allergan, inc. nda 21-701 tazarotene 1.5 and 4.5 mg capsules

04/19/23 20:53

Allergan, Inc. - Backup Files Presented

Allergan, Inc.Allergan, Inc.NDA 21-701NDA 21-701

tazarotene 1.5 and 4.5 mg capsulestazarotene 1.5 and 4.5 mg capsules

Backup slides presentedBackup slides presented

FDA Advisory CommitteeFDA Advisory Committee July 12, 2004July 12, 2004

04/19/23 20:53Allergan, Inc. - Backup Files Presented

Prior and Concomitant TherapyPrior and Concomitant Therapy• Patients were not to have used: Patients were not to have used:

– Systemic medications (other than corticosteroids) known to affect Systemic medications (other than corticosteroids) known to affect bone (eg, alendronate sodium) in bone (eg, alendronate sodium) in the 12 months before study entrythe 12 months before study entry

– Systemic retinoids (eg, isotretinoin, acitretin, bexarotene) or oral or Systemic retinoids (eg, isotretinoin, acitretin, bexarotene) or oral or injectable systemic corticosteroids in the 8 weeks before study entryinjectable systemic corticosteroids in the 8 weeks before study entry

– PUVA, methotrexate, or cyclosporine in the 4 weeks before study PUVA, methotrexate, or cyclosporine in the 4 weeks before study entryentry

– UVB treatment or topical therapies (eg, topical corticosteroids, UVB treatment or topical therapies (eg, topical corticosteroids, topical retinoids, topical calcipotriene) that may have altered the topical retinoids, topical calcipotriene) that may have altered the course of psoriasis in the course of psoriasis in the 2 weeks before study entry2 weeks before study entry

– Daily vitamin A supplements > 5,000 IU, vitamin D supplements > 400 Daily vitamin A supplements > 5,000 IU, vitamin D supplements > 400 IU, or calcium supplements IU, or calcium supplements > 1,300 mg in the 7 days before study entry> 1,300 mg in the 7 days before study entry

C-028


Prior and Concomitant TherapyPrior and Concomitant Therapy(cont.)(cont.)

• During their participation in the study, other than the use During their participation in the study, other than the use of study medication, patients were not to use any of study medication, patients were not to use any medications that could alter the course of their psoriasis medications that could alter the course of their psoriasis or could interfere with the evaluation of the study or could interfere with the evaluation of the study medicationmedication

• Therapies considered necessary for the patient’s welfare Therapies considered necessary for the patient’s welfare could be given at the discretion of the investigatorcould be given at the discretion of the investigator

• If the decision was made to administer a medication that If the decision was made to administer a medication that may have affected the outcome of the study, the may have affected the outcome of the study, the medication was to be administered in constant doses medication was to be administered in constant doses throughout the studythroughout the study

C-029


Liver Function TestsLiver Function TestsNot Elevated Compared With PlaceboNot Elevated Compared With Placebo

PlaceboPlacebo12 Week 12 Week

TxTx24 Week 24 Week

TxTx52 Week 52 Week

TxTx

ALTALT 25.3%*25.3%* 19.1%19.1% 26.1%26.1% 17.9%17.9%

ASTAST 14.9%14.9% 15.3%15.3% 29.3%29.3% 23.6%23.6%

GGTGGT 17.1%17.1% 17.9%17.9% 28.3%28.3% 21.3%21.3%

LDHLDH 3.1%3.1% 3.2%3.2% 6.5%6.5% 4.9%4.9%

Total BiliTotal Bili 3.4%*3.4%* 0.9%0.9% 1.1%1.1% 3.0%3.0%

Direct BiliDirect Bili 0.3%0.3% 0.0%0.0% 0.0%0.0% 0.0%0.0%

Indirect BiliIndirect Bili 1.7%1.7% 0.6%0.6% 1.1%1.1% 1.9%1.9%

Alk PhosAlk Phos 4.2%4.2% 3.8%3.8% 4.3%4.3% 14.1%14.1%^̂

Adverse Events (LFTs)Adverse Events (LFTs) 1.1%1.1% 1.1%1.1% 1.1%1.1% 5.7%5.7%

*Placebo higher than tazarotene in 12 weeks tx study*Placebo higher than tazarotene in 12 weeks tx study^ Higher than placebo and higher with long term tx^ Higher than placebo and higher with long term tx

S-035


Patient Satisfaction with Treatment at Week 12Patient Satisfaction with Treatment at Week 12

Mean satisfaction scores indicate statistically significant greater satisfaction with Mean satisfaction scores indicate statistically significant greater satisfaction with oral tazarotene than with placebo (oral tazarotene than with placebo (pp<0.001).<0.001).

Patients Treated with Oral Tazarotene Had Patients Treated with Oral Tazarotene Had Greater Satisfaction with Their Study MedicationGreater Satisfaction with Their Study Medication

(Study(Study 048P/049P)048P/049P)

24.0%26.2%

29.3%

19.3%

13.9%

19.3%

0.0%

5.0%

10.0%

15.0%

20.0%

25.0%

30.0%

35.0%

40.0%

Extremely Satisfied Very Satisfied Somewhat Satisfied

Oral Tazorotene 4.5mg Placebo

Oral Tazarotene 4.5 mgOral Tazarotene 4.5 mg79.5%79.5%

were satisfied with their study medicationwere satisfied with their study medication

Placebo52.3%

were satisfied with their study medication

E-134


-0.84

-1.87

-2.43

-2.96-3.5

-3

-2.5

-2

-1.5

-1

-0.5

0

OLA Improvement at Week 12OLA Improvement at Week 12Relative to PQOL-12 Change ScoresRelative to PQOL-12 Change Scores

Mea

n P

QO

L-1

2 M

ean

PQ

OL

-12

Ch

ang

e S

core

Ch

ang

e S

core

MID=1.24

Improvement in PQOL-12 is Correlated to Improvement in PQOL-12 is Correlated to Improvement in OLA (048P/049P)Improvement in OLA (048P/049P)

and Greater Than Placeboand Greater Than Placebo

[-2.08, -1.65]*[-2.08, -1.65]*

[-2.79, -2.07]*[-2.79, -2.07]*

[-3.42, -2.50]*[-3.42, -2.50]*

[-1.05, -0.62][-1.05, -0.62]

* 95% confidence interval of the mean* 95% confidence interval of the mean

1 grade OLA 1 grade OLA ImprovementImprovement

2 grade OLA 2 grade OLA ImprovementImprovementPlaceboPlacebo

OLA ofOLA ofmin or nonemin or none

E-141


S-212

Bone Mineral Density IssueBone Mineral Density IssueFemoral Neck BMD Data, 95% Tolerance Region, Femoral Neck BMD Data, 95% Tolerance Region,

and +/-5% Straight-Line Tolerance Regionand +/-5% Straight-Line Tolerance Region

0.5

0.75

1

1.25

1.5

0.5 0.75 1 1.25 1.5Baseline

Po

stT

rea

tme

nt

Elliptical 95% Tol Region

Y=0.95*X

Y=1.05*X

BMD Data

• 94% of points in TR94% of points in TR

• 83% in “slice” (vs. 81% expected)83% in “slice” (vs. 81% expected)

• 11% below “slice” (vs. 13% exp.)11% below “slice” (vs. 13% exp.)

• 6% above “slice” (vs. 5% exp.)6% above “slice” (vs. 5% exp.)

Mean shift: -0.01 (0.943 vs 0.933) Mean shift: -0.01 (0.943 vs 0.933)

Median shift: -0.003Median shift: -0.003


Bone Fractures Reported in 9 Patients Bone Fractures Reported in 9 Patients in 048P, 049P, 052P, and 050P Trialsin 048P, 049P, 052P, and 050P Trials

PatientPatientDuration Tx Duration Tx

when reportedwhen reportedStudy day Study day

of onsetof onset Duration, dDuration, d LocationLocation Age, yAge, y GenderGender

10881088 61 days p61 days placebolacebo 6161 5454 HandHand 3434 MaleMale

11011101 0 days taz0 days taz -6-6 4141 ToeToe 3535 FemaleFemale

10991099 87 days taz87 days taz 130130(post-Tx)(post-Tx)

3939 ToeToe 3737 MaleMale

23822382 80 days taz 80 days taz 9898(post-Tx)(post-Tx)

?? AnkleAnkle 3030 FemaleFemale

39153915 5 days taz5 days taz 55 22 Small toeSmall toe 4444 MaleMale

37583758 59 days taz59 days taz 5959 7272 ToeToe 4747 MaleMale

34573457 174 days taz174 days taz 174174 7878 Lower legLower leg 2828 MaleMale

35643564 277 days taz277 days taz 277277 147147 RibsRibs 7474 MaleMale

35533553 286 days taz286 days taz 286286 9393 HandHand 4040 MaleMale

S-086


No Apparent Association Between No Apparent Association Between Fractures and BMDFractures and BMD

LS = lumbar spine, H = total hip, FN = femoral neckLS = lumbar spine, H = total hip, FN = femoral neckS-087

PatientPatientDuration Tx when Duration Tx when fracture reportedfracture reported LocationLocation Age, yAge, y GenderGender

∆ ∆ BMDBMDnext scannext scan

11011101 0 days tazarotene0 days tazarotene ToeToe 3535 FemaleFemale LS: -1.9%LS: -1.9%H: +2.2%H: +2.2%FN: -1.1%FN: -1.1%

10991099 87 days tazarotene87 days tazarotene(post-Tx)(post-Tx)

ToeToe 3737 MaleMale LS: +0.6%LS: +0.6%H: -3.8%H: -3.8%FN: -1.8%FN: -1.8%

23822382 80 days tazarotene80 days tazarotene(post-Tx)(post-Tx)

AnkleAnkle 3030 FemaleFemale LS: -3.0%LS: -3.0%H: +2.4%H: +2.4%FN: +0.2%FN: +0.2%

39153915 5 days tazarotene5 days tazarotene ToeToe 4444 MaleMale LS: +4.2%LS: +4.2%H: -0.2%H: -0.2%FN: +0.9%FN: +0.9%

35643564 277 days tazarotene277 days tazarotene RibsRibs 7474 MaleMale LS: +5.2%LS: +5.2%H: +1.2%H: +1.2%FN: -6.5%FN: -6.5%

35533553 286 days tazarotene286 days tazarotene HandHand 40 40 MaleMale LS: +2.3%LS: +2.3%H: -1.2%H: -1.2%FN: +0.7%FN: +0.7%


Patient 1115 Patient 1115 (Apparent Loss of >50% Hip BMD (Apparent Loss of >50% Hip BMD

Due to Scan of Unacceptable Quality)Due to Scan of Unacceptable Quality)

Bone Density Bone Density (g/cm(g/cm22))

Change in Change in Bone Density Bone Density

(%)(%)

Lumbar spineLumbar spine ScreeningScreening

Wk 12Wk 12

Wk 24Wk 24

1.4171.417

1.3531.353

1.2941.294 -4.52%-4.52%

-8.68%-8.68%

Total hipTotal hip ScreeningScreening

Wk 12Wk 12

Wk 24Wk 24

1.1501.150

0.5350.535

1.1261.126[-53.48%]*[-53.48%]*

-2.09%-2.09%

Femoral neckFemoral neck ScreeningScreening

Wk 12Wk 12

Wk 24Wk 24

0.9790.979

0.8360.836

0.9310.931[-14.61%]*[-14.61%]*

-4.90%-4.90%*Unacceptable quality scan*Unacceptable quality scan

S-183


Apparent Loss of ≥ 20% BMD from Apparent Loss of ≥ 20% BMD from Baseline (Patient 3409)Baseline (Patient 3409)

Bone DensityBone Density(g/cm(g/cm22)) Change in Bone Density (%)Change in Bone Density (%)

ScreeningScreening Wk 24Wk 24 Wk 52Wk 52 Wk 64Wk 64

Lumbar spineLumbar spine 1.4201.420 -6.7%-6.7% -9.3%-9.3% -5.8%-5.8%

Total hipTotal hip 1.2871.287 -6.6%-6.6% -8.2%-8.2% -10.6%-10.6%

Femoral neckFemoral neck 1.2591.259 -8.5%-8.5% -9.8%-9.8% -28.3%-28.3%

S-206

• 50-year old male with obesity (151 kg), diabetes, and sleep apnea 50-year old male with obesity (151 kg), diabetes, and sleep apnea

• BMD assessment at limits of capability of BMD technology due to obesity BMD assessment at limits of capability of BMD technology due to obesity

• Patient started with high BMD/T scorePatient started with high BMD/T score

• Concomitant meds: aspirin, Glucovance, benazepril, amfebutamone, Concomitant meds: aspirin, Glucovance, benazepril, amfebutamone, sertraline, pramipexole, saw palmettosertraline, pramipexole, saw palmetto


Risk of Osteopenia and Osteoporosis Risk of Osteopenia and Osteoporosis In Patients with In Patients with ≥ 5% Loss in BMD ≥ 5% Loss in BMD

(050P)(050P)

• Of 32 patients with Of 32 patients with ≥ 5% loss in BMD at any time:≥ 5% loss in BMD at any time:– 14 (44%) had normal BMD throughout the study 14 (44%) had normal BMD throughout the study – 12 (38%) had osteopenia at baseline and never 12 (38%) had osteopenia at baseline and never

became osteoporoticbecame osteoporotic– 5 (16%) developed osteopenia (from normal at 5 (16%) developed osteopenia (from normal at

baseline) baseline) – None developed osteoporosis; 1 (3%) had None developed osteoporosis; 1 (3%) had

osteoporosis at baseline osteoporosis at baseline andand follow-up follow-up

• No greater risk of osteoporosis in patients with No greater risk of osteoporosis in patients with ≥ 5% loss vs. patients who do not have ≥ 5% loss≥ 5% loss vs. patients who do not have ≥ 5% loss

S-196


Minimal Effects on Thyroid FunctionMinimal Effects on Thyroid Function

S-188

048P & 049P combined 048P & 049P combined (12 weeks treatment)(12 weeks treatment) TazaroteneTazarotene PlaceboPlacebo P-valueP-valueHypothyroidismHypothyroidism 2/348 (0.6%)2/348 (0.6%) 0/358 (0.0%) 0/358 (0.0%) p = 0.243p = 0.243TSH > ULNTSH > ULN 23/346 (6.6%)23/346 (6.6%) 23/356 (6.5%)23/356 (6.5%) p = 0.920p = 0.920ThyroxineThyroxine 4/346 (1.2%)4/346 (1.2%) 9/356 (2.5%)9/356 (2.5%) p = 0.178p = 0.178

052P052PTaz → TazTaz → Taz(24 weeks)(24 weeks)

PlaceboPlacebo(12 weeks)(12 weeks)

HypothyroidismHypothyroidism 2/92 (2.2%)2/92 (2.2%) 0/220 (0.0%) 0/220 (0.0%) TSH > ULNTSH > ULN 8/92 (8.7%)8/92 (8.7%) 16/220 (7.3%)16/220 (7.3%)ThyroxineThyroxine 1/92 (1.1%)1/92 (1.1%) 7/220 (3.2%)7/220 (3.2%)

050P050P(52 weeks treatment)(52 weeks treatment) 0-24 weeks0-24 weeks 24-52 weeks24-52 weeks 0-52 weeks0-52 weeksHypothyroidismHypothyroidism 1/263 (0.4%)1/263 (0.4%) 1/199 (0.5%) 1/199 (0.5%) 1/263 (0.4%)1/263 (0.4%)

TSH > ULNTSH > ULN 20/263 (7.6%)20/263 (7.6%)

ThyroxineThyroxine 4/263 (1.5%)4/263 (1.5%)


Education Materials for PhysiciansEducation Materials for Physicians

• What Prescribers Need to KnowWhat Prescribers Need to Know Brochure Brochure

• Prescriber Introduction LetterPrescriber Introduction Letter

• Prescriber certification testPrescriber certification test

• Medication GuideMedication Guide

R-052


RiskMAP Roll-outRiskMAP Roll-out

R-055

• Broad target audienceBroad target audience

• Registration kits for physicians and Registration kits for physicians and pharmaciespharmacies

• Educational seminarsEducational seminars

• Professional meetingsProfessional meetings

• Field force participationField force participation


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Body Weight, Gender, and Age Body Weight, Gender, and Age Have No Effects on PK Have No Effects on PK

Study 048PStudy 048P

Study 049PStudy 049P

PC-017

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Logistic Regression: Clinical Success* Logistic Regression: Clinical Success* Versus Possible CovariatesVersus Possible Covariates

Studies 048P/049PStudies 048P/049P(N = 689)(N = 689)

VariableVariableParameterParameterEstimateEstimate

WaldWaldChi-SquareChi-Square p-valuep-value

TreatmentTreatment 1.8831.883 30.22530.225 < 0.001< 0.001

AgeAge 0.0180.018 3.0483.048 0.0810.081

SexSex -0.791-0.791 7.6997.699 0.0060.006

RaceRace 0.2210.221 0.4860.486 0.4860.486

Baseline OLABaseline OLA -0.489-0.489 2.6132.613 0.1060.106

Weight (kgs)Weight (kgs) -0.006-0.006 0.7220.722 0.3960.396

Baseline Body Baseline Body Surface AreaSurface Area

0.0100.010 1.6541.654 0.1990.199

C-136* Clinical success = None/Minimal OLA at Week 12* Clinical success = None/Minimal OLA at Week 12


Incidence of HyperglycemiaIncidence of Hyperglycemia

S-189

048P & 049P048P & 049P(12 Weeks)(12 Weeks) TazaroteneTazarotene PlaceboPlacebo P-valueP-value

Hyperglycemia (AEs)Hyperglycemia (AEs) 7/348 (2.0%)7/348 (2.0%) 0/358 (0.0%)0/358 (0.0%) p = 0.007p = 0.007

Incidence > ULNIncidence > ULN 51/346 (14.7%)51/346 (14.7%) 64/356 (18.0%)64/356 (18.0%) p = 0.247p = 0.247

052P052PTaz → TazTaz → Taz(24 weeks)(24 weeks)

Plac → TazPlac → Taz(12 weeks)(12 weeks)

Hyperglycemia (AEs)Hyperglycemia (AEs) 1/92 (1.1%)1/92 (1.1%) 4/220 (1.8%)4/220 (1.8%)

Incidence > ULNIncidence > ULN 31/92 (33.7%)31/92 (33.7%) 53/220 (24.1%)53/220 (24.1%)

050P050P(52 Weeks)(52 Weeks) 0-24 weeks0-24 weeks 24-52 weeks24-52 weeks 0-52 weeks0-52 weeks

Hyperglycemia (AEs)Hyperglycemia (AEs) 3/263 (1.1%)3/263 (1.1%) 3/199 (1.5%)3/199 (1.5%)

Incidence > ULNIncidence > ULN 61/263 (23.2%)61/263 (23.2%)

allergan, inc. nda 21-701 tazarotene 1.5 and 4.5 mg capsules

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