Summary Basis of Decision for Osphena

Review decision

The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.


Product type:

Drug

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Osphena is located below.

Recent Activity for Osphena

The SBDs written for eligible drugs (as outlined in Frequently Asked Questions: Summary Basis of Decision [SBD] Project: Phase II) approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. The PAATs will be updated regularly with post-authorization activity throughout the product life cycle.

The following table describes post-authorization activity for Osphena, a product which contains the medicinal ingredient ospemifene. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the List of abbreviations found in Post-Authorization Activity Tables (PAATs).

For additional information about the drug submission process, refer to the Guidance Document: The Management of Drug Submissions and Applications.

Updated: 2024-06-13

Drug Identification Number (DIN):

DIN 02518112 – 60 mg ospemifene, tablet, oral administration

Post-Authorization Activity Table (PAAT)

Activity/Submission Type, Control Number

Date Submitted

Decision and Date

Summary of Activities

SNDS # 261762

2022-02-24

Issued NOC 2022-09-02

Submission filed as a Level I – Supplement to add an alternate manufacturing site for the production of the ospemifene drug substance and for a change in the drug substance manufacturing process. The submission was reviewed and considered acceptable, and an NOC was issued.

Drug product (DIN 02518112) market notification

Not applicable

Date of first sale: 2022-01-13

The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.

NDS # 222001

2018-11-19

Issued NOC 2021-07-16

NOC issued for New Drug Submission.
Summary Basis of Decision (SBD) for Osphena

Date SBD issued: 2021-12-08

The following information relates to the New Drug Submission for Osphena.

Ospemifene

Drug Identification Number (DIN):

  • DIN 02518112 - 60 mg tablet, oral administration

Duchesnay Inc.

New Drug Submission Control Number: 222001

 

On July 16, 2021, Health Canada issued a Notice of Compliance to Duchesnay Inc. for the drug product Osphena.

The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada’s review, the benefit-harm-uncertainty profile of Osphena is favourable for use in postmenopausal women for the treatment of moderate to severe dyspareunia and/or vaginal dryness, symptoms of vulvar and vaginal atrophy, a component of genitourinary syndrome of menopause.

 

1 What was approved?

 

Osphena, a selective estrogen receptor modulator, was authorized for use in postmenopausal women for the treatment of moderate to severe dyspareunia and/or vaginal dryness, symptoms of vulvar and vaginal atrophy, a component of genitourinary syndrome of menopause.

The efficacy and safety of Osphena have not been established in pediatric subjects (<18 years of age). Osphena is therefore not authorized for pediatric use.

Of the 2,209 Osphena-treated women enrolled in the ten Phase II/III trials, more than 19 percent were 65 years of age or older. No overall differences in efficacy or safety were observed in geriatric women compared to younger women.

Osphena is contraindicated in women who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.

Osphena is contraindicated in women with any of the following conditions:

  • undiagnosed abnormal genital bleeding;
  • known or suspected estrogen-dependent neoplasia;
  • active deep vein thrombosis, pulmonary embolism, or a history of these conditions;
  • active arterial thromboembolic disease [for example, stroke and myocardial infarction], or a history of these conditions;
  • severe hepatic impairment ;
  • women who are or may become pregnant. Ospemifene (the medicinal ingredient in Osphena) may cause fetal harm when administered to a pregnant woman. Ospemifene was embryo-fetal lethal with labour difficulties and increased pup deaths in rats at doses below clinical exposures, and embryo-fetal lethal in rabbits at 10 times the clinical exposure based on mg/m2. If this drug is used during pregnancy, or if a woman becomes pregnant while taking this drug, she should be apprised of the potential hazard to a fetus ;
  • hypersensitivity (for example, angioedema, urticaria, rash, pruritus).

Osphena was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Osphena (60 mg ospemifene) is presented as tablet. In addition to the medicinal ingredient, the tablet also contains colloidal silicon dioxide, hypromellose, lactose monohydrate, magnesium stearate, mannitol, microcrystalline cellulose, polyethylene glycol, povidone, pregelatinized starch, sodium starch glycolate, titanium dioxide, and triacetin.

For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

Additional information may be found in the Osphena Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

2 Why was Osphena approved?

 

Health Canada considers that the benefit-harm-uncertainty profile of Osphena is favourable for use in postmenopausal women for the treatment of moderate to severe dyspareunia and/or vaginal dryness, symptoms of vulvar and vaginal atrophy, a component of genitourinary syndrome of menopause.

Vulvovaginal atrophy is a common condition in postmenopausal women. Vulvovaginal atrophy, often referred to as vaginal atrophy, urogenital atrophy, or atrophic vaginitis, is a condition associated with the declining estrogen levels during peri- and post-menopause.

The incidence of postmenopausal women with symptoms of vulvovaginal atrophy is estimated to be from 10% to 40%. However, only 20% to 25% of the estimated symptomatic women seek medical attention, suggesting that vulvovaginal atrophy is an underdiagnosed condition. In recent large cohort surveys in Western populations, 45% to 63% of postmenopausal women reported that they had experienced vulvovaginal symptoms, with a prevalence of 34% in Canada.

Genital symptoms of vulvovaginal atrophy include a decrease in vaginal lubrication due to the hormone insufficiency, dryness, burning, dyspareunia, loss of vaginal secretions, leucorrhea, vulvar pruritus, feeling of pressure, itching, and yellow malodorous discharge. Over time, the lack of vaginal lubrication often results in sexual dysfunction and associated emotional distress.

The estrogen reduction after menopause is followed by numerous cytologic transformations, such as proliferation of connective tissue, fragmentation of elastin, and hyalinization of collagen, changes that may result in granulation, fissures, ecchymoses, telangiectases, ulcerations, and atrophic changes in the female genital and lower urinary tracts. Genital atrophic changes include decreased maturation of the vaginal epithelial cells and progressive decrease in vascularity in the surrounding tissue.

Ospemifene (the medicinal ingredient in Osphena) is a selective estrogen receptor modulator with tissue selective effects (estrogenic or anti-estrogenic effects in different tissues of the body). Its biological actions are largely mediated through binding to estrogen receptors. This binding results in activation of estrogenic pathways in some tissues (agonist) and blockade of estrogenic pathways in others (antagonist). Osphena is an oral, non-hormonal option for the treatment of dyspareunia and/or vaginal dryness as a symptom of vulvovaginal atrophy due to menopause.

The efficacy and safety of Osphena 60 mg for the proposed indication were evaluated in three pivotal Phase III trials (15-50310, 15-50821, and 1517I0231) and one 52-week long-term safety trial (15-50718). In the four placebo-controlled trials, a total of 1,415 women received Osphena 60 mg and 1,101 women received a placebo.

All three pivotal trials were multicentre, randomized, double-blind, placebo-controlled, parallel-group clinical studies, each with a duration of 12 weeks. Subjects enrolled in these trials were healthy postmenopausal women between 40 and 80 years of age, who at baseline had ≤5% superficial cells on a vaginal smear, a vaginal pH >5.0, and who identified at least one moderate to severe vaginal symptom that was considered the most bothersome (i.e., vaginal dryness, pain during intercourse [dyspareunia]).

All women in the 12-week trials were assessed for improvement in the mean change from baseline to Week 12 for the co-primary efficacy endpoints of: ‘most bothersome symptom’ (MBS) of vulvar and vaginal atrophy (defined as the individual moderate to severe symptom that was identified by the woman as most bothersome at baseline), percentage of vaginal superficial and vaginal parabasal cells on a vaginal smear, and vaginal pH. All participants were given a non-hormonal vaginal lubricant for use as needed. The MBS approach is considered a meaningful standard for measurement of self-assessed vulvovaginal atrophy symptom changes and is currently accepted by the United States Food and Drug Administration.

Results from all three 12-week trials showed that women treated with Osphena 60 mg had statistically significant improvements (least square mean change from baseline to Week 12) in the moderate to severe MBS of dyspareunia (p< 0.0012) or vaginal dryness (p< 0.05) when compared to the women treated with a placebo. The effect sizes of treatment difference between Osphena and placebo groups in MBS for dyspareunia (-0.30) and MBS for vaginal dryness (-0.42) were considered small.

The three 12-week trials also showed statistically significant increases in the proportion of superficial cells (range between +7% and +10.8%) and statistically significant decreases in the proportion of parabasal cells (range between -23.7% and -40%) on a vaginal smear (p< 0.001 for all trials). The mean reductions in vaginal pH between baseline and Week 12 (range between -0.94 and -1.01) were statistically significant (p< 0.0001 for all trials).

The safety profile of Osphena was assessed in three 12-week pivotal trials and one 52-week long-term safety trial.  The long-term 52-week safety trial (15-50718) was a randomized, double-blind, placebo-controlled study that enrolled 426 healthy postmenopausal women between 49 and 79 years of age (mean 62 years of age) with an intact uterus. The safety results observed in the 52-week trial were similar to those observed in the three 12-week trials.

The most frequently reported adverse drug reactions in women treated with Osphena 60 mg for 12 weeks were hot flushes (6.5%), vaginal discharge (3.8%), muscle spasm (1.8%), and hyperhidrosis (1.1%). The less commonly (<1%) reported adverse drug reactions were breast pain/tenderness, endometrial hypertrophy, acne, pruritus, rash, depression, and insomnia.

The potential risk of cardiovascular disorders was examined. In the clinical trials, with a duration of treatment up to 15 months, the incidence rate of hemorrhagic stroke was 3.39 per 1,000 women-years (3 reported cases) in women treated with Osphena 60 mg compared with 0 in the placebo group. The incidence rate of thromboembolic stroke was 1.13 per 1,000 women-years (1 reported case) in the Osphena 60 mg group and 3.15 per 1,000 women-years (1 reported case) in the placebo group. The incidence of deep vein thrombosis was 2.26 per 1,000 women-years (2 reported cases) in the Osphena 60 mg group and 3.15 per 1,000 women-years (1 reported case) in the placebo group. In addition, deep vein thrombosis, thrombosis, pulmonary embolism, and hypersensitivity, angioedema, and headache have been reported in the global post-market surveillance systems.

Treatment with Osphena 60 mg may be associated with an increased risk of endometrial cancer. While current Osphena trials have not shown any cases of endometrial cancer with treatment exposure up to 52 weeks, one patient did have a biopsy that showed endometrial hyperplasia without atypia. In the endometrium, Osphena does have a weak estrogen agonistic effect. Based on scientific literature, there is a potential increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. Safety data collected beyond 52 weeks in Osphena clinical trials did show evidence of endometrial thickening equal to 5 mm or greater in the Osphena treatment groups at a rate of 72.5 per 1,000 women vs. 11.8 per 1,000 women for the placebo. This safety data set also showed the incidence of any type of proliferative (weakly plus active plus disordered) endometrium was 26.3 per thousand women in Osphena treatment groups vs. 0 per thousand women for the placebo. Safety data beyond 52 weeks also showed uterine polyps occurred at an incidence of 11.6 per thousand women in the Osphena treatment groups vs. 8.9 per thousand women for placebo.

The potential risk of cardiovascular disorders (thromboembolic stroke and hemorrhagic stroke, and deep vein thrombosis) and endometrial cancer have been included in the Serious Warnings and Precautions box of the Osphena Product Monograph.

A Risk Management Plan (RMP) for Osphena was submitted by Duchesnay Inc. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.

The submitted inner and outer labels, package insert and Patient Medication Information section of the Osphena Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.

A review of the submitted brand name assessment, including testing for look-alike sound-alike attributes, was conducted and the proposed name Osphena was accepted.

Overall, Osphena has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Osphena Product Monograph to address the identified safety concerns.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

 

3 What steps led to the approval of Osphena?

 

A New Drug Submission (NDS) for Osphena was filed with Health Canada on November 19, 2018. Upon Health Canada’s completion of the quality (chemistry and manufacturing) assessment, the Osphena NDS was found to be non-compliant with sub-section C.08.002 (2) of the Food and Drugs Act and its Regulations. As a result, Health Canada issued a Notice of Deficiency (NOD) to the sponsor on December 19, 2019 requesting the provision of additional quality information related to the drug substance. In response to the NOD, the sponsor submitted the requested information and all of the concerns that led to the NOD were satisfactorily addressed. Based on the information provided, Osphena was shown to have a positive benefit-risk profile and a Notice of Compliance was issued to Duchesnay Inc. on July 16, 2021.

 

Submission Milestones: Osphena

Submission Milestone Date
Pre-submission meeting 2018-06-13
Submission filed 2018-11-19
Screening 1  
Screening Deficiency Notice issued 2019-01-02
Response filed 2019-02-08
Screening Acceptance Letter issued 2019-03-08
Review 1  
Biostatistics Evaluation complete 2019-09-05
Review of Risk Management Plan complete 2019-10-15
Biopharmaceutics Evaluation complete 2019-11-26
Notice of Deficiency (NOD) issued by Director General, Therapeutic Products Directorate (quality issues) 2019-12-19
Response filed 2020-08-18
Screening 2  
Screening Acceptance Letter issued 2020-09-28
Review 2  
Quality Evaluation complete 2021-07-05
Labelling Review complete 2021-07-13
Non Clinical Evaluation complete 2021-07-14
Clinical/Medical Evaluation complete 2021-07-14
Notice of Compliance issued by Director General, Therapeutic Products Directorate 2021-07-16

 

The Canadian regulatory decision on the quality, non-clinical and clinical review of Osphena was based on a critical assessment of the data package submitted to Health Canada. The foreign reviews completed by the United States Food and Drug Administration were also used as an added reference.

For additional information about the drug submission process, refer to the Management of Drug Submissions and Applications Guidance.

 

4 What follow-up measures will the company take?

 

Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.

 

5 What post-authorization activity has taken place for Osphena?

 

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada’s decisions were negative or positive. The PAAT will continue to be updated during the product life cycle.

The PAAT for Osphena is found above.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

 

6 What other information is available about drugs?

 

Up-to-date information on drug products can be found at the following links:

 

7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical Basis for Decision

 

Clinical Pharmacology

Osphena is an estrogen receptor agonist/antagonist with tissue-selective effects, commonly referred to as selective estrogen receptor modulator. Its biological actions are mediated through binding to estrogen receptors. This binding results in activation of estrogenic pathways in some tissues (agonism) and blockade of estrogenic pathways in others (antagonism).

Ospemifene (the medicinal ingredient in Osphena) has an effect on the receptors of estrogens in the vagina, increasing the cellular maturation and mucification of the vaginal epithelium.

In general, food increased bioavailability of ospemifene by approximately 2 to 3-fold. Single dose of ospemifene 60 mg tablet administered with a high fat/high calorie meal (860 kcal) in postmenopausal women increased maximum plasma drug concentration (Cmax) and area under the plasma concentration-time curve extrapolated to infinity (AUC0-inf) by 2.3- and 1.7-fold, respectively, compared to fasted condition. Ospemifene is primarily metabolized by the liver and primarily undergoes metabolism via cytochrome P450 (CYP) 3A4, CYP2C9, and CYP2C19. The effect of severe hepatic impairment on the pharmacokinetics of ospemifene has not been evaluated. Osphena should not be used in women with severe hepatic impairment.

A thorough Phase I QTc study with moxifloxacin as a positive control and ospemifene used at the expected therapeutic dose of 60 mg and a supra-therapeutic dose of 240 mg was done in healthy men and women. Ospemifene showed no signal of any effect on heart rate, atrioventricular conduction or cardiac depolarization as measured by the PR and QRS interval durations.

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

Clinical Efficacy

The efficacy of Osphena was evaluated in three pivotal Phase III trials (15-50310, 15-50821, and 1517I0231), each lasting 12 weeks in duration. Long-term use of Osphena was also examined in a 52-week safety trial (15-50718). In these four placebo-controlled trials, a total of 1,415 women received Osphena 60 mg and 1,101 women received a placebo.

The study design of all three pivotal 12-week trials were multicentre, randomized, double-blind, placebo-controlled, parallel-group clinical trials. The total number of women randomized to the Osphena 60 mg treatment group was 1,052. The total number of women in the placebo group was 1,038. Subjects enrolled in these trials were healthy postmenopausal women between 40 and 80 years of age, who at baseline had ≤5% superficial cells on a vaginal smear, a vaginal pH >5.0, and who identified at least one moderate to severe vaginal symptom that was considered the most bothersome (i.e., vaginal dryness, pain during intercourse [dyspareunia]).

All women in the three 12-week trials were assessed for improvement in the mean change from baseline to Week 12 for the co-primary efficacy endpoints of: ‘most bothersome symptom’ (MBS) of vulvar and vaginal atrophy (defined as the individual moderate to severe symptom that was identified by the woman as most bothersome at baseline), percentage of vaginal superficial and vaginal parabasal cells on a vaginal smear, and vaginal pH. The MBS approach is considered a meaningful standard for measurement of self-assessed vulvovaginal atrophy symptom changes and is currently accepted by the United States Food and Drug Administration.

The long-term 52-week safety trial (15-50718) was a randomized, double-blind, placebo-controlled trial conducted in 426 healthy postmenopausal women aged 49 to 79 years (mean 62 years of age) with an intact uterus. This safety trial included two treatment groups, 60 mg Osphena (number of patients [n] = 363) and placebo (n = 63).

Efficacy Results

Results derived from the three 12-week pivotal trials demonstrated that women treated with Osphena 60 mg showed a statistically significant improvement in the moderate to severe MBS of dyspareunia or vaginal dryness when compared to women treated with a placebo. In addition, for all co-primary endpoints assessed, Osphena 60 mg was more effective than 30 mg.

Effect on Dyspareunia

In two clinical trials (15-50310 and 15-50821), the modified intent-to-treat population of women treated with Osphena 60 mg showed a statistically significant improvement (least square mean change from baseline to Week 12) in the moderate to severe MBS of dyspareunia (p = 0.0012 and p<0.0001, respectively) when compared to a placebo. The effect size of treatment difference between Osphena and a placebo in MBS for dyspareunia (-0.30) was considered small.

Effect on Vaginal Dryness

All three pivotal 12-week trials evaluated the MBS of vaginal dryness, however, trial 15-50821 did not demonstrate a statistically significant improvement in the moderate to severe MBS of vaginal dryness. In clinical trials 15-50310 and 1517I0231, the modified intent-to-treat population of women treated with Osphena 60 mg, when compared to a placebo, demonstrated a statistically significant improvement in the moderate to severe MBS of vaginal dryness (p<0.05 and p<0.0001, respectively). The effect size of treatment difference between Osphena and a placebo in MBS for vaginal dryness (-0.42) was considered small.

Effects on Vaginal Smear and Vaginal pH

Statistically significant increases in the proportion of superficial cells (range between +7% and +10.8%) and statistically significant decreases in the proportion of parabasal cells (range between -23.7% and -40%) on a vaginal smear were also demonstrated (p<0.001 for all trials). The mean reductions in vaginal pH between baseline and Week 12 (range between -0.94 and -1.01) were statistically significant (p<0.0001 for all trials).

Efficacy Conclusion

The totality of efficacy data submitted in the Osphena New Drug Submission supports the use of Osphena 60 mg for the treatment of moderate to severe dyspareunia and/or vaginal dryness, symptoms of vulvar and vaginal atrophy, a component of genitourinary syndrome of menopause in postmenopausal women. The clinical benefit of Osphena was measured by improvements of moderate to severe MBS of dyspareunia or vaginal dryness, in three 12-week pivotal trials. It is important to note however, the three 12-week trials enrolled healthy postmenopausal women between 40 and 80 years of age, therefore clinical efficacy among peri-menopausal women was not evaluated. Furthermore, long-term clinical efficacy remains unknown.

Indication

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

Osphena (ospemifene tablets) is indicated for the treatment of moderate to severe dyspareunia and/or vaginal dryness, symptoms of vulvar and vaginal atrophy (VVA), a component of genitourinary syndrome of menopause (GSM). Osphena 60 mg is indicated in postmenopausal women.

Health Canada approved the following indication:

Osphena (ospemifene tablets) is indicated in postmenopausal women for the treatment of moderate to severe dyspareunia and/or vaginal dryness, symptoms of vulvar and vaginal atrophy (VVA), a component of genitourinary syndrome of menopause (GSM).

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

Clinical Safety

The safety profile of Osphena was evaluated in three 12-week pivotal trials (15-50310, 15-50821, and 1517I0231) and one long-term 52-week safety trial (15-50718). For further details on these four placebo-controlled trials, please refer to the previous Clinical Efficacy section. Several other Phase II/III trials with doses ranging from 5 mg to 90 mg were also included as part of the evaluation. The duration of treatment in these trials ranged from 6 weeks to 15 months. The majority of women (n = 1,683) had treatment exposure up to 12 weeks, and the remainder of women (n = 432) had up to 52 weeks of exposure.

Adverse drug reactions most frequently reported in women treated with Osphena 60 mg for 12 weeks were hot flushes (6.5%), vaginal discharge (3.8%), muscle spasm (1.8%), and hyperhidrosis (1.1%). Less commonly (<1%) reported adverse drug reactions were breast pain/tenderness, endometrial hypertrophy, acne, pruritus, rash, depression, and insomnia.

The potential risk of cardiovascular disorders was examined. In the clinical trials, with a duration of treatment up to 15 months, the incidence rates of thromboembolic and hemorrhagic stroke were 1.13 per 1,000 women years (1 reported case of thromboembolic stroke) and 3.39 per 1,000 women years (3 reported cases of hemorrhagic stroke), respectively, in the Osphena 60 mg treatment group. In the placebo group, the incidence rates of thromboembolic and hemorrhagic stroke were 3.15 (1 case of thromboembolic stroke) and 0 per 1,000 women years, respectively. The incidence of deep vein thrombosis (DVT) was 2.26 per 1,000 women years in Osphena 60 mg treatment group (2 reported cases of DVT) and 3.15 (1 case of DVT) in placebo. The incidence of pulmonary embolism was 0 per 1,000 women years in the Osphena 60 mg and placebo treatment groups.

In the Osphena 60 mg treatment group, no cases of endometrial cancer were seen with exposure up to 52 weeks. Although one patient did have a biopsy that showed endometrial hyperplasia without atypia. Current Osphena trials have not shown any cases of endometrial cancer with treatment exposure up to 52 weeks. There is a potential increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. Based on scientific literature, the reported endometrial cancer risk among unopposed estrogen users is approximately 2 to 12 times greater than in non-users and appears dependent on duration of treatment and on estrogen dose. While most scientific-based studies show no significant increased risk associated with the use of estrogens for less than one year; the greatest risk appears to be associated with prolonged use, with increased risks of 15- to 24-fold for 5 to 10 years or more. In the endometrium, Osphena does have a weak estrogen agonistic effect. Safety data collected beyond 52 weeks did reveal evidence of endometrial thickening equal to 5 mm or greater in the Osphena treatment groups at a rate of 72.5 per 1,000 women vs. 11.8 per 1,000 women for the placebo. The safety data (>52 weeks) also showed the incidence of any type of proliferative (weakly plus active plus disordered) endometrium was 26.3 per thousand women in the Osphena treatment groups vs. 0 per thousand women for the placebo. The safety data (>52 weeks) also showed uterine polyps occurred at an incidence of 11.6 per thousand women in the Osphena treatment groups vs. 8.9 per thousand women for the placebo.

To address the potential risk of cardiovascular disorders (thromboembolic and hemorrhagic stroke, and deep vein thrombosis) and endometrial cancer, these identified safety concerns have been included in a Serious Warnings and Precautions box in the approved Osphena Product Monograph.

Osphena 60 mg has not been adequately studied in women with breast cancer; therefore, it should not be used in women with known or suspected breast cancer.

Safety Conclusion

The totality of evidence submitted in the Osphena New Drug Submission supports the safety of Osphena 60 mg for the treatment of moderate to severe dyspareunia and/or vaginal dryness, symptoms of vulvar and vaginal atrophy, a component of genitourinary syndrome of menopause in postmenopausal women. However, the safety of Osphena 60 mg was not evaluated in women with a history or risk factors of stroke or venous thromboembolism and beyond 52 weeks.

Potential risks of serious adverse events such as cardiovascular disorders (thromboembolic stroke and hemorrhagic stroke, and deep vein thrombosis) and endometrial hyperplasia or endometrial cancer have been identified with use of Osphena and shall be further characterized in post-marketing surveillance activities. These potential risks have also been included in a Warnings and Precaution box in the Osphena Product Monograph.

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

 

 

 

7.2 Non-Clinical Basis for Decision

 

For the non-clinical review of the Osphena New Drug Submission, the sponsor submitted a complete dossier of studies that evaluated primary and secondary pharmacodynamics, safety pharmacology studies, pharmacokinetics, general toxicology, genetic toxicology, carcinogenicity, reproductive and development toxicology studies. 

Ospemifene (the medicinal ingredient in Osphena) is a selective estrogen receptor modulator (SERM), also called an estrogen receptor agonist/antagonist, and is thus similar to raloxifene, tamoxifen, and toremifene. Ospemifene is intended to be used for vulvar and vaginal atrophy in postmenopausal women. Ospemifene is a tissue-specific SERM that binds specifically and with similar affinity to estrogen receptor (ER)α and ERβ.

The absorption of ospemifene is fast, but the extent of absorption especially at high doses is low. Distribution takes place in all tissues in rats and monkeys. The highest ospemifene-related radioactivities were observed in gastrointestinal mucosa, which may refer to unabsorbed material. Excretion to bile, first-pass metabolism and enterohepatic recirculation are evident. Metabolism in rats takes place by conjugation and oxidation. In monkeys, the oxidative metabolism is more prominent. Multiple cytochrome P450 (CYP) enzymes, including CYP3A4, CYP2C9 and CYP2C19 are involved in the metabolism of ospemifene. The main metabolites in humans, M-1 (major metabolite) and M-2 (minor metabolite) are found in all toxicological target species. These metabolites are pharmacologically active, resembling the parent drug in their pharmacological properties. There is no accumulation of ospemifene or its metabolites M-1 and M-2 in any animal species. Protein binding is extensive in all studies in animal species. Elimination takes place mainly via feces.

In repeat-dose toxicity studies in rats and monkeys, the main treatment-related effects in both species were observed in the reproductive tract. The changes in the reproductive organs are in line with the SERM-like activity of ospemifene and can be considered to be exaggerated pharmacological actions. The no-observable-effect-level (NOEL) for the rat toxicity study was <3 mg/kg/day and the no-observable-adverse-effect-level (NOAEL) was ≥300 mg/kg/day of ospemifene. The NOEL for the monkey toxicity study was <15 mg/kg/day and the NOAEL was ≥150 mg/kg/day.

In a two-year carcinogenicity study in female mice, ospemifene was orally administered at 100, 400, or 1,500 mg/kg/day. No evaluation for carcinogenicity was conducted in male mice. There was a significant increase in adrenal subcapsular cell adenomas at 4 and 5 times the human exposure based on the area under the curve (AUC), and adrenal cortical tumours at 5 times the human exposure. In the ovary, an increase in sex cord/stromal tumours, tubulestromal tumours, granulosa cell tumours, and luteomas were also seen. These findings occurred at doses 2 to 5 times the human exposure based on AUC, and are probably related to the estrogenic/anti-estrogenic effect of ospemifene in mice.

Ospemifene was not genotoxic in vitro in the Ames test in strains of Salmonella typhimurium or at the thymidine kinase (tk) locus of mouse lymphoma L5178Y cells in the absence and in the presence of a metabolic activator system. In in vivo testing, ospemifene was not genotoxic in a standard mouse bone marrow micronucleus test or in a determination of deoxyribonucleic acid adducts in the liver of rats.

The effect of ospemifene on fertility was not directly evaluated. In female rats and monkeys, decreases in ovarian and uterine weights, decreased number of corpora lutea, increased ovarian cysts, uterine atrophy, and disrupted cycles were observed when given repeated daily oral doses. In male rats, atrophy of the prostate and seminal vesicles was noted. The effects on reproductive organs observed in animals are consistent with the estrogen receptor activity of ospemifene and potential for impairment of fertility.

The embryo-fetal studies with ospemifene did not reveal any teratogenic effects. In the two-generation reproductive study in Han Wistar rats, ospemifene did not induce adverse effects in the first filial (F1) generation even at the highest dose tested (0.25 mg/kg/day). However, dose range-finding studies revealed that ospemifene doses of 1 mg/kg/day or higher caused severe impairment in maternal body weight gain, dam deaths at delivery, increased post-implantation losses and pup deaths. This reproductive toxicity may be partly explained by the observed severe reduction in body weight gain, but probably the hormonal properties of ospemifene were involved in causing the disability to normal delivery.

In the milk, ospemifene was detected in two of three animals in the 0.05 mg/kg/day group (6.2 or 7.7 ng/mL, 7.0 in average), and in three of three animals in the 0.25 mg/kg/day group (15.1-37.2 ng/mL, 24.0 in average). Compared to human average ospemifene plasma level (654 ng/mL) at clinical doses in steady state, the exposure in dams was low.

The non-clinical pharmacokinetics and toxicology profile of ospemifene was adequately characterized in non-clinical studies in support of the proposed clinical indication. No additional non-clinical studies are deemed necessary to support approval.

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

 

 

7.3 Quality Basis for Decision

 

The Chemistry and Manufacturing information submitted for Osphena has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life is acceptable when the drug product is stored at room temperature (15 ºC to 30 ºC).

Proposed limits of drug-related impurities are considered adequately qualified (i.e., within International Council for Harmonisation limits and/or qualified from toxicological studies).

All sites involved in production are compliant with Good Manufacturing Practices.

All non-medicinal ingredients (described earlier) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations.

 

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