINDICATED IN PREGNANT WOMEN, ORWOMEN OF CHILDBEARING POTENTIAL WHO ARENOT USING RELIABLE CONTRACEPTION.PREGNANCY MUST BE AVOIDED DURING ARAVATREATMENT OR PRIOR TO THE COMPLETION OF THEDRUG ELIMINATION PROCEDURE AFTER ARAVATREATMENT.

# Words = 48# Sentences = 3

Passives = 66%

Grade level = 12.0

Readability Comprehensibility=


--word familiarity

--sentence length


--word familiarity

--sentence length

--# idea units

--syntactic complexity

--etc.

LINGUISTIC STRUCTURE

LINGUISTIC STRUCTURE


PREGNANCY MUST BE EXCLUDED BEFORE THE START OF TREATMENT WITH ARAVA.

ARAVA IS CONTRAINDICATED IN PREGNANT WOMEN, OR WOMEN OF CHILDBEARING POTENTIAL WHO ARE NOT USING RELIABLE CONTRACEPTION.

PREGNANCY MUST BE AVOIDED DURING ARAVA TREATMENT OR PRIOR TO THE COMPLETION OF THE DRUG ELIMINATION PROCEDURE AFTER ARAVA TREATMENT.

“LARD”

“LARD”

Lard--extra words in a sentence--make it hard to extract its basic meaning

“LARD”

De-Larding Procedure

Rewrite each sentence using only: --essential prepositions --“full” verbs


“LARD”

De-Larding Procedure

Rewrite each sentence using only: --essential prepositions --“full” verbs


ExampleThis sentence is in need of an action verb.

This sentence needs an action verb.

“LARD”Sentence #1

OriginalPREGNANCY MUST BE EXCLUDED BEFORE THE START OF TREATMENT WITH ARAVA.

De-LardedEXCLUDE PREGNANCY BEFORE STARTING ARAVA TREATMENT.

LARD FACTOR


Exclude pregnancy before starting Arava treatment. Arava is contraindicated in pregnant women or women of childbearing potential who are not using reliable contraception. Avoid pregnancy during Arava treatment and after treatment (until completing the drug elimination procedure).


PREGNANCY MUST BE EXCLUDED BEFORE THE START OF TREATMENT WITH ARAVA. ARAVA IS CONTRAINDICATED IN PREGNANT WOMEN, OR WOMEN OF CHILDBEARING POTENTIAL WHO ARE NOT USING RELIABLE CONTRACEPTION. PREGNANCY MUST BE AVOIDED DUIRNG ARAVA TREATMENT OR PRIOR TO THE COMPLETION OF THE DRUG ELIMINATION PROCEDURE AFTER ARAVA TREATMENT.

Original

Revised

LARD FACTOR

Compute the Lard Factor:

# Words (Original) – # Words (Revision) # Words (Original)

LARD FACTOR

Compute the Lard Factor:

# Words (Original) – # Words (Revision) # Words (Original)

Lard Factor = .23

OTHER EXPERIMENTS

- Readability- Attention- Comprehension- Memory- etc.

OVERVIEW

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Free Recall Recognition

Why?

1) Location

2) Chunking

3) Legibility

4) Readability

5) Comprehensibility

6) etc…

Effective -- when:

1) Legible --NOT ALL CAPITALS --serif font

2) Chunked --by type of warning

3) Coded --titles for chunks

BLACK BOX

ADVANTAGES

Black Box Warnings

--Up front

--Box --visual --alerting

ADVANTAGES

Black Box Warnings

--Up front

--Box --visual --alerting

--Context --all warnings --specific type

Physically present

INFORMATION

Physically present

Functionally absent

INFORMATION

Evidence-Based Labeling


1) Clinical trials

2) Post-market surveillance


1) Clinical trials


3) Label comprehension


1) Clinical trials


3) Label comprehension

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rare & serious events label comprehension ruth s. day duke university [email protected] fda...

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