addyi tm - flibanserin manufacturer: sprout pharmaceuticals inc. fda approval date: august 18, 2015

AddyiTM - flibanserin

Manufacturer:

Sprout Pharmaceuticals Inc.

FDA Approval Date: August 18, 2015


Objectives

• At the end of this presentation participants will be able to:1. Appropriately recommend AddyiTM

(flibanserin)

2. Effectively educate patients on the purpose, proper use and potential adverse effects of 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



• 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)

AddyiTM [package insert].



• Pregnancy:• Unknown

• Lactation:• NOT recommended



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



Drug Facts

• Pharmacokinetics:

AF: 33%, Tmax: 0.8 hours, steady state: reached after 3 days

D 98% protein binding

MPrimarily CYP3A4 metabolism (lesser extent CYP2C19) into two inactive metabolites

E T1/2: 11 hours



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%


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%


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%]


Monitoring Parameters

• Efficacy Monitoring:• Increase in sexual desire

• Toxicity Monitoring:• Hypotension, syncope, and CNS

depression



Prescription Information

• Dosing:• Initial/Usual: 100mg PO HS

• Maximum: 200mg PO HS

• Renal adjustment: 50mg PO HS

• Cost: $400 for 30 day supply

AddyiTM [package insert].Forbes Accessed 8/18/15


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

Katz et al. BEGONIA trial. J Sex Med. 2013;10(7):1807-15.


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)



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



Literature Review

• General Baseline Characteristics:• Avg. age ~36

• ~74% Caucasian

• Avg. 74.7 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



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



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



Literature Review

• Safety Assessment• Evaluation of ADES

• Clinical laboratory parameters

• Vital signs

• Physical exam



Literature Review

Coprimary EndpointsResults

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 <0.001



Literature Review

Secondary EndpointsResults

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 <0.001

Change from baseline to week 24 PGI-I score

3.2 3.5 <0.001

PBE at week 24 44.7% 34.8% 0.001



Literature Review

• Adverse Events:• Somnolence (14.4%) [3.5%]

• Dizziness (10.3%) [1.1%]

• Nausea (7.6%) [2.2%]

• Fatigue (5.7%) [3.3%]



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.”



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)


References

1. AddyiTM [package insert]. Raleigh, NC: Sprout Pharmaceuticals Inc.; 2015.

2. 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):1807-15.

addyi tm - flibanserin manufacturer: sprout pharmaceuticals inc. fda approval date: august 18, 2015

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