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Sprout Pharmaceuticals Inc. FDA Approval Date: August 18, 2015

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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):


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