Summary Basis of Decision for Intrarosa
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 Intrarosa is located below.
Recent Activity for Intrarosa
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 Intrarosa, a product which contains the medicinal ingredient prasterone. 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: 2025-08-19
Drug Identification Number (DIN):
DIN 02493500 - 6.5 mg prasterone, ovule, intravaginal administration
Post-Authorization Activity Table (PAAT)
|
Activity/Submission Type, Control Number |
Date Submitted |
Decision and Date |
Summary of Activities |
|
SNDS # 282880 |
2024-01-16 |
Issued NOC 2024-08-23 |
Submission filed as a Level I – Supplement to add a manufacturing site for the drug substance. The information was reviewed and considered acceptable and an NOC was issued. |
|
Drug product (DIN 02493500) market notification |
Not applicable |
Date of first sale 2024-05-28 |
The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
|
NDS # 278262 |
2023-08-16 |
Issued NOC 2023-09-08 |
Submission filed to transfer ownership of the drug product from Endoceutics Inc to Cosette Pharmaceuticals Inc. An NOC was issued and the DIN was retained. |
|
Drug product (DIN 02493500) market notification |
Not applicable |
Date of first sale 2022-09-02 |
The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
|
SNDS # 253873 |
2021-06-23 |
Issued NOC 2021-10-21 |
Submission filed as a Level I – Supplement to update the PM with safety information and to migrate the PM to the 2020 format. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Contraindications, Adverse Reactions, Drug Interactions, Dosage and Administration, and Overdosage sections of the PM, and corresponding changes were made to Part III: Patient Medication Information and to the package insert. An NOC was issued. |
|
NDS # 198822 |
2016-10-05 |
Issued NOC 2019-11-01 |
NOC issued for New Drug Submission. |
Summary Basis of Decision (SBD) for Intrarosa
Date SBD issued: 2020-03-10
The following information relates to the New Drug Submission for Intrarosa.
Prasterone
Drug Identification Number (DIN):
- DIN 02493500 - 6.5 mg, ovule, intravaginal administration
Endoceutics, Inc.
New Drug Submission Control Number: 198822
On November 1, 2019, Health Canada issued a Notice of Compliance to Endoceutics, Inc. for the drug product Intrarosa.
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 Intrarosa is favourable for the treatment of postmenopausal vulvovaginal atrophy.
1 What was approved?
Intrarosa (prasterone vaginal ovules) was authorized for the treatment of postmenopausal vulvovaginal atrophy. The medicinal ingredient in Intrarosa, prasterone (also known as dehydroepiandrosterone, DHEA) is an inactive sex steroid precursor and is converted intracellularly into estrogens and androgens.
Intrarosa is indicated only in postmenopausal women. Among 1,196 patients who received Intrarosa in clinical trials, 17% of participants in the four 12-week placebo-controlled studies and 9.2% of participants in the 52-week open-label clinical trial were older than 65 years of age.
Intrarosa is contraindicated in:
- Patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.
- Women with undiagnosed abnormal genital bleeding. Any postmenopausal woman with undiagnosed, persistent or recurring genital bleeding should be adequately evaluated to determine the cause before considering initiating treatment with Intrarosa.
Intrarosa 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.
Intrarosa (6.5 mg prasterone) is presented as an ovule. In addition to the medicinal ingredient, the ovule contains Witepsol (hard fat).
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 Intrarosa Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Intrarosa approved?
Health Canada considers that the benefit-harm-uncertainty profile of Intrarosa is favourable for the treatment of postmenopausal vulvovaginal atrophy.
After menopause, women may experience genitourinary symptoms due to the cessation of ovarian estrogen production. In the absence of estradiol, the epithelium of the vaginal mucosa and of the vulvar skin becomes progressively atrophic, with decreased thickness and secretory activity of the contained glands, leading to an increased risk of inflammation and trauma of these tissues. Symptoms of vulvovaginal atrophy include vaginal dryness, vaginal irritation or itching, and dyspareunia (pain during sexual intercourse).
Prasterone (also known as dehydroepiandrosterone [DHEA]) is a natural steroid compound, inactive by itself, with no estrogenic, androgenic or other hormonal activity. Following intravaginal administration, it is transformed inside the vaginal cells into estrogens and androgens. The sex steroids made intracellularly are inactivated locally inside the same cells, thus avoiding exposure of other tissues.
Prasterone (DHEA) is listed on Schedule IV (under Anabolic steroids and their derivatives) of the Controlled Drugs and Substances Act.
The market authorization of Intrarosa was based on data derived from six clinical trials (one Phase I and five Phase III clinical trials) in postmenopausal women with vulvovaginal atrophy. Four of the five Phase III clinical trials were randomized, placebo-controlled, double-blind studies of a 12-week duration. The fifth Phase III trial was a single-arm, 52-week study, which provided longer-term safety data.
Across the trials, the prasterone vaginal ovules induced favourable changes at the level of the vaginal mucosa, including improved pH and maturation index. Dose-ranging studies defined the optimal dosage for complete transformation of the vaginal mucosa as 6.5 mg (0.50%) prasterone vaginal ovules daily. Improvement in the vaginal mucosa was evident following seven days of treatment and was maintained through 52 weeks. Daily administration of the drug was necessary, since decreasing the frequency of application to twice weekly led to diminished improvement in vaginal atrophic changes. Consistent with the observed cytological changes, patient-reported efficacy parameters were improved, with decreases in the mean severity scores of dyspareunia, as well as vaginal dryness, and vaginal irritation or itching.
Endometrial biopsies performed after 52 weeks of Intrarosa treatment showed no evidence of hyperplasia.
The most commonly reported adverse reaction to Intrarosa, reported in 8.3% of patients, was application site discharge.
In the 521 postmenopausal women who participated in the 52-week non-comparative, open-label clinical trial, 11 cases of abnormal Papanicolaou (Pap) smear (2.1%) were reported. The 11 cases of abnormal Pap smear at week 52 included 10 cases of atypical squamous cells of undetermined significance (ASCUS) and one case of low-grade squamous intraepithelial lesion (LSIL).The relationship, if any, of these cytological changes to Intrarosa exposure is unclear. The Intrarosa Product Monograph describes the occurrence of abnormal cervical cytology in the 52-week clinical trial, and recommends that patients undergo regular gynecological exams.
Estrogen is a metabolite of prasterone and the use of exogenous estrogen is contraindicated in women with a known history of breast cancer. Therefore, the Warnings and Precautions section of the Intrarosa Product Monograph highlights that Intrarosa has not been studied in women with a history of breast cancer and recommends regular breast exams.
A Risk Management Plan (RMP) for Intrarosa was submitted by Endoceutics, Inc. to Health Canada. Following revisions, the RMP was considered to be acceptable. Specifically, Health Canada recommended that the safety specifications for Intrarosa be amended to include "abnormal Pap smear" as an important identified risk. 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 Intrarosa Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.
A Look-alike Sound-alike brand name assessment was performed and the proposed name Intrarosa was accepted.
Intrarosa 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 Intrarosa 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 Intrarosa?
On December 16, 2008, Endoceutics, Inc. submitted New Drug Submission (Control Number 125625), for the same drug product under the brand name Vaginorm. A Notice of Deficiency was issued on October 5, 2009, which included only non-clinical and clinical comments. In particular, it was noted that none of the submitted clinical studies extended beyond 12 weeks, and thus safety data were considered inadequate. The New Drug Submission was withdrawn by the sponsor on October 8, 2009.
The current New Drug Submission (Control Number 198822) was filed on October 5, 2016. Review of the Chemistry and Manufacturing portion identified several deficiencies and data gaps, which precluded continuing review of the submission. A Notice of Deficiency was issued on September 28, 2017. A Response to the Notice of Deficiency was filed on February 28, 2018. During the review of the response, further deficiencies were identified in the Chemistry and Manufacturing portion of the submission. Consequently, a Notice of Non-Compliance was issued. In the submitted response to the Notice of Non-Compliance, all of the issues have been satisfactorily resolved.
Submission Milestones: Intrarosa
| Submission Milestone | Date |
|---|---|
| Submission filed: | 2016-10-05 |
| Screening | |
| Screening Deficiency Notice issued: | 2016-11-14 |
| Response filed: | 2016-11-15 |
| Screening Acceptance Letter issued: | 2016-12-05 |
| Review | |
| Labelling Review complete, including Look-alike Sound-alike brand name assessment: | 2017-09-01 |
| Quality Evaluation complete: | 2017-09-05 |
| Review of Risk Management Plan complete: | 2017-09-14 |
| Notice of Deficiency (NOD) issued by Director General, Therapeutic Products Directorate (quality issues): | 2017-09-28 |
| Response to NOD filed: | 2018-02-28 |
| Screening of the response to the NOD | |
| Screening Acceptance Letter (response to NOD) issued: | 2018-04-17 |
| Review of the response to the NOD | |
| Quality Evaluation complete: | 2019-02-05 |
| Notice of Non-Compliance (NON) issued by Director General, Therapeutic Products Directorate (quality issues): | 2019-02-08 |
| Response to NON filed: | 2019-05-09 |
| Screening of the response to the NON | |
| Screening Acceptance Letter (response to NON) issued: | 2019-06-06 |
| Review of the response to the NON | |
| Quality Evaluation complete: | 2019-10-28 |
| Labelling Review complete, including Look-alike Sound-alike brand name assessment: | 2019-10-29 |
| Clinical/Medical Evaluation complete: | 2019-10-30 |
| Notice of Compliance issued by Director General, Therapeutic Products Directorate: | 2019-11-01 |
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?
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.
- 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
Prasterone (also known as dehydroepiandrosterone [DHEA]) is a natural steroid compound, inactive by itself, with no estrogenic, androgenic or other hormonal activity. Following intravaginal administration, prasterone is transformed inside the vaginal cells into estrogens and androgens. The sex steroids made intracellularly are inactivated locally inside the same cells, thus precluding exposure of other tissues. Outside the vaginal cells, there are limited increases in serum estrogen (estradiol, E2) or androgen (testosterone) concentrations, which all remain within normal postmenopausal values.
Exogenous prasterone is metabolized in the same manner as endogenous prasterone. Prasterone as well as the resulting estrogens and androgens formed in the vagina are inactivated intracellularly and are excreted by the kidney and liver as inactive glucuronide and sulfate conjugates.
Serum prasterone and related steroid levels were determined for women aged 40 to 80 years with moderate to severe symptoms of vulvovaginal atrophy who received 6.5 mg intravaginal prasterone daily for 12 weeks (number of subjects [n] = 723) compared with those who received a placebo (n = 266). Serum steroid levels were measured on Day 1 and at Week 12 by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The serum levels of sex steroids did not increase beyond the normal upper limits for postmenopausal women.
The clinical pharmacology data support the use of Intrarosa for the recommended indication.
For further details, please refer to the Intrarosa Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
The clinical efficacy of Intrarosa for the treatment of postmenopausal vulvovaginal atrophy was supported by data derived from six clinical trials, including one Phase I and five Phase III clinical studies.
The Phase I clinical study (ERC-213) was a seven-day, randomized, placebo-controlled, double-blind trial. It assessed prasterone bioavailability following daily administration of vaginal prasterone ovules containing 0.5% (6.5 mg), 1% (13 mg), and 1.8% (23.4 mg) prasterone or placebo in postmenopausal women with vaginal atrophy.
Of the five Phase III clinical trials, four were 12-week, placebo-controlled, double-blind, randomized studies (ERC-210, ERC-231, ERC-238, and ERC-234) and one (ERC-230) was a 52-week single-arm (uncontrolled) study.
All the Phase III trials used the proposed 0.5% (6.5 mg) prasterone vaginal ovules. Three of the studies also examined the 0.25% strength, and one included the 1% strength. The studies examined cytological measures of vulvovaginal atrophy as well as symptoms, including pain during intercourse (dyspareunia). Overall, 1,552 subjects were exposed to prasterone, including 1,196 who received the proposed 6.5 mg prasterone vaginal ovules. Of these patients, 1,116 received at least 10 weeks of treatment, 468 received at least 24 weeks of treatment, and 435 received at least 50 weeks of treatment with the 6.5 mg prasterone vaginal ovules.
Across the clinical trials, it was demonstrated that the prasterone vaginal ovules induced favourable changes at the level of the vaginal mucosa, including improved pH and maturation index. Dose-ranging studies confirmed that the optimal dosage of the study drug for complete transformation of the vaginal mucosa was 6.5 mg (0.5%) prasterone vaginal ovules daily. Improvement in the vaginal mucosa was evident after seven days of treatment in Study ERC-213 and was maintained through 52 weeks in Study ERC-230. Daily administration of the drug was necessary, since decreasing the frequency of application to one vaginal ovule twice weekly led to diminished improvement in vaginal atrophic changes.
A number of patient-reported efficacy parameters were also assessed and were supportive of the observed beneficial vaginal changes. For example, in Study ERC-230, the mean severity score of pain during sexual activity (dyspareunia) for subjects who reported having moderate to severe dyspareunia as their most bothering symptom at baseline (n = 183) decreased steadily over the study from 2.57 at baseline to 0.87 at Week 52 (p<0.0001). The severity score of vaginal dryness for subjects presenting moderate to severe vaginal dryness as their most bothersome symptom at baseline (n = 81) decreased from 2.19 at baseline to 0.67 at Week 52 (p<0.0001).
Intensive monitoring by mass spectrometry of serum levels of prasterone and its metabolites including testosterone, estradiol and estrone, did not detect levels above the upper limit (95th percentile) defined as normal for postmenopausal women, suggesting that the dosage and route of administration of prasterone are likely to have limited systemic effects.
Indication
The New Drug Submission for Intrarosa was filed by the sponsor with the following indication, which Health Canada subsequently approved:
- Intrarosa (prasterone vaginal ovules) is indicated for treatment of postmenopausal vulvovaginal atrophy.
For more information, refer to the Intrarosa Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
The safety of Intrarosa for the treatment of postmenopausal vulvovaginal atrophy was supported by data derived from six clinical studies (described in the Clinical Efficacy section). The safety data were pooled for 1,196 postmenopausal women treated with vaginal ovules containing 6.5 mg of prasterone, including 435 women treated daily for one year.
The most commonly reported adverse reaction to Intrarosa, reported in 8.3% of patients, was application site discharge. The leakage from the vagina may be attributed to melting of the excipient Witepsol (hard fat) and increased vaginal secretions.
Endometrial biopsies performed after 52 weeks of treatment with Intrarosa revealed atrophic changes with no evidence of hyperplasia.
After using Intrarosa for 52 weeks, one patient developed infiltrating carcinoma of the breast and one patient had atypical ductal hyperplasia of the breast. One case of ovarian carcinoma (stage III high-grade serous adenocarcinoma) was diagnosed following completion of the 52-week study. No conclusion could be drawn regarding a possible association of these serious adverse events with the study drug.
More than 99% (430 of 432) of the subjects who received intravaginal prasterone for 52 weeks had an end-of-study cervical smear. The end-of-study Papanicolaou (Pap) smears yielded a diagnosis of atypical squamous cells of undetermined significance (ASCUS) in 10 women and low-grade squamous intraepithelial lesion (LSIL) in one woman. Seven of the 11 women had a negative test for human papilloma virus (HPV).
The Intrarosa Product Monograph describes the occurrence of abnormal cervical cytology in the clinical trials, and recommends that patients undergo regular gynecological exams according to current Canadian guidelines.
Serum levels of sex steroids remained within normal postmenopausal limits for women using Intrarosa.
Estrogen is a metabolite of prasterone, and the use of exogenous estrogen is contraindicated in women with a known history of breast cancer. Therefore, the Warnings and Precautions section of the Intrarosa Product Monograph highlights that Intrarosa has not been studied in women with a history of breast cancer and recommends regular breast exams according to current Canadian guidelines.
Appropriate warnings and precautions are in place in the approved Intrarosa Product Monograph to address the identified safety concerns.
For more information, refer to the Intrarosa Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
In non-clinical studies, conducted in rats and monkeys, the administration of prasterone through different routes, including the intravaginal route, induced changes in the vaginal mucosa and completely reversed the atrophic changes in the vaginal epithelium seen following ovariectomy. The locally produced sex steroids increased mucification (an androgenic effect), stratification and cornification (estrogenic effects) of the vaginal epithelium. Prasterone treatment of ovariectomized animals induced strong expression of androgen receptors in the three vaginal layers. The vaginal epithelium of prasterone-treated animals also showed increased expression of alpha estrogen receptors. In addition, prasterone prevented the decrease in vaginal innervation observed following ovariectomy. Prasterone did not inhibit any cytochrome P450 isoform activity.
Following the topical vaginal application of prasterone to rats, the areas under the concentration-time curve observed were proportional to the topical doses of prasterone, indicative of a dose-dependent absorption of the hormone precursor. Furthermore, as expected from intracellular synthesis and metabolism of estradiol and testosterone, only their glucuronidated and sulfated metabolites were detected in the blood stream following the intravaginal administration of prasterone.
Two repeat-dose oral toxicity studies of prasterone were performed: a 1-year study in male and female cynomolgus monkeys and a 26-week study in male and female Sprague Dawley rats. The larger doses used were 100 mg/kg (rats) and 10 mg/kg (monkeys), which produced peak serum prasterone concentrations 15 to 17 times higher (in monkeys) and 18 to 110 times higher (in rats) than the prasterone concentrations in human serum following the intravaginal administration of 6.5 mg prasterone. Prasterone was well tolerated in both species and there were no observable adverse effects that could be attributed to the prehormone.
The mutagenic potential of prasterone was evaluated in three standard genotoxicity assays: a bacterial mutagenicity assay, a human blood lymphocyte assay, and an in vivo mouse bone marrow micronucleus assay. Results were negative under the conditions of the assays.
Long-term studies in animals to determine carcinogenic potential have not been performed with prasterone. Estradiol and testosterone, two metabolites of prasterone, are carcinogenic in animals.
In view of the intended use of Intrarosa, there are no pharmacological or toxicological issues within this submission to preclude authorization of the product.
For more information, refer to the Intrarosa 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 Intrarosa 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. The drug product is stored at a temperature between 2ºC and 30ºC in the original package to protect from light.
Proposed limits of drug-related impurities are considered adequately qualified (i.e., within International Council for Harmonisation limits or qualified from toxicological studies).
All sites involved in production are compliant with Good Manufacturing Practices.
The only excipient, Witepsol (hard fat), used in the formulation of Intrarosa is acceptable for use in drugs according to the Food and Drug Regulations. Witepsol is not an excipient of human or animal origin.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| INTRAROSA | 02493500 | COSETTE PHARMACEUTICALS, INC. | PRASTERONE 6.5 MG |