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Imvaggis (estriol) 0.03mg pessary for vaginal atrophy1

An ultra-low dose estriol pessary that is easily inserted without the need for an applicator, designed with the patient in mind. 1,2
  • Some women suffering from Vaginal Atrophy may find the use of an applicator uncomfortable.
  • Imvaggis effectively treats the local vaginal symptoms associated with oestrogen deficiency in postmenopausal women:
    – significantly improving the symptoms of vaginal atrophy.1,3*
    – alleviating inflammatory disorders and restoring the vaginal Lactobacillus flora.1

*Study demonstrated superior efficacy of Estriol  (0.03mg) vs placebo  ( P<0.001) in 436 postmenopausal women with vaginal atrophy . This was a 12 week, prospective, multicenter, randomised, placebo controlled,double blind study. The treatment was well tolerated.

Imvaggis (estriol) 0.03mg pessary for vaginal atrophy1

An ultra-low dose estriol pessary that is easily inserted without the need for an applicator, designed with the patient in mind. 1,2
  • Some women suffering from Vaginal Atrophy may find the use of an applicator uncomfortable.
  • Imvaggis effectively treats the local vaginal symptoms associated with oestrogen deficiency in postmenopausal women:
    – significantly improving the symptoms of vaginal atrophy.1,3*
    – alleviating inflammatory disorders and restoring the vaginal Lactobacillus flora.1

*Study demonstrated superior efficacy of Estriol  (0.03mg) vs placebo  ( P<0.001) in 436 postmenopausal women with vaginal atrophy . This was a 12 week, prospective, multicenter, randomised, placebo controlled,double blind study. The treatment was well tolerated.

Imvaggis (estriol) 0.03mg pessary for vaginal atrophy1

An ultra-low dose estriol pessary that is easily inserted without the need for an applicator, designed with the patient in mind. 1,2
  • Some women suffering from Vaginal Atrophy may find the use of an applicator uncomfortable.
  • Imvaggis effectively treats the local vaginal symptoms associated with oestrogen deficiency in postmenopausal women:
    – significantly improving the symptoms of vaginal atrophy.1,3*
    – alleviating inflammatory disorders and restoring the vaginal Lactobacillus flora.1

*Study demonstrated superior efficacy of Estriol  (0.03mg) vs placebo  ( P<0.001) in 436 postmenopausal women with vaginal atrophy . This was a 12 week, prospective, multicenter, randomised, placebo controlled,double blind study. The treatment was well tolerated.

Efficacy

Imvaggis demonstrates superior efficacy in the treatment of vaginal atrophy vs placebo3

In a study of 436 postmenopausal women with vaginal atrophy, after 12 weeks of treatment with Imvaggis (estriol) 0.03mg:

  • Intensity of most bothersome symptom (MBS) was significantly improved vs placebo (p<0.001)
  • Vaginal maturation index (VMI) was significantly increased vs placebo (p<0.001)
  • Vaginal pH was significantly decreased vs placebo (p<0.001)

Imvaggis significantly improved MBS intensity at 12 weeks vs placebo*†3

Co-primary: After 12 weeks, MBS intensity measure on visual analogue scale (VAS) declined significantly more with 0.03 mg estriol (47.1±23.4) compared to placebo (−31.8±26.3; p < 0.001)

Secondary: Intensity of the MBS had decreased considerably after 20 days of treatment (from 78.9±9.2 at Screening to 47.5±23.4 under 0.03mg estriol after 20 days of treatment and from 77.8±9.1 to 55.5±21.4 under placebo). However, a further marked improvement was observed after 12 weeks of treatment (decrease to 31.3±22.7 under 0.03mg estriol and 45.3±25.1 under placebo)

Imvaggis reduced the severity of most bothersome symptom (MBS) by 60% after 12 weeks, compared with 42% in those treated with placebo3

The symptoms most frequently selected as most bothersome were dryness, dyspareunia, pain/burning sensation, pruritus and discharge.3

Adapted from Griesser H et al. 2012.
Subjects recorded the most severe symptom of vaginal atrophy (dryness, pain/burning sensation, pruritus, dis- charge or dyspareunia) which was defined as the MBS. Subjects were requested to mark the intensity of this symptom on a VAS which was evaluated again after 20 days and 12 weeks of treatment.
*In a 12-week randomised, placebo-controlled, multicentred, double-blind study of 436 postmenopausal women with vaginal atrophy. † p<0.001.

Imvaggis significantly increased VMI at week 12 vs placebo†3 

Co-primary: After 12 weeks, the increase in VMI was significantly greater with 0.03 mg estriol (38.4±19.4%) compared to placebo (23.9±21.5%; p < 0.001)

Secondary: Significant improvement in VMI was observed after 20 days of treatment, from 11.7±12.9% to 55.4±16.8% under 0.03mg estriol and from 12.3±13.1% to 37.8±18.2% under placebo whilst thereafter VMI showed a slight decline (to 50.1±14.4% under 0.03mg estriol and 35.7±19.3% under placebo after 12 weeks of treatment).

Imvaggis showed a significant improvement in Vaginal Maturation index seen at Week 12 compared with placebo p<0.0013

Adapted from Griesser H et al. 2012.
Determined by evaluating the proportion of superficial cells vs parabasal and intermediate cells.

Imvaggis significantly reduced vaginal pH at week 12 vs placebo*†3

Co-primary: After 12 weeks, vaginal pH decreased significantly more with 0.03 mg estriol (−1.4±0.9) compared to placebo (−0.6±0.8; p < 0.001)

Secondary: Vaginal pH showed the greatest decrease (improvement) after 20 days of treatment (from 6.5±0.6 at screening to 5.1±0.7 under 0.03mg estriol and from 6.5±0.6 to 5.8±0.8 using placebo); thereafter vaginal pH remained relatively unchanged (5.0±0.7 under 0.03mg estriol and 5.9±0.9 under placebo after 12 weeks of treatment).

Vaginal estriol alleviates the symptoms of vaginal atrophy, by relieving vaginal dryness, lowering vaginal pH, and increasing the proportion of superficial cells in the vaginal epithelium.4

Adapted from Griesser H et al. 2012.
A vaginal pH of >5 was required for inclusion and a vaginal pH of 5 or less was the criteria for efficacy for this endpoint.
* In a 12-week randomised, placebo-controlled, multicentred, double-blind study of 436 postmenopausal women.
† p<0.001.

After 12 weeks of treatment with Imvaggis (estriol) 0.03mg, 80% of patients had an efficacy rating of very good or good.**3

Safety

Imvaggis is generally well tolerated1,3

Adverse events were rare and occurred at similar rates in the 0.03mg and placebo groups.

During a pivotal clinical study, adverse event incidences were 21.8% in the Imvaggis group and 25.9% in the placebo group3

The most frequently reported adverse events were vulvovaginal burning sensation, application site pain and vulvovaginal pruritus. These were similar across all groups and occurred almost exclusively during the first 20 days of treatment. Tolerability of study treatment was mainly assessed by the subjects to be very good or good and showed a trend towards improvement with longer duration of use. Adverse events are often transient and of mild intensity.1,3

Imvaggis aligns with guidelines that recommend the lowest effective dose for treatment of urogenital atrophy5

No notable changes in endometrial thickness were observed, however, endometrial safety of long-term (more than one year) or repeated use of vaginally applied oestrogen is uncertain. Therefore, treatment should be reviewed at least annually.1,3

* A subject-based evaluation of tolerability using a 5-stage ordinal scale (ranking very good, good, satisfactory, fair or poor).
** Investigator evaluation of efficacy was established using a 4-stage ordinal scale (ranking very good, good, fair or poor).

Contraindications

Please refer to section 4.3 of SmPC

  • Known, past or suspected breast cancer
  • Known or suspected oestrogen-dependent malignant tumours (e. g. endometrial cancer)
  • Undiagnosed genital bleeding
  • Untreated endometrial hyperplasia
  • Previous or current venous thromboembolism (deep venous thrombosis, pulmonary embolism)
  • Known thrombophilic disorders (e. g. protein C, protein S, or antithrombin deficiency, see section 4.4 of SmPC)
  • Active or recent arterial thromboembolic disease (e.g. angina, myocardial infarction)
  • Acute liver disease, or a history of liver disease as long as liver function tests have failed to return to normal
  • Porphyria
  • Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 of SmPC

Pharmacokinetics of Imvaggis (estriol) 0.03mg6

Estriol mean plasma concentrations after single dose (day 1,2) and multiple dose (day 21/22) application (sd = single dose, one pessary applied; md = multiple dose, 21 pessaries applied).6

Pharmacokinetics of Imvaggis (estriol) 0.03mg5

Estriol mean plasma concentrations after single dose (day 1,2) and multiple dose (day 21/22) application (sd = single dose, one pessary applied; md = multiple dose, 21 pessaries applied).16

  • The initial administration increased the population mean estriol plasma concentration to a maximum of 42.1 pg/ml 1 h after dosing.
  • However, 12 h after administration the estriol concentration had again dropped below 5 pg/ml (lower limit of quantification) in all patients.
  • Repeated administration did not result in an accumulation of estriol, since 2 h after application of the 21st pessary, the population mean estriol concentration reached a maximum of 11.9 pg/ml.
  • Moreover, no severe or serious adverse events occurred, and no clinically relevant findings were reported.

Adapted from Buhling et al., 2012

Adapted from Buhling et al., 2012

  • The initial administration increased the population mean estriol plasma concentration to a maximum of 42.1 pg/ml 1 h after dosing.
  • However, 12 h after administration the estriol concentration had again dropped below 5 pg/ml (lower limit of quantification) in all patients.
  • Repeated administration did not result in an accumulation of estriol, since 2 h after application of the 21st pessary, the population mean estriol concentration reached a maximum of 11.9 pg/ml.
  • Moreover, no severe or serious adverse events occurred, and no clinically relevant findings were reported.
Drug analysis was done on day 1 and day 2 (one pessary applied) as well as on day 21/day 22 (21 pessaries applied).

Single vaginal application of pessaries containing 0.03 mg estriol resulted in a very low systemic bioavailability. This decreased further after multiple dosing, confirming a favourable tolerability profile of low dose pessaries administered daily over 21 days.

Mechanism of Action1

  • The active ingredient, semisynthetic oestriol, is chemically identical to human estriol which is produced naturally in the body.
  • Vaginally applied oestriol helps to alleviate the symptoms of vaginal atrophy due to oestrogen deficiency in postmenopausal women.
  • Instead of an atrophic cell profile, mainly intermediate cells and an increasing number of superficial cells are found in the vagina; inflammation reduces and restoration of the vaginal Lactobacillus flora (Doederlein’s flora) is supported.

How to use

Imvaggis is best inserted in the evening before going to bed.1 Imvaggis does not need an applicator as some patients may find this uncomfortable. With clean hands the pessary is removed from the foil packaging, held between finger and thumb, insert into the vagina and push the pessary as far as possible.

Duration of treatment1

Please refer to section 4 of the SmPC

For initiation and continuation of treatment of postmenopausal symptoms, the lowest effective dose for the shortest duration should be used.1

References

1. Imvaggis (estriol) 0.03mg Summary of Product Characteristics. Available from https://www.medicines.ie/medicines/imvaggis-0-03-mg-pessary-34870/spc#tabs last accessed September 2022 2. Data on file IMV/2020/017 3. Griesser H, et al. Low dose estriol pessaries for the treatment of vaginal atrophy: a double-blind placebo-controlled trial investigating the efficacy of pessaries containing 0.2mg and 0.03mg estriol. Maturitas. 2012;71(4):360-368 4. Goldman L, et al. Goldman’s Cecil Medicine. 24th ed. Philadelphia: Elsevier/Saunders, 2012. 5. WHC-FACTSHEET-HRT-Doses-MAY2022-01J 6. Buhling KJ, et al. Systemic bioavailability of estriol following single and repeated vaginal administration of 0.03mg estriol containing pessaries. Arzneimittelforschung. 2012;62: 378−383.

ADVERSE EVENT REPORTING

Adverse events and product complaints should be reported. To report an adverse event or product complaint for a Besins Healthcare product, please call Besins Healthcare on 01-4004466 or email pharmacovigilance@besins-healthcare.com. Adverse events and product complaints may also be reported to the Health Products Regulatory Authority. Reporting forms and information can be found at www.hpra.ie