1. Sprout Pharmaceuticals Inc. FDA Approval Date: August 18, 2015
AddyiTM - flibanserin
Manufacturer:
Sprout Pharmaceuticals Inc.
FDA Approval Date: August 18, 2015

2. AddyiTM - flibanserin Objectives
At the end of this presentation participants will be able to:
Appropriately recommend AddyiTM (flibanserin)
Effectively educate patients on the purpose, proper use and potential adverse effects of AddyiTM (flibanserin)

3. AddyiTM - flibanserin Clinical Application
Indications:
Treatment of generalized, acquired hypoactive sexual desire disorder (HSDD) in premenopausal women
Place in therapy:
Treatment of a rare disorder in premenopausal women (~10%)
AddyiTM [package insert].
BEGONIA Trial

4. AddyiTM - flibanserin Clinical Application
Contraindications:
Alcohol intake, hepatic impairment, and concomitant use with moderate or strong CYP3A4 inhibitors
Black Box Warning:
Hypotension and syncope in specific situations:
Contraindicated with alcohol
Contraindicated with strong or moderate CYP3A4 inhibitors
Contraindicated in patients with hepatic impairment
Precautions:
Hypotension and syncope with AddyiTM alone
CNS depression (i.e. somnolence and sedation)
CYP3A4 inhibitors: azoles and protease inhibitors
AddyiTM [package insert].

5. AddyiTM - flibanserin Clinical Application
Pregnancy:
Unknown
Lactation:
NOT recommended
AddyiTM [package insert].

6. AddyiTM - flibanserin Drug Facts
Pharmacology:
Agonist of 5-HT1A
Antagonist of 5-HT2A, 5-HT2B, 5-HT2C, and dopamine D4 receptor
Exact mechanism of action is unknown
Theorized that the cause of HSDD is an imbalance of excitatory neurotransmitters: dopamine, norepinephrine, and inhibitory neurotransmitters: serotonin
AddyiTM [package insert].

7. AddyiTM - flibanserin Drug Facts
Pharmacokinetics: A
F: 33%, Tmax: 0.8 hours, steady state: reached after 3 days D
98% protein binding M
Primarily CYP3A4 metabolism (lesser extent CYP2C19) into two inactive metabolites E
T1/2: 11 hours
AddyiTM [package insert].

8. AddyiTM - flibanserin Drug Interactions
Drug Interactions – Object Drugs:
AddyiTM Increases
AddyiTM Decreases
Digoxin 2-fold
Simvastatin 1-3 fold
Oral contraceptives 100%
PGP substrates
Bupropion (hydroxybupropion) 9%
Object drugs = drugs that the review drug effect
PGP substrates include: sirolimus
AddyiTM [package insert].

9. AddyiTM - flibanserin Drug Interactions
Drug Interactions – Precipitant Drugs:
Increases AddyiTM
Decreases AddyiTM
Strong CYP3A4 inhibitors: fluconazole 7-fold, ketoconazole 4.5-fold, itraconazole 2.6-fold,
GFJ 1.4-fold
Strong CYP2C19 inhibitors
Oral contraceptives 1.4-fold
CYP3A4 inducers: Rifampin 95%
Paroxetine 4%
Etravirine 21%
Precipitant drugs = drugs that effect the reviewed drug
CYP2C19 inhibitors (increased AddyiTM concentrations = increased risk of hypotension, CNS depression, and syncope)
PPIs, SSRI’s, BDZ, and antifungals
CYP3A4 inhibitors include: azoles and protease inhibitors (increased AddyiTM concentrations = increased risk of hypotension, CNS depression, and syncope)
CYP3A4 inducers include: (decreased AddyiTM concentrations =decreased efficacy )
Carbamazepine, phenobarbital. phenytion, rifampin, and St. John’s Wort
Other DDI: alcohol (CNS depression, hypotension, and syncope) and CNS depressants (antihistamines, opioids, hypnotics, and BDZ)
AddyiTM [package insert].

10. AddyiTM - flibanserin Adverse Effects
Common ADES
CNS depression (21%) [8%]
Dizziness (11.4%) [2.2%]
Somnolence (11.2%) [2.9%]
Nausea (10.4%) [3.9%]
Fatigue (9.2%) [5.5%]
Insomnia (4.9%) [2.8%]
Dry mouth (2.4%) [1.0%]
Syncope (0.4%) [0.2%]
Hypotension (0.2%) [<0.1%]
AddyiTM [package insert].

11. AddyiTM - flibanserin Monitoring Parameters
Efficacy Monitoring:
Increase in sexual desire
Toxicity Monitoring:
Hypotension, syncope, and CNS depression
AddyiTM [package insert].

12. AddyiTM - flibanserin Prescription Information
Dosing:
Initial/Usual: 100mg PO HS
Maximum: 200mg PO HS
Renal adjustment: 50mg PO HS
Cost: $400 for 30 day supply
Contraindicated in hepatic dysfunction
AddyiTM [package insert].
Forbes Accessed 8/18/15

13. AddyiTM - flibanserin Literature Review
Efficacy of Flibanserin in Women with Hypoactive Sexual Desire Disorder: Results from the BEGONIA Trial Purpose: To access the safety and efficacy of flibanserin in premenopausal women with HSDD Design: multi-center, randomized, double-blind, placebo-controlled
One of three phase III clinical trials that led to the approval of Addyi
Katz et al. BEGONIA trial. J Sex Med. 2013;10(7):

14. AddyiTM - flibanserin Literature Review
Methods:
4-week baseline period, followed by a 24-week treatment period, and a 1-week post-treatment period
Randomized to receive either flibanserin 100mg QHS (n = 543) or placebo (n = 547)
N = 1090
Baseline period: to determine % use of the eDiary to be eligibile to continue to randomization
1-week post: effects of discontinuation?
Katz et al. BEGONIA trial. J Sex Med. 2013;10(7):

15. AddyiTM - flibanserin Literature Review
Inclusion Criteria
Exclusion Criteria
> 18 years old
Premenopausal women
Diagnosed with acquired, generalized HSDD
Heterosexual monogamous relationship for > 1 year with a sexually functioning partner physically present for > 50% of every month during the trial
Willing to engage in sexual activity at least once monthly
Medications that may affect sexual function
Diagnosed with depression (> 14 score on Beck Depression scale)
Gynecological issues including endometriosis
diagnosed by the APA’s DSM-IV for > 24 weeks
Diagnosed by a clinician experienced and trained in female sexual disorders
Other:
Required to use a medically acceptable method of contraceptive for > 6 months prior to and during the trial
Only eligible after the 4-week baseline period if they used the eDiary > 80% of the time
Exclusive medications:
AEDs, CYP3A4 inducers, dopamine agonists, antiparkinson’s drugs, metoclopramide, androgens, anti-androgens, anti-estrogens (permitted if stable dose for > 6 months), fluoxetine, long-acting hormonal implant in 30 days prior to screening unless for contraception), grh analgoues, BDZ, non-BDZ sleep aids, sedatives, hypnotics, antidepressants, antipsychotics, mood stabilizers, narcotics, vaginal lubricants/moisturizers or any other enhancing agents.
APA = American Psychiatric Association
DSM = diagnostic and statistical manual of mental disorders
Katz et al. BEGONIA trial. J Sex Med. 2013;10(7):

16. AddyiTM - flibanserin Literature Review
General Baseline Characteristics:
Avg. age ~36
~74% Caucasian
Avg kg (164 lbs)
Avg. length of relationship 11 years
Avg. duration of HSDD 49 months
Avg. baseline FSFI total score 19
Avg. baseline SSE standardized to 28-days 2.6
Katz et al. BEGONIA trial. J Sex Med. 2013;10(7):

17. AddyiTM - flibanserin Literature Review
Intervention: Compare the safety and efficacy of flibanserin to placebo
Co-primary Endpoints:
Change from baseline to week 24 in FSFI score
Number of SSE standardized to 28-days
FSFI score = female sexual function index
6 domains: desire, arousal, orgasm, lubrication, satisfaction, and pain
Higher score = better function
SSE score = satisfying sexual event
Recorded in the eDiary and standardized to 28 days
Higher score = better
Katz et al. BEGONIA trial. J Sex Med. 2013;10(7):

18. AddyiTM - flibanserin Literature Review
Secondary Endpoints:
Change from baseline to week 24 in the FSDS-R Item 13
FSDS-R total scores
FSFI total scores
PGI-I score
Patient benefit evaluation (PBE) at week 24
FSDS-R = female sexual distress scale-revised
Frequency of distress over 7 days
Low number = better (less distress)
FSDS-R Item 13 = specifically distress associated with low sexual desire
FSFI score = female sexual function index
6 domains: desire, arousal, orgasm, lubrication, satisfaction, and pain
Higher score = better function
PGI-I = patient’s global impression of improvement
Scale from 1-7
1 = very much improved
4 = no change
7 = very much worse
Lower score = better (greater improvement)
PBE = self-administered questionnaire
Single question—meaningful benefit?
SSE score = satisfying sexual event
Recorded in the eDiary and standardized to 28 days
Higher score = better
Katz et al. BEGONIA trial. J Sex Med. 2013;10(7):

19. AddyiTM - flibanserin Literature Review
Safety Assessment
Evaluation of ADES
Clinical laboratory parameters
Vital signs
Physical exam
Clinical parameters include:
Testosterone, prolactin, hematology, biochemistry, and UA
Katz et al. BEGONIA trial. J Sex Med. 2013;10(7):

20. AddyiTM - flibanserin Literature Review
Coprimary Endpoints
Results
Flibanserin
PBO
P value
Change from baseline to week 24 in FSFI desire domain score
1.0
0.7
<0.001
Number of SSE standardized to 28 days
2.5
1.5
Katz et al. BEGONIA trial. J Sex Med. 2013;10(7):

21. AddyiTM - flibanserin Literature Review
Secondary Endpoints
Results
Flibanserin
PBO
P value
Change from baseline to week 24 FSDS-R Item 13
-1.0
-0.7
<0.001
Change from baseline to week 24 FSDS-R total score
-9.4
-6.1
Change from baseline to week 24 PGI-I score
3.2
3.5
PBE at week 24
44.7%
34.8%
0.001
Katz et al. BEGONIA trial. J Sex Med. 2013;10(7):

22. AddyiTM - flibanserin Literature Review
Adverse Events:
Somnolence (14.4%) [3.5%]
Dizziness (10.3%) [1.1%]
Nausea (7.6%) [2.2%]
Fatigue (5.7%) [3.3%]
Katz et al. BEGONIA trial. J Sex Med. 2013;10(7):

23. AddyiTM - flibanserin Literature Review
Conclusions: results from this trial, “indicate that flibanserin 100mg QHS has the potential to improve sexual desire and sexual function and reduce distress related to loss of sexual desire in premenopausal women with HSSD.”
Statistically significant, but minimal improvement and therefore one might argue not a clinically significant improvement
Katz et al. BEGONIA trial. J Sex Med. 2013;10(7):

24. AddyiTM - flibanserin Summary
First-in-class for HSDD in premenopausal women
Dosing is 100mg PO daily at bedtime or 50mg for any renal impairment
Most common ADEs: dizziness, CNS depression, nausea, and sleep issues
BBW: hypotension, syncope, and CNS depression (REMS program)
Indicated for a small, specific patient population (i.e. PREmenopausal women without another cause of HSDD that will not drink alcohol)
REMS = Risk Evaluation and Mitigation Strategy
Manage known ADEs (serious)
Ensures that benefit outweighs risk; way to protect patients
Simple as a Patient Package Insert/Medication Guide or as complicated as an implementation system (like Accutane)
Addyi’s REMS is unknown at this point
VIOLET Trial: premenopausal women
Safety and efficacy
SAME endpoints
Different dosing: 50mg, 100mg and PBO
Results: improved SSE and FSFI in premenopausal women
DAISY Trial: premenopausal women
Efficacy and tolerability
Different dosing: 25mg BID, 50mg BID and 100mg QD
Results: well tolerated and improved SSE and FSFI scores compared to PBO
ADES: solmnolence, dizziness, fatigue,
SNOWDROP Trial: POSTmenopausal women
Efficacy and safety
SAME dosing as BEGONIA: 100mg QHS
Results: improved SSE, reduces stress, and well tolerated in POSTmenopausal women

25. AddyiTM - flibanserin References
AddyiTM [package insert]. Raleigh, NC: Sprout Pharmaceuticals Inc.; 2015.
Katz M, Derogatis LR, Ackerman R, et al. Efficacy of flibanserin in women with hypoactive sexual desire disorder: results from the BEGONIA trial. J Sex Med. 2013;10(7):