Summary Basis of Decision for Addyi

Clinical Pharmacology

The medicinal ingredient of Addyi, flibanserin, exerts its effects on the central nervous system (CNS). Flibanserin increases basal dopamine activity and transiently reduces serotonin (5-hydroxytryptamine or 5-HT) activity in the CNS by activating serotonin 1A receptors and blocking serotonin 2A receptors. The mechanism of action of flibanserin in the treatment of premenopausal women with hypoactive sexual desire disorder is not known.

The clinical pharmacology studies for Addyi included data on the safety, tolerability, pharmacokinetics, and pharmacodynamics in humans. Overall, the clinical pharmacology of Addyi has been sufficiently characterized.

As flibanserin is predominantly metabolized by the cytochrome P450 (CYP) liver enzyme CYP3A4 and, to a lesser extent, by CYP2C19, exposure to flibanserin can be dramatically affected by drug interactions, liver enzyme polymorphisms and poor hepatic health. The use of Addyi in patients with any degree of hepatic impairment, as well as concomitant use of moderate or strong drugs that are CYP3A4 inhibitors, significantly increases flibanserin concentrations, which can lead to increased risks of adverse events, including serious events such as severe hypotension, syncope and CNS depression. Therefore, Addyi is contraindicated for use with moderate or strong CYP3A4 inhibitors and in patients with any degree of hepatic impairment. Warnings regarding genetic polymorphisms in hepatic enzymes and drug interactions are extensively addressed in Addyi Product Monograph.

Use of Addyi can result in various adverse events, ranging from fatigue and nausea, to severe hypotension and syncope. These adverse events were noted in the numerous clinical studies that formed a part of the development program of flibanserin. The risk of adverse events appears to increase with increased doses of flibanserin, or increased exposures to flibanserin. While there was no effect of race on the safety profile of Addyi, women with a lower body mass index were found to have greater exposure to flibanserin.

The labelling in the Addyi Product Monograph aims to mitigate the risks of adverse events as much as possible. The dosing is limited to 100 mg daily, to be taken at bedtime, as administration during waking hours increases the risks of hypotension, syncope and CNS depression. The patient is instructed to not drive for 6 hours after ingestion of Addyi, and when driving the next morning, to be careful until they know how the drug affects them. The patient is also instructed to abstain from alcohol use or to use limited amounts, depending on their resting blood pressure readings.

The effect of flibanserin on the QT interval was evaluated in a randomized, double-blind, placebo- and active- (single-dose moxifloxacin) controlled crossover study in 56 healthy men and women. Subjects in the Addyi groups received either 50 mg twice a day (equivalent to the daily recommended dosage) or 100 mg three times a day (tid, 3 times the daily recommended dosage) administered for 5 days. The time frame for electrocardiogram (ECG) measurements covered maximum plasma concentrations of flibanserin and relevant metabolites.

The QT interval study did not identify Addyi as having any effect on QTc interval, but it recorded increases in heart rate, as well as 3 instances of palpitations and 1 of general tachycardia in patients taking 100 mg tid flibanserin (3-times the daily Addyi dose). These findings are in line with those from the Phase III studies, where a post-hoc analysis also recorded greater instances of tachycardia in patients who were administered Addyi (0.3%) than placebo (<0.1%). In the QT study, other serotonergic adverse events such as hyperthermia and agitation were also seen more frequently in women who were administered Addyi than placebo. Due to the potential to increase the heart rate and cause tachycardia/palpitations, the Addyi Product Monograph contains text advising that Addyi should be used with caution in patients with cardiovascular disorders.

For further details, please refer to the Addyi Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

Health Canada evaluated several Phase III studies that examined the efficacy of Addyi, of which Study 511.147 was determined to be the pivotal study supporting efficacy. Studies 511.71 and 511.75 were initially identified as being pivotal, but upon review it was determined that both studies failed to show significant effect in their primary endpoint, and therefore they were used as supportive evidence only.

The three studies were randomized, double-blind, placebo-controlled, parallel group, North American studies of 24-week duration. They included a total of 3,548 premenopausal patients (White 88.6%, Black 9.6%, and Asian 1.5%) with a mean age of 36 years (range 19 to 55 years) with acquired, generalized hypoactive sexual desire disorder (HSDD) of at least 6-month duration. Each study used the Diagnostic and Statistical Manual, Fourth Edition (DSM-IV) criteria for diagnosis of HSDD. The mean duration of HSDD in patients participating in these clinical studies was approximately 4 years. The completion rate across the three studies was 70% and 78% for the Addyi and placebo groups, respectively. All three studies included the dosing regimen of 100 mg every night at bedtime. A total of 1,227 patients received Addyi (100 mg flibanserin) once daily at bedtime and 1,238 received placebo.

The two primary efficacy endpoints in the pivotal study were the number of Satisfying Sexual Events (SSEs) and the Female Sexual Function Index - Desire Domain (FSFI-D). The SSE parameter measured the mean change in the number of satisfying sexual events, standardized to a 28-day period. The patient judged whether the event was satisfying, based on whether it was gratifying, fulfilling, satisfactory, and/or successful, irrespective of whether the patient had an orgasm. The FSFI-D score was based on patient-reported answers to two questions regarding frequency and intensity of sexual desire over the prior 28 days.

The pivotal study (Study 511.147) assessed whether Addyi could produce a clinically meaningful therapeutic response in premenopausal women with HSDD as primarily assessed by change in SSEs and FSFI-D. The intent-to-treat group included 1,087 patients (542 randomized to Addyi and 545 to placebo) and the final analysis set included 1,068 patients (532 randomized to Addyi and 536 to placebo).

The Addyi group had a mean increase from baseline of 2.5 SSEs compared with 1.5 SSEs for the placebo group (p<0.0001) at Week 24. At Weeks 8, 12, 16 and 20, the changes were also statistically significant. The increase from baseline of 1.0 in the FSFI-D scoring in the Addyi group, compared to an increase of 0.7 for the placebo group at Week 24 was statistically significant (p<0.0001). At Weeks 4, 8, 12 and 16, the changes were also statistically significant.

Key secondary parameters included the Female Sexual Distress Scale-Revised (FSDR-R) score, where Item 13 of the FSDS-R specifically assessed bother related to low sexual desire. Compared to placebo, the Addyi group had a statistically greater decrease in the FSDR-R score from baseline (p = 0.0001) at Week 24. At Weeks 4, 8, and 16 the changes were also statistically significant. The Patient Global Impression of Improvement (PGI-I) was another secondary parameter, and it showed significant improvements with Addyi over placebo starting at Week 4 (p<0.005).

The efficacy findings of the pivotal study, Study 511.147, were supported by Studies 511.71 and 511.75 where both studies demonstrated significant improvements in the number of SSEs and FSFI-D scores (primary and secondary parameters, respectively, in both studies). The supporting studies evaluated an additional primary endpoint, an electronic diary (eDiary), measuring a total monthly desire score. This endpoint did not show statistical significance in either of the supporting studies.

Long-Term Efficacy

Long-term efficacy of Addyi in the treatment of HSDD was demonstrated in Study 511.74 (a supportive study due to open-label phase), which involved 24 weeks of open-label Addyi treatment followed by 24 weeks of double-blind randomized treatment with either Addyi or placebo. Patients who continued on Addyi maintained improvements in both co-primary endpoints (SSEs and eDiary), whereas patients who were switched to placebo did not.

It is noted that in Study 511.74, patients who continued to receive Addyi were enriched with those who demonstrated a response to Addyi in the open-label portion of the study, and were therefore not representative of the general population. This supports the view that a subpopulation of women diagnosed with HSDD may experience some benefit from the treatment with Addyi. However, the issue of how this subpopulation of women diagnosed with HSDD may be identified prior to the start of treatment has not been explored within this submission. Based on population characteristics recorded in the Phase III studies, there are no outstanding characteristics that would enable one to identify a likely responder.

Consultations

To gain a better understanding of the clinical significance of the efficacy of Addyi, as well as the ability of Canadian practitioners to identify the target patient population, Health Canada consulted with two practising physicians (a psychiatrist and a gynecologist), as well as with Health Canada's Bureau of Medical Sciences (BMS) and Bureau of Cardiology, Allergy and Neurological Sciences (BCANS). The results of these consultations have been carefully considered in the context of the benefits, harms and uncertainties associated with Addyi.

One expert stated that the efficacy did not show clinical significance, but others argued that some women might benefit from the drug and that, as currently there is no pharmaceutical treatment for the condition, Addyi might present a valuable starting point from which to grow the medical community's understanding of HSDD.

All experts expressed concern regarding the diagnosis of the condition, citing insufficient diagnosis experience, complexity of the condition and limited time spent with patients as key issues. It was recommended that the focus of the diagnosis should be on the distress aspect of the condition, that a questionnaire be used to facilitate the discussion, and that proper diagnosis may require the assessment to take place over multiple visits.

To address the concerns identified in the consultations, additional wording regarding diagnostic considerations was added to the Addyi Product Monograph. Also, the sponsor and Health Canada jointly developed a Prescribing Checklist, as well as a Pharmacist Checklist, intended to assist in making an accurate diagnosis and facilitate a discussion on the risks and benefits of Addyi with the patient.

Overall Analysis of Efficacy

The pivotal study, Study 511.147, showed statistically significant changes in favour of Addyi as compared to placebo in SSEs, which amounted to about 1 additional satisfying sexual event per month. This study also showed statistically significant changes as compared to placebo on the FSFI-D scale, where the final scores were an increase of 1.0 for the Addyi group and 0.7 for the placebo group.

The clinically meaningful effect of Addyi was established by the Patient's Global Impression of Improvement (PGI-I) scores, using PGI-I anchoring. Patients reporting "no change" (PGI-I scores of 4) were defined as non-responders, and patients reporting "minimal improvement" (PGI-I scores of 3) were defined as responders. For each of the key efficacy endpoints, the difference between patients answering "no change" and "minimally improved" was used as the responder criterion. The PGI-I anchoring analysis determined that in the pivotal and supporting studies, the absolute difference in percent responders in patients treated with Addyi over placebo ranged from 10.1% to14.6% for SSE and from 11.6% to 12.9% for FSFI-D.

In conclusion, the overall efficacy of Addyi was found to be low; however, it was determined that Addyi may provide a novel pharmacological means by which physicians may attempt to address HSDD in their patients and that for some individuals the drug may bring substantial improvements in their conditions.

For more information, refer to the Addyi Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

Safety findings from all of the Addyi (flibanserin) studies were taken into account, and safety findings from five Phase III 24-week, double-blind, placebo-controlled randomized studies in premenopausal women with HSDD (including the three studies presented in the Clinical Efficacy section) were pooled into an integrated safety analysis (Studies 511.70, 511.71, 511.75, 511.77 and 511.147). A total of 1,543 patients were treated with Addyi 100 mg given as a single dose before bedtime, and 1,950 received placebo.

In the pooled safety analysis, the most common adverse events (AEs) were dizziness (Addyi 11.4%, placebo 2.2%), somnolence (Addyi 11.2%, placebo 3.1%), nausea (Addyi 10.4%, placebo 3.7%) and fatigue (Addyi 9.2%, placebo 5%). The majority of these AEs were of mild to moderate intensity, emerged during the first 14 days of treatment and lasted for a few weeks to a few months.

The discontinuation rate due to AEs in patients treated with Addyi was 12.8% compared to 5.9% in placebo-treated patients. The AEs that most commonly caused discontinuation of Addyi were dizziness (1.7%), nausea (1.2%), insomnia (1.1%), somnolence (1.1%), anxiety (1.0%), and fatigue (0.9%).

The events of dizziness, somnolence, and fatigue raised concerns as to whether Addyi administration may increase the risk of accidents or injury when driving, operating machinery, or during other routine activities. In the pooled analysis, 2 road traffic accidents (<0.1%) occurred among patients who received placebo, and 5 (0.2%) among those who received Addyi. Accidental injuries occurred in 7 (0.25%) patients who received placebo and in 12 (0.49%) patients who received Addyi. Overall, while road traffic accidents and accidental injuries were rare, they occurred at approximately double the rate in patients taking Addyi than placebo. In a randomized, placebo-controlled, 4-way crossover study in 83 healthy premenopausal female subjects, no adverse effect was detected on measures of driving performance itself or psychomotor performance thought to be important for driving performance when assessed 9 hours following single and multiple doses of Addyi 100 mg once daily at bedtime. The increased risk of accidents is addressed in the Addyi Product Monograph, and patients are instructed to not drive for 6 hours after taking Addyi and to use caution thereafter.

Other AEs of particular concern included syncope, hypotension and circulatory collapse. In the pooled analysis, a total of 2 (<0.1%) syncope events were recorded in the placebo group, vs. 5 (0.3%) in the Addyi group. Furthermore, there was 1 (<0.1%) of hypotension in the placebo group, vs. 4 (0.2%) in the Addyi group. Similar events were also reported in other study reports included in the submission.

In Phase I studies, syncope and hypotension were more common in patients concomitantly taking alcohol, or in those who had elevated exposure to flibanserin due to concomitant use of moderate or strong CYP3A4 inhibitors. Flibanserin is predominantly metabolized by the liver enzyme CYP3A4 and, to a lesser extent, by CYP2C19. The use of Addyi in patients with any degree of hepatic impairment, as well as concomitant use of moderate or strong drugs that are CYP3A4 inhibitors, significantly increases flibanserin concentrations, which can lead to increased risks of AEs including serious events such as severe hypotension, syncope and CNS depression. Therefore, Addyi is contraindicated for use with moderate or strong CYP3A4 inhibitors and in patients with any degree of hepatic impairment. Warnings of the use of Addyi in patients with hepatic impairment, in patients consuming alcohol, or taking moderate or strong inhibitors of CYP3A4 are included in a Serious Warnings and Precautions box in the Addyi Product Monograph.

There were no deaths directly attributed to treatment with Addyi. However, in Study 511.130 (conducted in postmenopausal women, for whom the indication of Addyi has not been approved), one woman died in her sleep due to alcohol poisoning after 13 days of Addyi use. The interaction of alcohol with Addyi could not be ruled out. The original drug submission to Health Canada included a dedicated alcohol interaction study (SPR-12-03); however, this study was found to be inadequate to determine the risk of hypotensive and/or syncopal events associated with the combination of Addyi and alcohol. The concern regarding the risk of alcohol interaction was one of the primary reasons Health Canada issued a Notice of Deficiency (NOD) in 2016.

In response to the NOD, the sponsor submitted two dedicated alcohol interaction studies, SPR-12-03 (previously submitted) and SPR15-001 (newly submitted, conducted in premenopausal women). Overall, there were similarities between the side effects observed in the first (SPR-12-03) and second (SPR15-001) alcohol interaction study, where Addyi and alcohol were found to have an additive interaction for side effects such as dizziness and nausea. The maximum alcohol intake tested corresponded to doses of >0.6 g/kg of 95% ethanol, estimated to be about three 1.5 oz spirit-type drinks for a 70 kg person. While the first study had reports of hypotension/syncope, the second study did not. In the second study, co-administration of Addyi and ethanol demonstrated an ethanol dose-dependent increase in heart rate, which may constitute a physiologic response to the hypotensive effects associated with the interaction. Furthermore, patients with borderline low blood pressure were excluded from the second study, which is not an exclusion that had been made in the earlier study. In the Phase III studies, which did not exclude women with low blood pressure, a slight increase in hypotensive events was seen in women who were given Addyi and who self-identified as "drinkers", as opposed to "non-drinkers". Given the totality of data, including the new alcohol interaction study, a warning regarding concomitant use of Addyi and alcohol, as well as a contraindication for concomitant use of Addyi and alcohol in women with low blood pressure, has been added to the Addyi Product Monograph.

Review of the individual Phase III studies indicated several other infrequent AEs that may be related to Addyi administration. These events included mental impairment, disturbance in attention, aggression, anger, confusion, mood swings, affective disorder, affect lability and cognitive deterioration. While the overall incidence of these events was rare, they constitute serious adverse events likely to be related to Addyi use and are identified in the Addyi Product Monograph.

The potential for abuse of flibanserin was investigated in an abuse liability study (SPR-12-05). This study was found to be inadequate for addressing the concerns and constituted a major objection for the NOD that was issued in 2016. Further review of the clinical studies showed that there was no evidence of abuse, misuse or diversion of flibanserin in the clinical development program or in the post-marketing data collected so far. Overall, it was determined that the abuse potential of Addyi is low. However, a case report has been recently published describing a child overdosing on about 600 mg of flibanserin, and toxicology testing revealing the presence of 1-(3-trifluoromethylphenyl)-piperazine (TFMPP, a recreational drug and also a flibanserin metabolite) in his blood (Granzella et al., 2018). Therefore, the abuse potential of Addyi should continue to be monitored.

Abuse in the form of off-label use was also of concern, particularly in light of the fact that up to 90% of physicians have reported having no experience in diagnosing hypoactive sexual desire in women. To address these concerns, the sponsor and Health Canada developed a Prescribing Checklist, as well as a Pharmacist Checklist, intended to assist in making an accurate diagnosis and facilitate a discussion on the risks and benefits of Addyi with the patient.

Additional concerns about abuse potential were raised because increased flibanserin dosing was associated with a rapid escalation in adverse reactions. This was of concern, as a strong desire for efficacy may cause women to self-administer a dose that is higher than that prescribed. Off-label use in postmenopausal women, as well as in women whose low libido is associated with the use of selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) was also a concern. To mitigate this risk, the Addyi Product Monograph contains extensive text stating that Addyi is not for use in menopausal/postmenopausal women or in women whose low libido may be due to other medication, as well as providing clear instructions to take only 1 tablet a day.

Indication

The New Drug Submission for Addyi was filed by the sponsor with the following indication:

• Addyi is indicated for the treatment of premenopausal women with acquired, generalized hypoactive sexual desire disorder (HSDD), as characterized by low sexual desire that causes marked distress or interpersonal difficulty and is not due to:

  • A coexisting medical or psychiatric condition,
  • Problems within the relationship, or
  • The effects of a medication or other drug substance.

  
  Acquired HSDD refers to HSDD that develops in a patient who previously had no problems with sexual desire. Generalized HSDD refers to HSDD that occurs regardless of the type of stimulation, situation or partner.

  Addyi is not indicated for the treatment of HSDD in postmenopausal women or in men. Addyi is not indicated to enhance sexual performance

To ensure safe and effective use of the product, Health Canada approved the following indication:

• Addyi is indicated for the treatment of premenopausal women with acquired, generalized hypoactive sexual desire disorder (HSDD), as characterized by low sexual desire for a minimum of 6 months, which occurs 75-100% of the time, that causes marked distress or interpersonal difficulty and is not due to:
  • A coexisting medical or psychiatric condition,
  • Problems within the relationship, or
  • The effects of a medication or other drug substance.
  
  

  Special Diagnostic Considerations

  • "Acquired" refers to HSDD that develops in a patient who previously had no problems with sexual desire.
  • "Generalized" refers to HSDD that occurs regardless of the type of stimulation, situation or partner.
  • There is no normative age- or gender-related data on frequency or degree of sexual desire. Therefore, the diagnosis must rely on clinical judgement based on the individual's characteristics, interpersonal determinants, life context and cultural settings.
  • The clinician may need to assess both partners when discrepancies in sexual desire prompt the call for professional attention.
  • It is recommended to use the Addyi Prescriber Checklist when making the diagnosis. The checklist can be obtained from addyi.ca.

  
  Limitations of Use

  • Addyi is not indicated for the treatment of HSDD in menopausal or postmenopausal women or in men.
  • Addyi is not indicated to enhance sexual performance.

Overall Analysis of Safety

The most frequent adverse reactions attributed to Addyi were dizziness, somnolence, nausea, and fatigue. Infrequent events included severe hypotension, fainting, tachycardia and agitation, as well as disturbances to sleep, mood, cognition and attention. It was also found that the likelihood of experiencing adverse events increased if the patient had liver or heart problems, was taking other medication, consuming alcohol or deviating from the dosing instructions.

The Addyi Product Monograph contains extensive warnings advising of the possible risks associated with Addyi. It also contains contraindications for women with hepatic impairment, for those who are taking drugs that are moderate to strong CYP3A4 inhibitors, and for those who are pregnant and breastfeeding. Women who use Addyi and have low blood pressure should not consume alcohol. To minimize the impact of side effects, Addyi should be taken only once a day, before bed and patients should abstain from driving for at least 6 hours after taking the drug.

For more information, refer to the Addyi Product Monograph, approved by Health Canada and available through the Drug Product Database.