Safety Issues with 5-ARI Therapy

Colca Canyon, Peru

Safety Issues with 5-ARI Therapy

Dutasteride 17,000+ subjects evaluated in 3 studies for up to 4 years

Dutasteride 0.5 mg once daily is marketed in more than 101 countries

for treatment of BPH

Cumulative post-marketing exposure to dutasteride for BPH treatment

is estimated to be 8.7 million patient-years (as of March 2012)

Cumulative post-marketing exposure to dutasteride-tamsulosin for

treatment of BPH is estimated to be 461,627 patient-years
Safety Issues with 5-ARI Therapy

Sexual side effects are the most common and erectile dysfunction the
most common (9-12%) of those

Low withdrawal rate from studies (<2%) for side effects

Recent question about increased risk for high grade prostate cancer

Rare reports of male breast cancer, testicular pain and swelling,

depressed mood, congestive heart failure, glucose dysregulation from
postmarketing experience
 High Grade Prostate Cancer?

Wild Camel
Very rare, highly endangered

Gobi Desert, Mongolia

 REDUCE: Gleason score
Proportion of men
25%
p<0.0001
20% 18.1%

15% 13.3% p=0.81

10%
6.8% 6.7%
p=0.15
5%
0.6% 0.9%
0% n=617 n=437 n=233 n=220 n=19 n=29
≤6 7–10 8–10
Gleason score
Placebo group (n=3406) Dutasteride group (n=3298)

Andriole GL et al. N Engl J Med 2010;362:1192–1202

Possible explanations for more Gleason 8-10
on second REDUCE biopsy

Study design artifact

Prostate volume artifact

Dutasteride preferentially suppresses low-grade

pattern 3 tumors
 REDUCE
Study Design Artifact?
Years 1–2 Years 3–4

Dut. Placebo Dut. Placebo

Number of biopsies 3239 3346 2447 2343

Gleason 5–7 417 558 211 273

17 18 12 1
Gleason 8–10 (0.5%) (0.5%) (0.5%) (0.04%)

Andriole GL et al. N Engl J Med 2010;362:1192

REDUCE
Study Design Artifact?

141 more men on placebo were removed from the trial

because the first REDUCE biopsy showed Gleason 5-7
cancer.

Choo et al (Prostate 2007;67:1614–1620) showed 8% of

men with Gleason 5-7 are discovered to have Gleason 8-
10 on re-biopsy.

Had this been done in REDUCE, the total number of

Gleason 8-10 would be identical.
 REDUCE Radical Prostatectomy
Biopsy grade was more accurate
in men taking dutasteride
Subjects who had a radical prostatectomy reviewed centrally
Dutasteride Placebo
n=133 n=202
Biopsy Gleason score
58.2% 44.2%
confirmed at surgery
Gleason score revised
21.8% 28.7%
from low to high grade

• Men on dutasteride had less frequent

upgrading compared to those on placebo

Andriole et al. Submitted Eur Urol

 Gleason 8-10 Tumor Volume
Cancer volume mL x 10-3

In the dutasteride arm,

the PSA undetected
Gleason 8–10 cancers
had a smaller volume

n= 22 6 14 4
NCCN guidelines:
PSA velocity 3 tests over 18–24 mos
0.35 ng/mL/yr increase with PSA 2.5–4
Rise from nadir NCCN guideline 0.75 ng/mL/yr increase with PSA ≥4.0
Marberger M et al. BJU Int. 2011
 Higher incidence of Gleason 8-10 in
men with small PV at Baseline
Placebo Dutasteride P value*
Baseline PV Cases of Gleason 8–10 cancer / total no.
subjects (%†)

PV <30 cm3 7/671 (1.0%) 16/620 (2.6%) 0.0558

PV ≥30 cm3 12/2736 (0.4%) 13/2679 (0.5%) 0.84

Overall REDUCE
19/3407 (0.6%) 29/3299 (0.9%) 0.15
population
*P value dutasteride vs. placebo calculated by Fisher’s exact test
PV=prostate volume

Note: Recommended PV for BPH tx >30cm3

Pettaway C et al. AUA 2011 Poster Abstract
Sexual Side Effects

HOMO SAPIENS FOOTPRINTS

80,000 yrs

TANZANIA
Sexual Side Effects and BPH Medical Therapy

Sexual side effects can occur in some patients who use medications
for relief of symptoms related to BPH

Different classes of medications cause varying degrees of sexual

dysfunction in those affected

Growing awareness of the impact of sexual side effects

Greater need to understand and characterize sexual side effects

Sexual Side Effects in 5-ARI Clinical Studies
Advisory Board Consensus
There is no well defined and consistent definition of sexual side effects

There are no long term clinical data regarding persistence, progression, and
duration of sexual side effects while on medication and once medication is
discontinued

The mechanism of action for sexual side effects is unknown and is likely
different for the varying side effects related to libido, ejaculatory dysfunction,
and erectile dysfunction

It is unknown whether structural changes occur with 5-ARI use and if present,
whether they are reversible after discontinuation

There are no established animal models to evaluate sexual dysfunction

The patient population for which Avodart is indicated in North America is not
representative of the patient population taking finasteride for androgenic
alopecia
Sexual Side Effects in Dutasteride Clinical Studies

17,000+ subjects evaluated in 3 studies for up to 4 years

4 year incidence for dutasteride subjects was

– Erectile dysfunction 9-12%
– Decrease libido 5-7%
– Ejaculation disorders 3-4%
– Gynecomastia 4%

The majority of these sexual side effects occurred within the first 6
months (except gynecomastia)
Sexual Side Effects in Dutasteride Clinical Studies

Side effects more likely to occur in treated versus placebo patients

– Erectile dysfunction 1.4 to 1.7
– Decreased libido 1.7
– Ejaculation disorders 2.8 to 3.2
– Gynecomastia 1.9 to 3.8

Only ~20-30% of sexual side effects resolved

– 40-60% of gynecomastia resolved
– >50% of remaining side effects resolved on treatment.

Low withdrawal from studies due to sexual side effects (<2%).

Sexual Side Effects in Dutasteride Clinical Studies

There is only one study with direct comparison between

finasteride and dutasteride

One year duration

Similar occurrence of side effects

Enlarged Prostate International Comparator Study (EPICS)

J. Curtis Nickel, Peter Gilling*, Teuvo L. Tammela, Betsy Morrill,
Timothy H. Wilson and Roger S. Rittmaster
BJU International 2011; 108: 388
 Phase III Finasteride vs Dutasteride
EPICS 1 year study

Study Treatment Impotence Decreased Ejaculation Gynecomastia

Libido Disorders

ARI40001 Fin (n=817) 9.1% 6.1% 1.7% 1.2%

Dut (n=813) 7.8% 5.0% 1.7% 1.1%
Dutasteride Phase III Studies Assessed

Phase III Pivotal Studies (n=4325)

Treatments: Dutasteride (n=2167) or Placebo (n=2158)
Duration: 2 year double-blind study, 2 year open label D (n=2340)
Population: BPH pts

REDUCE (n=8231)
Treatments: Dutasteride (n=4105) or Placebo (n=4126)
Duration: 4 year double-blind study
Population: At risk for PCa

CombAT (n=4844)
Treatments: Dutasteride + Tamsulosin 0.4mg (n=1610), Dutasteride
(n=1623) or Tamsulosin (0.4mg)
Duration: 4 year double-blind study
Population: BPH subjects
Phase III Studies Demographics

Demographic Phase III Pivotal REDUCE CombAT

Studies (n=4325) (n=8231) (n=4844)

Mean Age 66.3 62.8 66.1

Mean IPSS 17.0 8.7 16.4
Mean Qmax 10.2 15.3 10.7
Mean PV 54.5 45.7 55.0
Mean PSA 4.0 5.9 4.0
% Sexually Active 69% 81% 73%

% Impotence in 41% 28% 37%

previous 3 mos

% Decreased 32% 22% 28%

Libido in previous
3 mos
Phase III Studies: Impotence Incidence

Study Treatment 6 month 1 year 2 year 4 year

incidence incidence incidence incidence

Pivotal Placebo 2.2% 3.8% 5.3%

Dut 5.5% 7.2% 9.0%
REDUCE Placebo 3.0% 4.5% 6.5% 8.8%
Dut 6.2% 8.3% 10.5% 12.1%
CombAT Dut +Tam 6.1% 7.2% 9.2% 10.4%
Dut 5.0% 6.3% 8.3% 9.1%
Tam 2.8% 3.7% 5.2% 6.8%
Phase III Studies: Decreased Libido Incidence

Study Treatment 6 month 1 year 2 year 4 year

incidence incidence incidence incidence

Pivotal Placebo 1.9% 2.5% 2.8%

Dut 3.5% 4.2% 4.8%
REDUCE Placebo 2.1% 2.9% 3.6% 4.1%
Dut 4.2% 5.3% 6.3% 6.9%
CombAT Dut +Tam 4.8% 6.0% 6.8% 7.0%
Dut 3.8% 4.4% 5.3% 5.4%
Tam 2.0% 2.7% 3.3% 3.6%
Phase III Studies: Ejaculation Disorders Incidence

Study Treatment 6 month 1 year 2 year 4 year

incidence incidence incidence incidence

Pivotal Placebo 0.6% 0.9% 1.1%

Dut 1.8% 2.4% 3.0%
REDUCE Placebo 0.3% 0.6% 0.9% 1.1%

Dut 1.7% 2.7% 3.3% 3.5%

CombAT Dut +Tam 8.2% 9.6% 10.3% 10.7%
Dut 1.2% 1.7% 2.1% 2.5%
Tam 2.3% 2.8% 3.2% 3.7%
Phase III Studies: Gynecomastia Incidence

Study Treatment 6 month 1 year 2 year 4 year

incidence incidence incidence incidence

Pivotal Placebo 0.2% 0.6% 0.8%

Dut 0.6% 1.4% 2.9%
REDUCE Placebo 0.7% 1.1% 1.5% 2.1%
Dut 1.1 % 2.0% 3.0% 3.9%
CombAT Dut +Tam 1.1% 2.2% 2.8% 3.9%
Dut 0.9% 2.0% 3.1% 4.1%
Tam 0.5% 0.9% 1.4% 1.6%
Phase III Studies: Impotence Resolution

Study Treatment % Resolved Median days % Resolved

to on
Resolution Treatment

Pivotal Placebo 26% 120 73%

Dut 28% 107 69%
REDUCE Placebo 22% 164 78%
Dut 24% 331 67%
CombAT Dut +Tam 26% 138 60%
Dut 25% 183 61%
Tam 20% 95 64%
Phase III Studies: Decreased Libido Resolution

Study Treatment % Resolved Median days % Resolved

to Resolution on Treatment

Pivotal Placebo 22% 81 46%

Dut 27% 160 54%

REDUCE Placebo 29% 188 77%

Dut 30% 324 51%
CombAT Dut +Tam 30% 152 62%
Dut 25% 127 68%
Tam 34% 100 55%
Phase III Studies: Ejaculation Disorders
Resolution

Study Treatment % Resolved Median days % Resolved

to on
Resolution Treatment

Pivotal Placebo 35% 31 88%

Dut 25% 96 63%
REDUCE Placebo 29% 163 69%
Dut 22% 187 56%
CombAT Dut +Tam 30% 183 54%
Dut 26% 143 80%
Tam 36% 134 62%
Phase III Studies: Gynecomastia Resolution

Study Treatment % Resolved Median days % Resolved

to on
Resolution Treatment

Pivotal Placebo 41% 132 86%

Dut 44% 176 71%
REDUCE Placebo 49% 155 76%
Dut 59% 201 73%
CombAT Dut +Tam 48% 142 60%
Dut 70% 159 79%
Tam 58% 116 80%
 Phase III Studies: Withdrawals from Study

Study Treatment Impotence Decreased Ejaculation Gynecomastia

Libido Disorders

Pivotal Placebo 0.7% 0.6% 0.1% 0.2%

Dut 1.1% 1.0% 0.2% 0.8%
REDUCE Placebo 0.7% 0.6% <0.1% 0.1%
Dut 1.6% 1.2% 0.4% 0.5%
CombAT Dut +Tam 1.4% 1.0% 1.2% 0.8%
Dut 0.9% 0.8% 0.1% 0.3%
Tam 0.9% 0.4% 0.6% 0.2%
 Sexual Side Effects and BPH Medical Therapy
5-ARIs and Androgenic Alopecia

Androgenic alopecia (AGA) affects 30% of men age 30

and 50% of men age 50

High prevalence and associated psychosocial morbidity*

Differences between AGA population and BPH population

• Younger age: only 20% of pts taking 5-ARI >age 50
• Longer duration of treatment
• Different doses: finasteride 1 mg AGA vs 5 mg BPH
dutasteride 0.1 mg AGA vs 0.5 mg BPH
• Probable greater impact of sexual side effects

Other considerations
• Dermatologist is primary physician
• PSA not often used in this population age
• PSA decreases less in younger men
• No epidemiological data indicating risk of HG PC in AGA population
* Williamson, et al. Eur Acad Derm & Vener 2001; Wells, et al. Br J Psychol 1995; Hunt N, McHale S. BMJ 2005.
 Sexual Side Effects and BPH Medical Therapy
5-ARIs and Androgenic Alopecia

RECENT PUBLICATION
Finasteride persistent sexual side effects. Irwig MS, Kolokula S. J Sex Med 2011

• 71 men age 21-46 who reported new onset sexual SE which persisted for at
least 3 mos after drug DC.

• Standardized interview with pts from clinical practice and Propeciahelp.com

(1400 member internet forum for unresolved finasteride SEs)

• 94% low libido, 92% ED, 92% decreased arousal, 69% orgasm problems

• Mean duration of finasteride use was 28 months

• Mean duration of persistent sexual side effects was 40 months from time of
finasteride cessation to interview date
 Sexual Side Effects and BPH Medical Therapy
5-ARIs and Androgenic Alopecia

OTHER PUBLICATIONS

• Finasteride vs placebo for AGA Kaufman KD, et al. J Am Acad Dermatol 1998
1553 men, decreased libido (1.9 vs. 1.3%), ED (1.4 vs. 0.9%)

• Finasteride vs placebo for AGA Merck. McClellan KJ, Markham A. Drugs 1999;57:111–26.
1879 men, decreased libido (1.8 vs. 1.3%), ejaculation disorders (1.2 vs.
0.7%), and erectile dysfunction (1.3 vs. 0.7%)

• Finasteride efficacy and safety. Sato A, Takeda A. J Dermatol 2011

3177 men, 0.7% AEs, 0.23% withdrawal for SEs

• Dutasteride change sex fn over 1 yr BPH Chi BH, Kim SC. Korean J Urol 2011
55 men, sexual fn restored at 6 mos except ED
 Sexual Side Effects and BPH Medical Therapy
5-ARIs and Androgenic Alopecia

META-ANALYSIS EFFICACY and SAFETY

FINASTERIDE FOR AGA
• 3927 pts in 12 RCTs (out of 128 studies reviewed)

• 4 databases and 2 Cochrane registers

• Quality of evidence moderate

• 3570 pts in 9 studies for safety review

Mella JM, et al. Arch Dermatol 2010;146(10):1141-1150.

 Sexual Side Effects and BPH Medical Therapy
5-ARIs and Androgenic Alopecia

META-ANALYSIS EFFICACY and SAFETY

FINASTERIDE FOR AGA
• Global sexual disturbances (any or all of ED, ejaculatory dysfunction, libido
decrease) RR 1.39 (95% CI, 0.99-1.95)

• 6 studies reported ED 3110 pts

RR 2.2 (95% CI, 1.03-4.78); NNH 82.1 (95% CI, 56-231)

• 6 studies reported decreased libido 3002 pts

RR 1.08 (95% CI, 0.67-1.76)

• 4 studies reported ejaculatory dysfunction 2437 pts

RR 1.75 (95% CI, 0.79-3.88)

• 5 studies reported withdrawal due to sexual AEs 2487 pts

RR 0.88 (95% CI, 0.51-1.49)
 Sexual Side Effects and BPH Medical Therapy
5-ARIs and Androgenic Alopecia

META-ANALYSIS EFFICACY and SAFETY

FINASTERIDE FOR AGA
CONCLUSIONS

• No significant difference between 1 mg and 5 mg finasteride

• Clinical implication: Men taking medication for AGA should be aware that there is a
30% chance of noticeable improvement and absolute risk of ED of 1.5%

• Study strengths: explicit eligibility criteria, comprehensive search, use of RCTs, high
agreement by investigators, sophisticated and appropriate statistical analysis

• Study limitations: most did not mention randomization methods and concealment
allocations, no high-quality evidence for any of either the benefit or the harm
outcomes
Sexual Side Effects and BPH Medical Therapy
Conclusions
Significant sexual dysfunction exists in the population treated medically for
BPH

Sexual SEs can occur in some patients who use medications for relief of
symptoms related to BPH

Most sexual SEs occur within the first 6 mos of 5-ARI use

Most sexual SEs resolve spontaneously or with treatment

Combination therapy has a greater number of sexual side effects

Further study is required to determine long term clinical data regarding

persistence, progression, and duration of sexual side effects while on
medication and once medication is discontinued
Rare Side Effects

CENTRAL
AFRICAN
RAIN FOREST

BAY’AKA
PYGMIES
 Dutasteride Phase III Studies
Cardiac Failure
Phase III Pivotal Studies (n=4325)
Treatments: Dutasteride (n=2167) or Placebo (n=2158)
BPH pts, 2 year double-blind study, 2 year open label D (n=2340)
No increased risk of CV events

REDUCE (n=8231)
Treatments: Dutasteride (n=4105) or Placebo (n=4126)
Pts at risk for Pca, 4 year double-blind study
Similar overall CV events, CF 0.7% for D, 0.4% for P

CombAT (n=4844)
Treatments: Dutasteride + Tamsulosin 0.4mg (n=1610), D or T (n=1623)
BPH pts, 4 year double-blind study
Similar overall CV events, CF 0.1% for D, 0.6% for T, 0.7% Combo

The clinical significance of the numerical imbalances

in cardiac failure is unknown

No causal relationship has been established

 Safety Issues with 5-ARI Therapy
CNS Effects

Recent publications about depression with dutasteride use

Dutasteride crosses blood-brain barrier

Post marketing cases rare but compelling

No suicide signal

“Depressive mood” added to label in 6/12, effective

immediately. Testing for depression added to all future
protocols.
39
 Safety Issues with 5-ARI Therapy
Male Breast Cancer (MBC)
Male Breast Cancer

MBC is rare event

– 2 cases in dutasteride clinical trials, 24 spontaneous reports
– 1 case each in dutasteride and placebo in pivotal P III trials
– No cases in REDUCE or CombAT trials

MBC monitored because of known assoc of 5-ARI use and gynecomastia

ASCO poster 6/12 with 20 authors RADAR group report association MBC
with 5-ARI used crude methodology and most cases were actually female.

Relationship between use of dutasteride and male breast cancer is

unknown
40
 Safety Issues with 5-ARI Therapy
Other Rare Events

Testicular pain and testicular swelling <1% in clinical trials.

Rare postmarketing reports. Added to postmarketing section of
label.

Very few cases of increased serum glucose, no safety signal.

No label change anticipated.

FDA to analyze pooled PSA data from GSK and Merck in

review of PSA doubling rule with recommendation of label
change after consensus.

41
 Safety Issues with Combination
Dutasteride and Tamsulosin Therapy

Label for Jalyn/Combodart consistent with tamsulosin label

Side effects related to tamsulosin

– Intraoperative floppy iris syndrome
– Orthostasis
– Priapism
– Stevens-Johnson syndrome
– Atrial fibrillation, tachycardia, arrhythmias

Benefit to risk ratio not affected

42
THE END

AVO-000336-ENERO-2013