Overview. Isotretinoin Pregnancy Exposures: Spontaneous Reports 1-year Prior to, & 1-year After Implementation of the Current RMP – Marilyn R. Pitts, Pharm.D., Office of Drug Safety Isotretinoin Pregnancy Prevention Program Evaluation – Allen Brinker, M.D., M.S., Office of Drug Safety. - PowerPoint PPT Presentation
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1 Joint Dermatologic and Ophthalmic Drugs & Drug Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee Safety and Risk Management Advisory Committee February 26 & 27, 2004 February 26 & 27, 2004 Overview Isotretinoin Pregnancy Exposures: Spontaneous Reports 1-year Prior to, & 1- year After Implementation of the Current RMP – Marilyn R. Pitts, Pharm.D., Office of Drug Safety Isotretinoin Pregnancy Prevention Program Evaluation – Allen Brinker, M.D., M.S., Office of Drug Safety
Transcript
1Joint Dermatologic and Ophthalmic Drugs & Drug Safety Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee and Risk Management Advisory Committee February 26 & 27, 2004February 26 & 27, 2004
OverviewOverview
Isotretinoin Pregnancy Exposures: Spontaneous Reports 1-year Prior to, & 1-year After Implementation of the Current RMP– Marilyn R. Pitts, Pharm.D., Office of Drug Safety
Isotretinoin Pregnancy Prevention Program Evaluation– Allen Brinker, M.D., M.S., Office of Drug Safety
Isotretinoin Pregnancy Exposures: Spontaneous Reports 1-year Prior to, & 1-year After Implementation of the Current RMP– Marilyn R. Pitts, Pharm.D., Office of Drug Safety
Isotretinoin Pregnancy Prevention Program Evaluation– Allen Brinker, M.D., M.S., Office of Drug Safety
Joint Dermatologic and Ophthalmic Drugs & Drug Safety Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee and Risk Management Advisory Committee February 26 & 27, 2004February 26 & 27, 2004
Isotretinoin Pregnancy Exposures: Isotretinoin Pregnancy Exposures: Spontaneous Reports 1-year Prior to, Spontaneous Reports 1-year Prior to, & 1-year After Implementation of the & 1-year After Implementation of the Current RMPCurrent RMP
Isotretinoin Pregnancy Exposures: Isotretinoin Pregnancy Exposures: Spontaneous Reports 1-year Prior to, Spontaneous Reports 1-year Prior to, & 1-year After Implementation of the & 1-year After Implementation of the Current RMPCurrent RMP
February 26, 2004Marilyn R. Pitts, Pharm.D.,
Office of Drug Safety
In Collaboration:Claudia Karwoski, Pharm.D.,
Aaron Mendelsohn, Ph.D., M.P.H.
February 26, 2004Marilyn R. Pitts, Pharm.D.,
Office of Drug Safety
In Collaboration:Claudia Karwoski, Pharm.D.,
Aaron Mendelsohn, Ph.D., M.P.H.
3Joint Dermatologic and Ophthalmic Drugs & Drug Safety Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee and Risk Management Advisory Committee February 26 & 27, 2004February 26 & 27, 2004
– Pregnancy Testing– Contraceptive Use– Pregnancy and Fetal Outcomes
• Drug Use Data• Conclusions
4Joint Dermatologic and Ophthalmic Drugs & Drug Safety Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee and Risk Management Advisory Committee February 26 & 27, 2004February 26 & 27, 2004
ObjectivesObjectivesObjectivesObjectives
• Compare spontaneous adverse event reports of women who were pregnant while using isotretinoin one year before RMP* and one year after RMP
• Provide isotretinoin drug use data before RMP and after RMP
• Compare spontaneous adverse event reports of women who were pregnant while using isotretinoin one year before RMP* and one year after RMP
• Provide isotretinoin drug use data before RMP and after RMP
* RMP = risk management program
5Joint Dermatologic and Ophthalmic Drugs & Drug Safety Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee and Risk Management Advisory Committee February 26 & 27, 2004February 26 & 27, 2004
MethodsMethodsMethodsMethods
• Case Search– All reported cases of maternal exposure– Exposure during or < 30 days after
discontinuation of isotretinoin – August 15, 2003
• Categorized: by Conception Date– Prior RMP: 04-01-01 to 03-31-02– Current RMP: 04-01-02 to 03-31-03– Unknown
• Case Search– All reported cases of maternal exposure– Exposure during or < 30 days after
discontinuation of isotretinoin – August 15, 2003
• Categorized: by Conception Date– Prior RMP: 04-01-01 to 03-31-02– Current RMP: 04-01-02 to 03-31-03– Unknown
6Joint Dermatologic and Ophthalmic Drugs & Drug Safety Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee and Risk Management Advisory Committee February 26 & 27, 2004February 26 & 27, 2004
325 Cases Of Women Who Were 325 Cases Of Women Who Were Pregnant While Using IsotretinoinPregnant While Using Isotretinoin 325 Cases Of Women Who Were 325 Cases Of Women Who Were Pregnant While Using IsotretinoinPregnant While Using Isotretinoin
• Prior RMP – 127
• Current RMP – 120
• Unknown - 78
• Prior RMP – 127
• Current RMP – 120
• Unknown - 78
7Joint Dermatologic and Ophthalmic Drugs & Drug Safety Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee and Risk Management Advisory Committee February 26 & 27, 2004February 26 & 27, 2004
Source of 325 Exposure ReportsSource of 325 Exposure Reports Source of 325 Exposure ReportsSource of 325 Exposure Reports
Prior RMP
Current RMP
Unknown RMP Total
Total 127 120 78 325
Manufacturer 99 86 72 257
Surveys 25 32 6 63
Direct - FDA 3 2 0 5
8Joint Dermatologic and Ophthalmic Drugs & Drug Safety Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee and Risk Management Advisory Committee February 26 & 27, 2004February 26 & 27, 2004
Limitations of Case ReportsLimitations of Case ReportsLimitations of Case ReportsLimitations of Case Reports
• Spontaneous Adverse Event Reports
– Variable reporting– Variable quality– Variable completeness– Lack of RMP specific information
• Experiences of women who were pregnant in our case series may not be representative to general isotretinoin users
• Spontaneous Adverse Event Reports
– Variable reporting– Variable quality– Variable completeness– Lack of RMP specific information
• Experiences of women who were pregnant in our case series may not be representative to general isotretinoin users
9Joint Dermatologic and Ophthalmic Drugs & Drug Safety Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee and Risk Management Advisory Committee February 26 & 27, 2004February 26 & 27, 2004
Age of Women Pregnant While Age of Women Pregnant While Using IsotretinoinUsing Isotretinoin
Age of Women Pregnant While Age of Women Pregnant While Using IsotretinoinUsing Isotretinoin
Prior RMP
Current RMP
Unknown RMP
N = 111/127 101/120 27/78
Median 24 23 24
Range 14 – 36 years 14 – 42 years 15 – 50 years
10Joint Dermatologic and Ophthalmic Drugs & Drug Safety Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee and Risk Management Advisory Committee February 26 & 27, 2004February 26 & 27, 2004
Estimated Timing of Conception Estimated Timing of Conception Relative to Isotretinoin TreatmentRelative to Isotretinoin TreatmentEstimated Timing of Conception Estimated Timing of Conception
Relative to Isotretinoin TreatmentRelative to Isotretinoin TreatmentPrior RMP
Current RMP
Unknown RMP
N = 127 120 78
Before treatment 12 (10%) 7 (6%) 1 (1%)
During treatment
1st month
83 (65%)
18
80 (67%)
13
66 (85%)
1
Within 30 days of discontinuation
31 (24%) 31 (26%) 7 (9%)
Indeterminate/ NR 1 (1%) 2 (1.7%) 4 (5%)
11Joint Dermatologic and Ophthalmic Drugs & Drug Safety Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee and Risk Management Advisory Committee February 26 & 27, 2004February 26 & 27, 2004
Duration of Isotretinoin Exposure Duration of Isotretinoin Exposure After ConceptionAfter Conception
Duration of Isotretinoin Exposure Duration of Isotretinoin Exposure After ConceptionAfter Conception
Prior RMP
Current RMP
Unknown RMP
N = 71 54 8
Range (days) 1 to 91 1 to 52 3 to 105
Mean (days) 19.1 19.3 26.1
Median (days) 17 17 14
12Joint Dermatologic and Ophthalmic Drugs & Drug Safety Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee and Risk Management Advisory Committee February 26 & 27, 2004February 26 & 27, 2004
Pregnancy Testing - Baseline Pregnancy Testing - Baseline Current Label InformationCurrent Label Information
Pregnancy Testing - Baseline Pregnancy Testing - Baseline Current Label InformationCurrent Label Information
• Baseline (Before Starting Isotretinoin)
– Screening test at time of decision to pursue isotretinoin
– Confirmatory test during first 5 days of cycle immediately preceding initiation of isotretinoin
• Baseline (Before Starting Isotretinoin)
– Screening test at time of decision to pursue isotretinoin
– Confirmatory test during first 5 days of cycle immediately preceding initiation of isotretinoin
13Joint Dermatologic and Ophthalmic Drugs & Drug Safety Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee and Risk Management Advisory Committee February 26 & 27, 2004February 26 & 27, 2004
14Joint Dermatologic and Ophthalmic Drugs & Drug Safety Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee and Risk Management Advisory Committee February 26 & 27, 2004February 26 & 27, 2004
Baseline Pregnancy Testing in 20 Baseline Pregnancy Testing in 20 Women Pregnant Before IsotretinoinWomen Pregnant Before Isotretinoin
Baseline Pregnancy Testing in 20 Baseline Pregnancy Testing in 20 Women Pregnant Before IsotretinoinWomen Pregnant Before Isotretinoin
• Baseline Pregnancy Testing– 16 reported at least one baseline pregnancy test
• 9 reported at least 2 baseline pregnancy tests
– 11 reported pregnancy test results• 8 reported negative baseline test results • 3 reported positive baseline test results
– 14 of 16 did not have test during menses
• Baseline Pregnancy Testing– 16 reported at least one baseline pregnancy test
• 9 reported at least 2 baseline pregnancy tests
– 11 reported pregnancy test results• 8 reported negative baseline test results • 3 reported positive baseline test results
– 14 of 16 did not have test during menses
Prior RMP
Current RMP
Unknown RMP
Pregnant Before Starting Isotretinoin
12 7 1
15Joint Dermatologic and Ophthalmic Drugs & Drug Safety Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee and Risk Management Advisory Committee February 26 & 27, 2004February 26 & 27, 2004
Pregnancy Testing – During TreatmentPregnancy Testing – During Treatment Current Label Information Current Label Information
Pregnancy Testing – During TreatmentPregnancy Testing – During Treatment Current Label Information Current Label Information
• Each month of therapy, the patient must have a negative result from a urine or serum pregnancy test.
• A pregnancy test must be repeated every month prior to the female patient receiving each prescription
• Each month of therapy, the patient must have a negative result from a urine or serum pregnancy test.
• A pregnancy test must be repeated every month prior to the female patient receiving each prescription
16Joint Dermatologic and Ophthalmic Drugs & Drug Safety Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee and Risk Management Advisory Committee February 26 & 27, 2004February 26 & 27, 2004
Pregnancy Testing During Pregnancy Testing During Isotretinoin TreatmentIsotretinoin Treatment
Pregnancy Testing During Pregnancy Testing During Isotretinoin TreatmentIsotretinoin Treatment
Prior RMP
Current RMP
N = 127 120
Any Pregnancy Test during Treatment
45 (35%) 47 (39%)
No Pregnancy Test during Treatment 4 (3%) 2 (2%)
No Report of Pregnancy Testing Info 78 (61%) 71 (59%)
17Joint Dermatologic and Ophthalmic Drugs & Drug Safety Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee and Risk Management Advisory Committee February 26 & 27, 2004February 26 & 27, 2004
Contraception Contraception Current Label InformationCurrent Label Information
Contraception Contraception Current Label InformationCurrent Label Information
• 2 forms of effective contraception– At least one primary* method
18Joint Dermatologic and Ophthalmic Drugs & Drug Safety Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee and Risk Management Advisory Committee February 26 & 27, 2004February 26 & 27, 2004
Contraceptive Use during Contraceptive Use during Isotretinoin TherapyIsotretinoin Therapy
Contraceptive Use during Contraceptive Use during Isotretinoin TherapyIsotretinoin Therapy
Prior RMP
Current RMP
N = 127 120
Any Birth Control Method 68 (54%) 70 (59%)
No Birth Control Used/Abstinence 15 (12%) 6 (5%)
No Report of Birth Control Info 44 (34%) 44 (36%)
19Joint Dermatologic and Ophthalmic Drugs & Drug Safety Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee and Risk Management Advisory Committee February 26 & 27, 2004February 26 & 27, 2004
Any Birth Control UseAny Birth Control Use Prior RMP and Current RMP Prior RMP and Current RMP
Any Birth Control UseAny Birth Control Use Prior RMP and Current RMP Prior RMP and Current RMP
Prior RMP
Current RMP
N = 68 70
One Method – 50/68(74%) 61/70 (87%)
Two Methods – 18/68 (26%) 9/70 (13%)
20Joint Dermatologic and Ophthalmic Drugs & Drug Safety Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee and Risk Management Advisory Committee February 26 & 27, 2004February 26 & 27, 2004
Other Findings Related to Other Findings Related to Contraceptive Use Contraceptive Use
Other Findings Related to Other Findings Related to Contraceptive Use Contraceptive Use
• Non-Adherence to Contraception Directions– Prior RMP 18%– Current RMP 25%
• Contraceptive Failure Reported equally
• Non-Adherence to Contraception Directions– Prior RMP 18%– Current RMP 25%
• Contraceptive Failure Reported equally
Joint Dermatologic and Ophthalmic Drugs & Drug Safety Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee and Risk Management Advisory Committee February 26 & 27, 2004February 26 & 27, 2004
OutcomesOutcomesOutcomesOutcomes
Pregnancy and FetalPregnancy and Fetal
22Joint Dermatologic and Ophthalmic Drugs & Drug Safety Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee and Risk Management Advisory Committee February 26 & 27, 2004February 26 & 27, 2004
Pregnancy Outcomes of Pregnancy Outcomes of Isotretinoin ExposuresIsotretinoin Exposures
Pregnancy Outcomes of Pregnancy Outcomes of Isotretinoin ExposuresIsotretinoin Exposures
Prior RMP
Current RMP
UnknownRMP
N = 127 120 78
Terminations 62 (49%) 54 (45%) 20 (26%)
Elective 47 48 18
Spontaneous and/or Ectopic
15 6 2
Live Births 18 (14%) 7 (6%) 4 (5%)
Unknown 47 (37%) 59 (49%) 54 (69%)
23Joint Dermatologic and Ophthalmic Drugs & Drug Safety Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee and Risk Management Advisory Committee February 26 & 27, 2004February 26 & 27, 2004
Outcome of 29 Live BirthsOutcome of 29 Live BirthsOutcome of 29 Live BirthsOutcome of 29 Live Births
PriorRMP
Current RMP
UnknownRMP
Total
No abnormalities identified – at birth
13 5 2 20
Abnormal 4 2 1 7
Unknown Outcome
1 ------- 1 2
Total 18 7 4 29
Joint Dermatologic and Ophthalmic Drugs & Drug Safety Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee and Risk Management Advisory Committee February 26 & 27, 2004February 26 & 27, 2004
Drug UtilizationDrug UtilizationDrug UtilizationDrug Utilization
25Joint Dermatologic and Ophthalmic Drugs & Drug Safety Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee and Risk Management Advisory Committee February 26 & 27, 2004February 26 & 27, 2004
National Prescription Audit Plus (NPA Plus)
National Prescription Audit Plus (NPA Plus)
• Measures the “retail outflow” of prescriptions from pharmacies to consumers in retail stores, mail order and long-term care
• Obtained from a sample of approximately 22,000 pharmacies in the U.S.– Represents ~45% of US prescriptions
• Data are projected nationally
• Measures the “retail outflow” of prescriptions from pharmacies to consumers in retail stores, mail order and long-term care
• Obtained from a sample of approximately 22,000 pharmacies in the U.S.– Represents ~45% of US prescriptions
• Data are projected nationally
26Joint Dermatologic and Ophthalmic Drugs & Drug Safety Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee and Risk Management Advisory Committee February 26 & 27, 2004February 26 & 27, 2004
AdvancePCSAdvancePCS AdvancePCSAdvancePCS
• Large U.S. Pharmacy Benefits Manager (PBM)
• Covers over 50 million patient lives & over 300 million prescriptions annually
• Dimension Rx tool accesses information on paid prescription claims for patients with prescription drug benefits administered by AdvancePCS™
• Large U.S. Pharmacy Benefits Manager (PBM)
• Covers over 50 million patient lives & over 300 million prescriptions annually
• Dimension Rx tool accesses information on paid prescription claims for patients with prescription drug benefits administered by AdvancePCS™
27Joint Dermatologic and Ophthalmic Drugs & Drug Safety Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee and Risk Management Advisory Committee February 26 & 27, 2004February 26 & 27, 2004
LimitationsLimitationsLimitationsLimitations
• Data do not permit a more detailed analysis of the observed trends
• National estimates from IMS health may be variable due to small numbers in certain subgroups
• AdvancePCS™ data may not be nationally representative
• Data do not permit a more detailed analysis of the observed trends
• National estimates from IMS health may be variable due to small numbers in certain subgroups
• AdvancePCS™ data may not be nationally representative
28Joint Dermatologic and Ophthalmic Drugs & Drug Safety Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee and Risk Management Advisory Committee February 26 & 27, 2004February 26 & 27, 2004
Isotretinoin Utilization in the U.SIsotretinoin Utilization in the U.S. . Isotretinoin Utilization in the U.SIsotretinoin Utilization in the U.S. .
Prior RMP(Apr 01 – Mar 02)
Current RMP(Apr 02 – Mar 03)
# of Prescriptions* ~1.5 million ~1.2 million
% Refills* 15.6 2.4
% Generic* ----- 10.3
% Rx’es by Dermatologists*
76.1 79.9
% Female** 50.4 49.2Source: *IMS Health, IMS National Prescription Audit PlusTMTM (3 Dec 03) & **AdvancePCSTMTM (11 Dec 03)
29Joint Dermatologic and Ophthalmic Drugs & Drug Safety Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee and Risk Management Advisory Committee February 26 & 27, 2004February 26 & 27, 2004
Drug UtilizationDrug Utilization ConclusionsConclusions
Drug UtilizationDrug Utilization ConclusionsConclusions
• Number of dispensed isotretinoin prescriptions declined 23% following RMP implementation
• Percent of refill prescriptions for isotretinoin dropped from 16% to 2%
• Other utilization variables did not appear to be influenced by RMP (prescriber, gender)
• Number of dispensed isotretinoin prescriptions declined 23% following RMP implementation
• Percent of refill prescriptions for isotretinoin dropped from 16% to 2%
• Other utilization variables did not appear to be influenced by RMP (prescriber, gender)
30Joint Dermatologic and Ophthalmic Drugs & Drug Safety Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee and Risk Management Advisory Committee February 26 & 27, 2004February 26 & 27, 2004
• Women who were pregnant while using isotretinoin (prior -127, current – 120)
• Slight decline reported in number of women pregnant prior to starting isotretinoin (prior – 12, current – 7)
• Pregnancies reported occurring throughout isotretinoin therapy for both risk management programs
• Women who were pregnant while using isotretinoin (prior -127, current – 120)
• Slight decline reported in number of women pregnant prior to starting isotretinoin (prior – 12, current – 7)
• Pregnancies reported occurring throughout isotretinoin therapy for both risk management programs
31Joint Dermatologic and Ophthalmic Drugs & Drug Safety Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee and Risk Management Advisory Committee February 26 & 27, 2004February 26 & 27, 2004
• No difference reported in days of exposure after conception between programs
• No improvement reported in baseline pregnancy testing between programs
• Slight improvement reported in pregnancy testing during treatment in current RMP
• Slight improvement reported in the use of at least one method of contraception in current RMP
• No difference reported in days of exposure after conception between programs
• No improvement reported in baseline pregnancy testing between programs
• Slight improvement reported in pregnancy testing during treatment in current RMP
• Slight improvement reported in the use of at least one method of contraception in current RMP
32Joint Dermatologic and Ophthalmic Drugs & Drug Safety Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee and Risk Management Advisory Committee February 26 & 27, 2004February 26 & 27, 2004
