Summary Basis of Decision for Fibristal
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:
Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Fibristal is located below.
Recent Activity for Fibristal
SBDs written for eligible drugs 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. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.
Post-Authorization Activity Table (PAAT) for Fibristal
Updated:
The following table describes post-authorization activity for Fibristal, a product which contains the medicinal ingredient ulipristal acetate. 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 that are found in PAATs.
For additional information about the drug submission process, refer to the Management of Drug Submissions and Applications Guidance.
Drug Identification Number (DIN):
- DIN 02408163 - 5 mg ulipristal acetate, tablet, oral
Post-Authorization Activity Table (PAAT)
| Activity/submission type, control number | Date submitted | Decision and date | Summary of activities |
|---|---|---|---|
| Health Professional Risk Communication | Not applicable | Posted2020-09-30 | Health Professional Risk Communication posted (Fibristal [ulipristal acetate tablets, 5 mg] – Voluntary Withdrawal in Canada due to Risk of Drug-Induced Liver Injury), containing important information about product withdrawal and safety for healthcare professionals. |
| Public advisory | Not applicable | Posted2020-09-30 | Public advisory posted (Allergan Inc. voluntarily withdraws its drug Fibristal, used to treat uterine fibroids, from the Canadian market), containing important safety information for the general public and healthcare professionals. |
| Drug Recall | Not applicable | Posted2020-09-24 | Drug Recall posted on the Healthy Canadians website for the general public, healthcare professionals, and hospitals. |
| DIN 02408163 cancelled (post-market) | Not applicable | Discontinuation date:2020-09-24 | The manufacturer notified Health Canada that sale of the drug has been discontinued post market. Health Canada cancelled the DIN pursuant to section C.01.014.6(1)(a) of the Food and Drug Regulations. |
| Drug product (DIN 02408163) market notification | Not applicable | Date of first sale:2020-01-06 | The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
| NC # 227397 | 2019-05-02 | Issued NOL2019-07-03 | Submission filed as a Level II (90 day) Notifiable Change to update the PM. As a result of the NC, modifications were made to the Warnings and Precautions, Dosage and Administration, and Action and Clinical Pharmacology sections of the PM, and corresponding changes were made to Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued. |
| Information Update | Not applicable | Posted2019-01-11 | Information Update posted (Health Canada safety review finds possible link between Fibristal and risk of liver injury). |
| SNDS # 219076 | 2018-10-19 | Issued NOC2018-12-20 | Submission filed as a Level I - Supplement to update the PM with new safety information. The changes were in response to an Advisement Letter issued by Health Canada dated August 20, 2018 requesting revisions related to the risk of liver injury with the use of Fibristal. Modifications were made to the Contraindications, and Warnings and Precautions sections of the PM and corresponding changes were made to the PM Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOC was issued. |
| Summary Safety Review posted | Not applicable | Posted2018-09-07 | Summary Safety Review posted for Fibristal (Assessing the potential risk of rare but serious liver injury). |
| NDS #217996 | 2018-07-05 | Issued NOC2018-07-30 | Submission filed to transfer ownership of the product (that is [i.e.] drug sponsor name) from Allergan Pharma Co. to Allergan Inc. An NOC was issued. |
| NC # 214324 | 2018-03-08 | Issued NOL2018-06-25 | Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the PM with safety information in response to the Issues-Related Summary Report request dated January 04, 2018 by Health Canada, related to the risk of liver injury with the use of Fibristal. Modifications were made to the Contraindications, and Warnings and Precautions sections of the PM and corresponding changes were made to the PM Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued. |
| New safety review started by Health Canada | Not applicable | Started between2018-02-01 | Health Canada started a safety review for Fibristal between 2018-02-01 and 2018-02-28. |
| Information Update | Not applicable | Posted2018-03-15 | Information Update posted (Health Canada to conduct review of a new potential safety risk of Fibristal [ulipristal acetate], a medication used to treat fibroids), containing important safety information for the general public. |
| Drug product (DIN 02408163) market notification | Not applicable | Date of first sale:2018-02-22 | The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
| NC # 209518 | 2017-09-21 | Issued NOL2018-01-10 | Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the PM to reflect revisions in the company core data sheet. As a result of the NC, modifications were made to the Warnings and Precautions, and Adverse Reactions sections of the PM, and corresponding changes were made to the PM Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued. |
| NC # 205771 | 2017-05-19 | Issued NOL2017-10-23 | Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the PM with new safety information. As a result of the NC, modifications were made to the Adverse Reactions section of the PM. The submission was reviewed and considered acceptable, and an NOL was issued. |
| NDS # 198880 | 2016-10-11 | Issued NOC2016-11-25 | Submission filed to transfer ownership of the product from Actavis Specialty Pharmaceuticals Co. to Allergan Pharma Co. An NOC was issued. |
| SNDS # 190760 | 2015-12-29 | Issued NOC2016-11-10 | Submission filed as a Level I - Supplement to expand the duration of use of the 5 mg dose of Fibristal. Upon a thorough review of submitted data, it was found that submitted results of Part II of study PGL11-006 confirmed that four 3-month courses of treatment with 5 mg/day ulipristal acetate did control heavy menstrual bleeding, which is the primary symptom for women with uterine fibroids. The benefits of Fibristal outweigh its risks, and extension of the indication was recommended for approval. Modifications were made to the Contraindications, Warnings and Precautions, Adverse Reactions, Drug Interactions, and Dosage and Administration sections of the PM, and corresponding changes were made to the PM Part III: Patient Medication Information. The submission was reviewed and considered acceptable. An NOC was issued. |
| Drug product (DIN 02408163) market notification | Not applicable | Date of first sale:2016-03-10 | The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
| NDS # 181261 | 2015-01-13 | Issued NOC2015-02-15 | Submission filed to transfer ownership of the product from Watson Laboratories Inc. to Actavis Specialty Pharmaceuticals Co. Notice of Compliance issued. |
| SNDS # 167592 | 2013-08-21 | Issued NOC2014-03-21 | Submission filed as a Level I - Supplement to add an alternate manufacturing site for the production of the ulipristal acetate drug substance. There were no changes to the drug product as a result. The data were reviewed and considered acceptable, and an NOC was issued. |
| Drug product (DIN 02408163) market notification | Not applicable | Date of first sale:2013-07-04 | The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
| NDS # 156861 | 2012-06-29 | Issued NOC2013-06-24 | Notice of Compliance issued for New Drug Submission. |
Summary Basis of Decision (SBD) for Fibristal
Date SBD issued: 2013-07-29
The following information relates to the new drug submission for Fibristal.
Ulipristal acetate, 5 mg, tablet, oral
Drug Identification Number (DIN):
- 02408163
Watson Laboratories Inc.
New Drug Submission Control Number: 156861
On June 24, 2013, Health Canada issued a Notice of Compliance to Watson Laboratories Inc. for the drug product, Fibristal.
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/risk profile of Fibristal is favourable for the treatment of moderate to severe signs and symptoms of uterine fibroids in adult women of reproductive age who are eligible for surgery. The duration of treatment is limited to 3 months.
1 What was approved?
Fibristal, a selective progesterone receptor modulator, was authorized for the treatment of moderate to severe signs and symptoms of uterine fibroids in adult women of reproductive age who are eligible for surgery. The duration of treatment is limited to 3 months. The safety and efficacy of Fibristal have not been established in women ≥65 years of age or women <18 years of age.
Fibristal is contraindicated for women who are hypersensitive to ulipristal acetate or to any ingredient in the formulation. Fibristal is also contraindicated for women who are pregnant or who are breastfeeding, women with genital bleeding of unknown etiology or for reasons other than uterine fibroids, and women with uterine, cervical, ovarian or breast cancer. Due to lack of long-term data, the duration of treatment should not be longer than 3 months of continuous use. Fibristal was approved for use under the conditions stated in the Fibristal Product Monograph taking into consideration the potential risks associated with the administration of this drug product.
Fibristal (5 milligrams ulipristal acetate) is presented as a tablet. In addition to the medicinal ingredient ulipristal acetate, the tablet contains croscarmellose sodium, magnesium stearate, mannitol, microcrystalline cellulose, and talc.
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 Fibristal Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Fibristal approved?
Health Canada considers that the benefit/risk profile of Fibristal is favourable for the treatment of moderate to severe signs and symptoms of uterine fibroids in adult women of reproductive age who are eligible for surgery. The duration of treatment is limited to 3 months.
Uterine fibroids are benign, monoclonal, hormone-sensitive, smooth muscle tumours of the uterus. They are the most common tumour of the female reproductive tract in pre-menopausal women, affecting approximately 40% of women between 35 and 55 years, with a higher incidence in Black women than in White women. They are often asymptomatic, but when symptomatic, the primary symptoms are heavy uterine bleeding, anemia, abdominal pressure, abdominal pain, increased urinary frequency, and infertility. Beyond physical morbidity, fibroids are a frequent cause of significant impairment of quality of life. Surgery is the current mainstay of symptomatic fibroids, the most commonly performed being hysterectomy, with uterine fibroids being a leading cause of this procedure.
Fibristal has been shown to be efficacious in the treatment of moderate to severe signs and symptoms of uterine fibroids in adult women of reproductive age who are eligible for surgery. Administration of Fibristal in the Phase III studies (Study 1 and Study 2) was found to be statistically significantly superior to placebo (Study 1), and non-inferior to the Gonadotropin-releasing hormone (GnRH) agonist, leuprorelin (Study 2) for the primary/co-primary efficacy variable, the percentage of patients with a reduction of uterine bleeding at Week 13 [defined as a Pictorial Bleeding Assessment Chart (PBAC) score <75]. In Study 1, the difference in the proportion of patients with a PBAC <75 between Fibristal (>90%) and placebo (<20%) was statistically significant. Fibristal was also found to be statistically superior to placebo for the co-primary efficacy variable, the change in total fibroid volume from screening to Week 13. In Study 2, excessive bleeding was controlled more rapidly in patients who received Fibristal 5 mg than those who received leuprorelin, with the majority of patients treated with Fibristal achieving persistent amenorrhea within 10 days. Results showed that Fibristal reduced fibroid size to a similar extent as leuprorelin, and reduced uterine size to a slightly lesser extent than leuprorelin.
The majority of adverse events with Fibristal were mild or moderate in intensity and were spontaneously resolved. In the clinical studies for women treated with Fibristal 5 mg, the most common adverse drug reactions (≥5%) were hot flushes (13.0% overall) and headaches (8.3% overall). In addition to its treatment benefits and favorable tolerability profile, Fibristal also demonstrated that its use for 12 weeks was well-tolerated and no major risks were identified. The effects of Fibristal on the endometrium appeared to be without clinical consequence apart from temporary induction of amenorrhea which is beneficial for patients with uterine fibroids.
A Risk Management Plan (RMP) for Fibristal was submitted by Watson Laboratories 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.
Overall, the therapeutic benefits observed in the pivotal studies are positive and the benefits of Fibristal therapy is considered to outweigh the risks. The clinical data obtained thus far show that Fibristal is effective for the short-term treatment of symptomatic fibroids in patients who are eligible for surgery. Fibristal 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 Fibristal Product Monograph to address the identified safety concerns. Based on the review of the data, the overall risk/benefit ratio is considered positive for market authorization when Fibristal is prescribed under the conditions of use recommended in the Fibristal Product Monograph.
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 Fibristal?
Submission Milestones: Fibristal
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2012-02-15 |
| Submission filed: | 2012-06-29 |
| Screening | |
| Screening Deficiency Notice issued: | 2012-08-20 |
| Response filed: | 2012-08-24 |
| Screening Acceptance Letter issued: | 2012-08-30 |
| Review | |
| Quality Evaluation complete: | 2013-06-07 |
| Clinical Evaluation complete: | 2013-06-14 |
| Labelling Review complete: | 2013-06-07 |
| Notice of Compliance issued by Director General, Therapeutic Products Directorate: | 2013-06-24 |
For additional information about the drug submission process, refer to the Management of Drug Submissions 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.
6 What other information is available about drugs?
Up to date information on drug products can be found at the following links:
- See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
- See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
- See the Drug Product Database (DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada and have been market notified (that is, the company has told Health Canada the product is being marketed).
- See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the Notice of Compliance with Conditions (NOC/c) Guidance Document, if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.
- See the Patent Register for patents associated with medicinal ingredients, if applicable.
- See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.
7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical basis for decision
Clinical Pharmacology
The medicinal ingredient of Fibristal, ulipristal acetate, is an orally-active selective progesterone receptor modulator characterized by a tissue-specific, partial progesterone antagonist effect. Ulipristal acetate exerts a direct effect on the endometrium and exerts a direct action on fibroids reducing their size through inhibition of cell proliferation and induction of apoptosis
The clinical pharmacology included reports on the human pharmacodynamic and the pharmacokinetic studies. Because ulipristal acetate acts as a selective progesterone receptor modulator, several studies investigated the effects of ulipristal acetate on ovarian, pituitary, hypothalamic, and endometrial function. Daily administration of ulipristal acetate partially suppressed follicle stimulating hormone (FSH) levels, and estrogen levels tended to be in the mid-follicular range during the period of hypomenorrhea. Progesterone levels were reduced but there was no effect on prolactin, thyroid-stimulating hormone (TSH), or adrenocorticotropic hormone (ACTH) levels.
The clinical pharmacology studies provided a thorough characterization of the clinical pharmacology of ulipristal acetate and provided substantive support for labelling claims. Together, the clinical and pharmacological data support the use of Fibristal for the specified indication.
For further details, please refer to the Fibristal Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
The efficacy of Fibristal (ulipristal acetate) 5 mg once daily was evaluated in two Phase III randomized, double-blind, multicentre 13-week studies (Study 1 and Study 2). Both studies recruited women with heavy menstrual bleeding associated with uterine fibroids and with at least one myoma measuring 3 cm or more in diameter. In both studies menstrual blood loss was assessed using the Pictorial Bleeding Assessment Chart (PBAC). A PBAC score of >100 (corresponds to approximately 80 mL) within the first 8 days of menses was considered to represent excessive menstrual blood loss.
Study 1 was placebo-controlled and recruited women with fibroid and anemia. At study entry, the women had hemoglobin levels of <10.2 g/dL. During the study, the women received 80 mg of elemental iron orally once daily in addition to the study drug or placebo. The women were randomized to receive Fibristal 5 mg [number of patients (n) = 95] or Fibristal 10 mg (n = 98), or placebo (n = 48).
The primary endpoints for Study 1 were the percentage of women with a reduction in uterine bleeding defined as a PBAC score <75 at the end-of-treatment visit (Week 13) and the change in total myoma volume assessed by magnetic resonance imaging (MRI) from screening to the end-of-treatment visit (Week 13). Secondary endpoints included the following: change from baseline to Week 5, Week 9, and Week 13 visits in bleeding pattern recorded by women using the PBAC; change from baseline to Week 5, Week 9 and Week 13 visits in hemoglobin (Hb), hematocrit (Hct) and ferritin; percentage of women with Hb >12 g/dL and Hct >36% at the Week 5, Week 9 and Week 13 visits; percentage of women in amenorrhea at the Week 5, Week 9, and Week 13 visits; percentage of women with a volume reduction of ≥25% of the total myoma volume assessed by MRI at the Week 13 visit; percentage of women with a reduction of ≥25% of uterine volume assessed by MRI at the Week 13 visit; change from screening to Week 13 visit in uterine volume assessed by MRI; change from baseline to Week 5, Week 9, and Week 13 visits in global pain score [Short Form McGill Pain Questionnaire (SF-MPQ)]; and change from baseline to Week 13 visit in symptoms related to uterine myomas (measurement of discomfort due to uterine fibroids questionnaire).
Study 2 contained the active comparator, leuprorelin 3.75 mg (a drug not approved in Canada for the treatment of uterine fibroids) administered once per month by intramuscular injection. The women were randomized to receive Fibristal 5 mg (n = 97), or Fibristal 10 mg (n = 103), or the active comparator (n = 101). A double-dummy method was used to maintain the blind.
The primary endpoint for Study 2 was the percentage of women with a reduction of uterine bleeding defined as a PBAC score <75 at the end-of-treatment visit (Week 13 visit). The secondary endpoints included the following: change from baseline to Week 5, Week 9 and Week 13 visits in Hb, Hct, and ferritin; percentage of women in amenorrhea at the Week 5, Week 9, and Week 13 visits; change from screening to Week 13 visit in the total volume of the three largest myomas assessed by ultrasound (US); change from screening to Week 13 visit in uterine volume assessed by US; change from baseline to Week 5, Week 9, and Week 13 visits in global pain score (SF-MPQ); and change from baseline to Week 13 visit in Uterine Fibroid Symptom and health-related Quality of Life (UFS-QOL) score.
The administration of Fibristal in the Phase III studies was found to be statistically significantly superior to placebo (Study 1), and non-inferior to the Gonadotropin-releasing hormone (GnRH) agonist, leuprorelin (Study 2) for the co-primary/primary efficacy endpoints.
In Study 1 at Week 13, the percentage of women with a PBAC score of <75 was much greater with Fibristal 5 mg/day and 10 mg/day (91.5% and 92.5%, respectively) than with placebo (18.8%) (p <0.001 for the comparison of placebo with both Fibristal doses). These results represented a difference of 72.7% for Fibristal 5 mg/day and 73.7% for Fibristal 10 mg/day compared with placebo. Total fibroid volume increased from screening to Week 13 with placebo (median change of +3.0%) and decreased with Fibristal 5 mg/day (-21.2%) and 10 mg/day (-12.3%). These differences were statistically significant for Fibristal at both doses 5 mg/day and 10 mg/day.
The following secondary endpoints measured at Week 13 supported the co-primary efficacy endpoint discussed above.
- The median decreases from baseline in PBAC Score were -59 with placebo and -329 and -326 with Fibristal 5 mg/day and 10 mg/day, respectively.
- The percentage of women in amenorrhea was 6% with placebo, and 73% and 82% with Fibristal 5 mg/day and 10 mg/day, respectively.
- A statistically significantly greater proportion of women had a reduction in total fibroid volume ≥25% with Fibristal 5 mg/day (41%) and 10 mg/day (41%) compared with placebo (18%).
- A statistically significant difference in the change in uterine volume from screening to Week 13 reported between placebo and Fibristal, with a median % change of +5.9 cm3 with placebo and -12.1 cm3 and -12.0 cm3 with Fibristal 5 mg/day and 10 mg/day, respectively.
- The increase in Hb and Hct from baseline was statistically significantly greater with both doses of Fibristal compared with placebo at Weeks 5, 9 and 13. At Week 13, the adjusted mean increase in Hb was 3.1 g/dL with placebo compared with 4.1 g/dL with both doses of Fibristal, and a mean increase of Hct at Week 13 of 7.4% with placebo compared with 10.0% with both Fibristal doses.
- All three treatment groups showed an improvement (a decrease) in the levels of pain as assessed by the SF-MPQ Part A and Part B scores at all visits. There was a statistically significantly greater improvement in the Part A score with Fibristal 10 mg/day compared to placebo at Week 13 and in the Part B scores between Fibristal 5 mg/day and placebo at Week 9. The changes from baseline in SF-MPQ Part C scores were similar at all timepoints in each group.
Study 2 had a similar primary endpoint (the reduction of uterine bleeding defined as a PBAC score <75). The primary efficacy objective of this study was to demonstrate non-inferior efficacy of Fibristal versus the GnRH-agonist, leuprolide. At Week 13, the proportion of women with PBAC <75 at Week 13 was similar with leuprolide (89%) and Fibristal 5 mg/day (90%), and was slightly higher with Fibristal 10 mg/day (98%). The non-inferiority of both doses of Fibristal to leuprolide was demonstrated for the per-protocol (PP) population.
The secondary endpoints provided supportive data to the primary endpoint.
- From data collected at Weeks 9 and 13, the median decreases from baseline in PBAC Score were similar in the three treatment groups, with a median decrease at Week 13 of -274 with leuprolide and -268 with both doses of Fibristal.
- At Week 13, there was no statistically significant difference in the proportion of subjects in amenorrhea with leuprolide compared with Fibristal (80% with leuprolide, 75% with Fibristal 5 mg/day and 90% with Fibristal 10 mg/day). The results of the analysis of amenorrhea indicate a possible dose-response.
- Total volume of the three largest fibroids decreased in all groups from screening to Week 13, and there were no statistically significant differences between the treatment groups.
- There was a decrease in the mean and median uterine volume from screening to Week 13 with all three treatments, which was statistically significantly greater with leuprolide (median % change of -47.1 cm3) compared with both doses of Fibristal (-20.40 cm3 and -22.29 cm3 with Fibristal 5 mg/day and 10 mg/day, respectively). However, from Week 13 to Week 17, uterine volume increased in women in the leuprolide group, while in women treated with Fibristal the decrease in uterine volume was maintained after the end of treatment. At Week 38, the median % change from screening was -21.8%, and -14.9% for the Fibristal 5 mg and 10 mg groups, respectively.
- Throughout the study, the proportion of women with Hb >12g/dL and Hct >36% increased in all treatment groups, with no indication of a difference between the treatments.
- In all three treatment groups there was a reduction in pain as evidenced by the SF-MPQ Part A and Part B scores, which improved (decreased) greatly at all visits, with no evidence of any difference between the treatment groups in any of the SF-MPQ parts.
Fibristal doses of 5 mg and 10 mg were chosen for evaluation in the Phase III studies based on the results of a dose-finding study which indicated that 5 mg/day was required to produce an appreciable effect on uterine bleeding and from two studies that demonstrated there was no increase in efficacy with the 20 mg/day dose compared to the 10 mg/day dose.
For the two Phase III studies, Study 1 and Study 2, Fibristal doses of 5 mg and 10 mg were administered daily for 12 weeks and resulted in similar improvements, regardless of dose, on a range of efficacy endpoints including reduction of excessive menstrual bleeding, induction of amenorrhea, reduction of fibroid size and uterine volume, reduction in pain, and improvement in quality of life. Therefore based on the available data, Watson Laboratories Inc. proposed the 5 mg/day Fibristal dose for the treatment of moderate to severe signs and/or symptoms of uterine fibroids for this drug submission.
Following a careful review of data submitted within the context of this submission, the following indication was recommended and accepted: "Treatment of moderate to severe signs and symptoms of uterine fibroids in adult women of reproductive age who are eligible for surgery. The duration of treatment is limited to 3 months." No long-term data on Fibristal use was available to evaluate the benefit/risk profile beyond 3 months of treatment.
For more information on Fibristal, refer to the Fibristal Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
The clinical safety of Fibristal was evaluated in the two Phase III studies (Study 1 and Study 2) described in the Clinical Efficacy section. In these studies, a total of 393 (192 + 201) women in the 5 mg and 10 mg Fibristal groups, respectively, were included in the safety analysis.
Overall, Fibristal was well-tolerated, and the number of treatment-emergent adverse events (TEAEs) overall and the number of serious adverse events (SAEs) were similar with Fibristal and placebo (Study 1). In Study 2, Fibristal demonstrated a better overall safety profile than the active comparator leuprorelin.
The number of TEAEs leading to discontinuation was very low with Fibristal and placebo (1-2% of women in each group across both Phase III studies), and was higher with leuprorelin (6%). The majority of Fibristal adverse events were mild or moderate in severity and spontaneously resolved.
In Study 1, the most common TEAE was headache, reported in 4.2% of patients in both the Fibristal 5 mg/day group and the placebo group, and in 10.2% of the patients in the Fibristal 10 mg/day group. Of the TEAEs which occurred in ≥3% of patients in any treatment group, only hypothyroidism and dizziness occurred in a higher proportion of patients with both Fibristal doses compared with placebo. Hypothyroidism occurred in 2.1% and 4.1% of patients with Fibristal 5 and 10 mg/day respectively, and in no patients with placebo. However, in most cases, there was a history of thyroid disorder or abnormal baseline thyroid stimulating hormone (TSH) levels. Dizziness occurred in 1.1% and 3.1% of patients with Fibristal 5 and 10 mg/day, respectively, and no patients with placebo. In addition, the similar preferred terms of breast pain, breast tenderness and breast discomfort, when pooled, were also reported in a greater proportion of patients with both Fibristal doses (2.1% and 6.1% of patients with Fibristal 5 and 10 mg/day, respectively) than with placebo (no patients).
In Study 2, both the total number of TEAEs reported and the proportion of patients who experienced TEAEs were higher with leuprorelin (323 TEAEs in 84.2% of patients) than with Fibristal 5 mg/day (216 TEAEs in 77.3% of patients) and Fibristal 10 mg/day (254 TEAEs in 76.7% of patients). The most common TEAE was hot flush, which was reported in more patients treated with leuprorelin (65.3%) than with Fibristal 5 mg/day and 10 mg/day (25.8% and 24.3%, respectively), with moderate and severe events of hot flush reported in statistically significantly more patients with leuprorelin than with Fibristal (p<0.001 for both doses). The higher frequency of adverse events reported with leuprorelin was mainly due to the increased incidence of hot flush. Psychiatric disorders (most notably insomnia) were also reported more often with leuprorelin (in 12.9% of patients) than with Fibristal 5 mg/day and 10 mg/day (4.1% and 3.9%, respectively).
Headache was the second most common TEAE in Study 2, reported in 29 patients (28.7%) with leuprorelin, 25 patients (25.8%) with UPA 5 mg/day and 19 patients (18.4%) with Fibristal 10 mg/day. Other TEAEs which occurred in >5% of patients in any group were (in descending order of frequency overall) procedural pain, abdominal pain, nausea, fatigue, anemia, nasopharyngitis, abdominal pain upper, acne influenza, insomnia and pharyngitis. There were no notable differences in the frequency of these events between the Fibristal and leuprorelin treatment groups. Breast pain, breast tenderness and breast disorder (pooled) were reported in 5.1% and 2.9% of subjects with Fibristal 5 and 10 mg/day, respectively, and 3.0% of patients with leuprorelin.
Endometrial changes
Ulipristal acetate has a specific pharmacodynamic action on the endometrium, and increases in thickness of the endometrium may occur. In Study 1, endometrial thickness > 16 mm at Week 13 was higher with Fibristal 5 mg/day and 10 mg/day (11% and 7%, respectively), than with placebo (2%), but there was no statistically significant difference.
In Study 2, there was a statistically significant difference between Fibristal and leuprorelin (p<0.001 for both Fibristal doses) for endometrial thickness >16 mm at Week 13. However, by Week 17 there was no difference between the treatments, indicating that any treatment-related changes in the endometrium were reversible.
Safety data for treatment periods longer than 3 months were not available. The risk of an adverse impact on the endometrium is unknown if treatment is continued; therefore, treatment with Fibristal was resticted to 3 months in the approved indication.
In summary, the two pivotal studies demonstrated that the 3-month administration of Fibristal 5 mg/day was well-tolerated and provided effective treatment for uterine fibroids. Appropriate warnings and precautions are in place in the approved Fibristal Product Monograph to address the identified safety concerns.
For more information, refer to the Fibristal Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
The non-clinical pharmacology and toxicology studies support the use of Fibristal for the treatment of uterine fibroids. Even though the non-clinical studies demonstrated increased prolactin levels and inhibition of transport mediated by P-glycoprotein, these effects were observed at exposure levels that exceeded clinically achievable plasma levels of ulipristal acetate in the proposed dosage form. In terms of neoplastic observations, the results demonstrated no increase in tumour incidence following chronic administration in rats. There was no evidence of any test article-induced carcinogenicity. Overall, the toxicity studies suggest no major concerns with ulipristal acetate.
The results of the non-clinical studies as well as the potential risks to humans have been included in the Fibristal Product Monograph. There are no pharmacological/toxicological issues within this submission which preclude authorization of the product.
For more information, refer to the Fibristal 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 Fibristal 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 of Fibristal is considered acceptable.
The drug product standard is claimed as 'professed' with specifications that conform to the current Health Canada requirements.
All sites involved in production are compliant with Good Manufacturing Practices.
All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The excipients used in the product formulation are not of animal or human origin.