INTRAROSA 6.5mg ova medication leaflet

Intrarosa 6.5 mg pessary

Each pessary contains 6.5 mg of prasterone.

For the full list of excipients, see section 6.1.

Pessary

White to off-white, bullet-shaped pessary approximately 28 mm long and 9 mm in diameter at itswidest end.

Intrarosa is indicated for the treatment of vulvar and vaginal atrophy in postmenopausal womenhaving moderate to severe symptoms.

The recommended dose is 6.5 mg prasterone (one pessary) administered once daily, at bedtime.

For the treatment of postmenopausal symptoms, Intrarosa should only be initiated for symptoms thatadversely affect quality of life. In all cases, a careful appraisal of the risks and benefits should bereassessed at least every 6 months and Intrarosa should only be continued as long as the benefitoutweighs the risk.

If a dose is forgotten, it should be taken as soon as the patient remembers. However, if the next dose isdue in less than 8 hours, the patient should skip the missed pessary. Two pessaries should not be usedto make up for a forgotten dose.

No dose adjustment is considered necessary in elderly women.

Patients with renal and/or hepatic impairment

Since Intrarosa acts locally in the vagina, no dose adjustment is needed for postmenopausal womenhaving renal or hepatic impairment or any other systemic anomaly or disease.

There is no relevant use of Intrarosa in female children of any age group for the indication of vulvarand vaginal atrophy due to menopause.

Vaginal use

Intrarosa can be inserted in the vagina with the finger or with an applicator provided within theidentified pack.

The pessary should be inserted in the vagina as far as it can comfortably go without force.

If inserted with an applicator, the following steps should be followed:

1. The applicator should be activated (by pulling back the plunger) before use.2. The flat end of the pessary should be placed into the open end of the activated applicator.3. The applicator should be inserted into the vagina as far as it can comfortably go without force.4. The plunger of the applicator should be pressed to release the pessary.5. The applicator should then be withdrawn and disassembled, and the two pieces of the applicatorshould be rinsed for 30 seconds under running water before wiping with paper towel andreassembled. The applicator should be kept in a clean place until next use.

6. Each applicator should be discarded after one week of usage (two extra applicators areprovided).

* Hypersensitivity to the active substance or to the excipient listed in section 6.1;

* Undiagnosed genital bleeding;

* Known, past or suspected breast cancer;

* Known or suspected oestrogen-dependent malignant tumours (e.g endometrial cancer);

* Untreated endometrial hyperplasia;

* Acute liver disease, or a history of liver disease as long as liver function tests have failed toreturn to normal;

* Previous or current venous thromboembolism (VTE) (deep vein thrombosis, pulmonaryembolism);

* Known thrombophilic disorders (e.g. protein C, protein S, or antithrombin deficiency, seesection 4.4);

* Active or recent arterial thromboembolic disease (e.g. angina, myocardial infarction);

* Porphyria.

For the treatment of postmenopausal symptoms, Intrarosa should only be initiated for symptoms thatadversely affect quality of life. In all cases, a careful appraisal of the risks and benefits should bereassessed at least every 6 months and Intrarosa should only be continued as long as the benefitoutweighs the risk following discussions with their doctor.

Medical examination/follow-up

Before initiating Intrarosa, a complete personal and family medical history should be taken. Physical(including pelvic and breast) examination should be guided by this and by the contraindications andspecial warnings and precautions for use according to the decision of their doctor. During treatment,periodic check-ups are recommended of a frequency and nature adapted to the individual woman.

Women should be advised what changes in their breasts should be reported to their doctor or nurse(see ‘Breast cancer’ below). Investigations, including Pap smears and blood pressure measurementsshould be carried out in accordance with currently accepted screening practices, modified to theclinical needs of the individual.

Conditions which need supervision

* If any of the following conditions are present, have occurred previously, and/or have beenaggravated during pregnancy or previous hormone treatment, the patient should be closelysupervised. It should be taken into account that these conditions may recur or be aggravatedduring treatment with Intrarosa, in particular:

- Leiomyoma (uterine fibroids) or endometriosis- Risk factors for thromboembolic disorders (see below)- Risk factors for oestrogen dependent tumours, e.g. 1st degree heredity for breast cancer- Hypertension- Liver disorders (e.g. liver adenoma)- Diabetes mellitus with or without vascular involvement- Cholelithiasis- Migraine or (severe) headache- Systemic lupus erythematosus.- A history of endometrial hyperplasia (see below)- Epilepsy- Asthma- Otosclerosis

Reasons for immediate withdrawal of therapy

Therapy should be discontinued in case a contraindication is discovered and in the following situation:- Jaundice or deterioration in liver function- Significant increase in blood pressure- New onset of migraine-type headache- Pregnancy.

Endometrial hyperplasia and carcinoma

* Estrogen is a metabolite of prasterone. In women with an intact uterus, the risk of endometrialhyperplasia and carcinoma is increased when exogenous oestrogens are administered forprolonged periods. No cases of endometrial hyperplasia have been reported in women treatedfor 52 weeks during the clinical studies. Intrarosa has not been studied in women withendometrial hyperplasia.

* For oestrogen products for vaginal application of which the systemic exposure to oestrogenremains within the normal postmenopausal range, it is not recommended to add a progestagen.

* Endometrial safety of long-term of local vaginally administered prasterone has not been studiedfor more than one year. Therefore, if repeated, treatment should be reviewed at least annually.

* If bleeding or spotting appears at any time on therapy, the reason should be investigated, whichmay include endometrial biopsy to exclude endometrial malignancy.

* Unopposed oestrogen stimulation may lead to premalignant or malignant transformation in theresidual foci of endometriosis. Therefore, caution is advised when using this product in womenwho have undergone hysterectomy because of endometriosis, especially if they are known tohave residual endometriosis since intravaginal prasterone has not been studied in women withendometriosis.

Prasterone is metabolised into estrogenic compounds. The following risks have been associated withsystemic Hormone Replacement Therapy (HRT) and apply to a lesser extent for oestrogen productsfor vaginal application of which the systemic exposure to the oestrogen remains within the normalpostmenopausal range. However, they should be considered in case of long term or repeated use ofthis product.

Breast cancer

The overall evidence suggests an increased risk of breast cancer in women taking combined oestrogen-progestagen and possibly also oestrogen-only systemic HRT, that is dependent on the duration oftaking HRT. The excess risk becomes apparent within a few years of use but returns to baseline withina few (at most five) years after stopping treatment.

Intrarosa has not been studied in women with active or past breast cancer. One case of breast cancer atweek 52 has been reported on 1196 women who have been exposed with the 6.5 mg dose which isbelow the incidence rate observed in the normal population of the same age.

Ovarian cancer

Ovarian cancer is much rarer than breast cancer.

Epidemiological evidence from a large meta-analysis suggests a slightly increased risk in womentaking oestrogen-only systemic HRT, which becomes apparent within 5 years of use and diminishesover time after stopping.

Intrarosa has not been studied in women with active or past ovarian cancer. One Case of ovariancancer has been reported on 1196 women who have been exposed with the 6.5 mg dose which isabove the incidence rate observed in the normal population of the same age. Of note, this case waspresent before start of treatment and was bearing a BRCA1 mutation.

Abnormal Pap smear

Intrarosa has not been studied in women with abnormal Pap smears (Atypical Squamous Cells of

Undetermined Significance (ASCUS)) or worse. Cases of abnormal Pap smears corresponding to

ASCUS or Low Grade Squamous Intraepithelial Lesion (LSIL) have been reported in women treatedwith the 6.5 mg dose (common frequency).

Intrarosa has not been studied in women with current or previous venous thromboembolic disease.

* Systemic HRT is associated with a 1.3-3 fold risk of developing venous thromboembolism (VTE),i.e. deep vein thrombosis or pulmonary embolism. The occurrence of such an event is more likelyin the first year of HRT than later (see section 4.8).

* Patients with known thrombophilic states have an increased risk of VTE and HRT may add to thisrisk. HRT is therefore contraindicated in these patients (see section 4.3).

* Generally recognised risk factors for VTE include, use of oestrogens, older age, major surgery,prolonged immobilisation, obesity (BMI > 30 kg/m2), pregnancy/postpartum period, systemiclupus erythematosus (SLE), and cancer. There is no consensus about the possible role of varicoseveins in VTE.

As in all postoperative patients, prophylactic measures need be considered to prevent VTEfollowing surgery. If prolonged immobilisation is to follow elective surgery temporarily stopping

HRT 4 to 6 weeks earlier is recommended. Treatment should not be restarted until the woman iscompletely mobilised.

* In women with no personal history of VTE but with a first degree relative with a history ofthrombosis at young age, screening may be offered after careful counselling regarding itslimitations (only a proportion of thrombophilic defects are identified by screening).

If a thrombophilic defect is identified which segregates with thrombosis in family members or ifthe defect is ‘severe’ (e.g, antithrombin, protein S, or protein C deficiencies or a combination ofdefects) HRT is contraindicated.

* Women already on chronic anticoagulant treatment require careful consideration of the benefit-risk of use of HRT.

* If VTE develops after initiating therapy, Intrarosa should be discontinued. Patients should be toldto contact their doctors immediately when they are aware of a potential thromboembolic symptom(e.g. painful swelling of a leg, sudden pain in the chest, dyspnoea).

One case of pulmonary embolism has been reported in the 6.5 mg group and one in the placebo groupduring clinical studies.

Coronary artery disease (CAD)/Hypertension

Intrarosa has not been studied in women with uncontrolled hypertension (blood pressure above140/90 mmHg) and cardiovascular disease. Cases of hypertension have been reported in clinicalstudies with an uncommon frequency and similar incidence rates were observed in both groups(6.5 mg prasterone and placebo). No case of coronary artery disease has been reported during clinicalstudies.

Ischaemic stroke

Systemic oestrogen-only therapy is associated with an up to 1.5-fold increase in risk of ischaemicstroke. The relative risk does not change with age or time since menopause. However, as the baselinerisk of stroke is strongly age-dependent, the overall risk of stroke in women who use HRT willincrease with age (see section 4.8).

Intrarosa has not been studied in women with current or previous arterial thromboembolic disease.

No cases of arterial thromboembolic disease have been reported during clinical studies.

Other conditions observed with HRT

* Oestrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunctionshould be carefully observed.

* Women with pre-existing hypertriglyceridaemia should be followed closely during oestrogenreplacement or HRT, since rare cases of large increases of plasma triglycerides leading topancreatitis have been reported with oestrogen therapy in this condition.

* Oestrogens increase thyroid binding globulin (TBG), leading to increased circulating totalthyroid hormone, as measured by protein-bound iodine (PBI), T4 levels (by column or by radio-immunoassay) or T3 levels (by radio-immunoassay). T3 resin uptake is decreased, reflecting theelevated TBG. Free T4 and free T3 concentrations are unaltered. Other binding proteins may beelevated in serum, i.e. corticoid binding globulin (CBG), sex-hormone-binding globulin(SHBG) leading to increased circulating corticosteroids and sex steroids, respectively. Free orbiological active hormone concentrations are unchanged. Other plasma proteins may beincreased (angiotensinogen/renin substrate, alpha-I-antitrypsin, ceruloplasmin).

* HRT use does not improve cognitive function. There is some evidence of increased risk ofprobable dementia in women who start using continuous combined or oestrogen-only HRT afterthe age of 65.

None of these conditions has been observed with Intrarosa during the clinical studies.

Women with vaginal infection should be treated with appropriate antimicrobial therapy before starting

Intrarosa.

Due to melting of the hard fat base added to an expected increase in vaginal secretions due totreatment, vaginal discharge can occur although it does not require to stop Intrarosa (see section 4.8).

Use of Intrarosa with condoms, diaphragms or cervical caps made of latex must be avoided since therubber may be damaged by the preparation.

Intrarosa has not been studied in women with a current hormonal treatment: HRT (oestrogens alone orcombined with progestogens) or androgens treatment.

Concomitant use with systemic HRT (oestrogen-only or oestrogen-progestagen combination orandrogen treatment) or vaginal oestrogens has not been investigated and is therefore notrecommended.

Intrarosa is not indicated in pre-menopausal women of child-bearing age, including pregnancy.

If pregnancy occurs during treatment with Intrarosa, the treatment should be withdrawn immediately.

There are no data on the use of Intrarosa in pregnant women.

No studies in animals were performed with regard to the reproductive toxicity (see section 5.3). Thepotential risk in humans is unknown.

Intrarosa is not indicated during breast-feeding.

Intrarosa is not indicated in fertile women.

Intrarosa has no influence in the ability to drive and use machines.

The most frequently observed adverse reaction was vaginal discharge. This is due to melting of the hardfat used as vehicle, added to the expected increase in vaginal secretions due to treatment. It is notrequired to stop Intrarosa if vaginal discharge occurs (see section 4.4).

Adverse reactions observed with prasterone 6.5 mg pessaries obtained from clinical studies are tabulatedin Table 1 below.

Table 1: Adverse reactions observed with prasterone 6.5 mg pessaries in clinical studies

MedDRA System Organ Common Uncommon

Class (≥ 1/100 to < 1/10) (≥ 1/1,000 to < 1/100)

General disorders and Application site discharge -administration site conditions

Reproductive system and Abnormal Pap smear (mostly Cervical/ uterine polypsbreast disorders ASCUS or LGSIL)

Breast mass (benign)

Investigations Weight fluctuation -

Breast cancer risk

* An up to 2-fold increased risk of having breast cancer diagnosed is reported in women takingcombined oestrogen-progestagen therapy for more than 5 years.

* Any increased risk in users of oestrogen-only therapy is substantially lower than that seen inusers of oestrogen-progestagen combinations.

* The level of risk is dependent on the duration of use (see section 4.4).

* Results of the largest randomised placebo-controlled study (WHI-study) and largestepidemiological study (MWS) are presented.

Million Women study- Estimated additional risk of breast cancer after 5 years’ use

Age Additional cases per 1000 never- Risk ratio & Additional cases per 1000 HRTrange users of HRT over a 5-year period1 95%CI# users over 5 years (95%CI)(years)

Oestrogen only HRT50-65 9-12 1.2 1-2 (0-3)#Overall risk ratio. The risk ratio is not constant but will increase with increasing duration on use

Note: Since the background incidence of breast cancer differs by EU country, the number of additionalcases of breast cancer will also change proportionately.

US WHI studies - additional risk of breast cancer after 5 years’ use

Age range Incidence per 1000 women Risk ratio & Additional cases per 1000 HRT(years) in placebo arm over 5 years 95%CI users over 5 years (95%CI)

CEE oestrogen-only50-79 21 0.8 (0.7 - 1.0) -4 (-6 - 0)*2

Ovarian cancer

Use of oestrogen-only or combined oestrogen-progestagen HRT has been associated with a slightlyincreased risk of having ovarian cancer diagnosed (see section 4.4).

A meta-analysis from 52 epidemiological studies reported an increased risk of ovarian cancer inwomen currently using HRT compared to women who have never used HRT (RR 1.43, 95% CI 1.31-1.56). For women aged 50 to 54 years taking 5 years of HRT, this results in about 1 extra case per2000 users. In women aged 50 to 54 who are not taking HRT, about 2 women in 2000 will bediagnosed with ovarian cancer over a 5-year period.

Risk of venous thromboembolism

HRT is associated with a 1.3-3-fold increased relative risk of developing VTE, i.e. deep veinthrombosis or pulmonary embolism. The occurrence of such an event is more likely in the first year ofusing HT (see section 4.4). Results of the WHI studies are presented:

WHI Studies - Additional risk of VTE over 5 years’ use

Age range Incidence per 1000 women in Risk ratio and Additional cases per 1000(years) placebo arm over 5 years 95%CI HRT users

Oral oestrogen-only*350-59 7 1.2 (0.6 - 2.4) 1 (-3 - 10)

Risk of coronary artery disease

* The risk of coronary artery disease is slightly increased in users of combined oestrogen-progestagen

HRT over the age of 60 (see section 4.4).

1 *Taken from baseline incidence rates in developed countries2 *WHI study in women with no uterus, which did not show an increase in risk of breast cancer3 *Study in women with no uterus

Risk of ischaemic stroke

* The use of oestrogen-only and oestrogen + progestagen therapy is associated with an up to1.5 fold increased relative risk of ischaemic stroke. The risk of haemorrhagic stroke is notincreased during use of HRT.

* This relative risk is not dependent on age or on duration of use, but as the baseline risk isstrongly age-dependent, the overall risk of stroke in women who use HRT will increase withage, see section 4.4.

WHI studies combined - Additional risk of ischaemic stroke*4 over 5 years’ use

Age range Incidence per 1000 women in Risk ratio and Additional cases per 1000(years) placebo arm over 5 years 95%CI HRT users over 5 years50-59 8 1.3 (1.1-1.6) 3 (1-5)

Other adverse reactions have been reported in association with oestrogen/progestagen treatment:

- Gall bladder disease.- Skin and subcutaneous disorders: chloasma, erythema multiforme, erythema nodosum, vascularpurpura.- Probable dementia over the age of 65 (see section 4.4).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

In the event of overdose, vaginal douching is recommended.

Pharmacotherapeutic group: Other sex hormones and modulators of the genital system,

ATC code: G03XX01.

Intrarosa contains the active substance prasterone, i.e. dehydroepiandrosterone (DHEA), which isbiochemically and biologically identical to the endogenous human DHEA, a precursor steroid which isinactive by itself and it is converted into oestrogens and androgens. Intrarosa is thus different from theoestrogens preparations since it delivers also androgen metabolites.

An oestrogen-mediated increase in the number of superficial and intermediate cells and decrease in thenumber of parabasal cells in the vaginal mucosa is noted. In addition, the vaginal pH decreasedtowards the normal range, thus facilitating the growth of the normal bacterial flora.

4 *no differentiation was made between ischaemic and haemorrhagic stroke

Physiological responses (objective measures)

Efficacy data were obtained from two US and Canadian randomised, double-blind, placebo-controlled,multicentre, pivotal phase III studies (ERC-231/Study 1 and ERC-238/Study 2) performed inpostmenopausal women aged 40 to 80 years (mean age = 58.6 years in Study 1 and 59.5 years in

Study 2) with vulvar and vaginal atrophy (VVA ). At baseline, women had ≤ 5.0% superficial cells inthe vaginal smear, a vaginal pH ˃ 5.0 and they had identified dyspareunia (moderate to severe) as theirmost bothersome symptom (MBS) of VVA. After 12 weeks of daily treatment with a prasterone6.5 mg pessary (n=81 in Study 1 and n=325 in Study 2), the change from baseline, in comparison withplacebo treatment (n=77 in Study 1 and n=157 in Study 2), demonstrated significant improvements ofthe 3 co-primary endpoints compared to placebo in both studies, namely increase of the percentage ofsuperficial cells (p<0.0001), decrease of the percentage of parabasal cells (p<0.0001), and decrease inthe vaginal pH (p<0.0001).

Symptoms (subjective measures)

The MBS dyspareunia (co-primary endpoint) was assessed at baseline and 12 weeks with the severityscored as follows: None=0, Mild=1, Moderate=2, Severe=3. Table 2 shows the mean change inseverity score in MBS dyspareunia after 12 weeks with associated statistical testing for the differencevs. placebo for Study 1 (ERC-231) and Study 2 (ERC-238).

Table 2: Primary efficacy analysis - Change from baseline to week 12 in the most bothersomesymptom dyspareunia (ITT population; LOCF)

Study Dyspareunia

Intrarosa 6.5 mg Placebo p-value

Study 1 -1.27 -0.87 0.0132

Study 2 -1.42 -1.06 0.0002

Table 3 shows the percentage of subjects who reported a change from baseline in their MBSdyspareunia at week 12. “Improvement” was defined as a reduction in the severity score of 1 or more.“Relief” was defined as no or only mild symptoms at week 12. “Substantial improvement” wasrestricted to patients who had moderate or severe MBS at baseline and changed from severe to mild orsevere or moderate to none.

Table 3: Percentage of patients with improvement, relief or substantial improvement of

MBS dyspareunia after 12 weeks on Intrarosa vs. placebo (ITT, LOCF)

Improvement Relief Substantialimprovement

Intrarosa Placebo Intrarosa Placebo Intrarosa Placebo

Study 1 72.8% 58.4% 58.0% 44.2% 43.2% 29.9%(Intrarosa: n= 81) (p=0.0565) (p=0.0813) (p=0.0821)(Placebo: n= 77)

Study 2 80.3% 65.0% 68.6% 51.6% 47.1% 35.7%(Intrarosa: n= 325) (p=0.0003) (p=0.0003) (p=0.0179)(Placebo: n= 157)

Apart from the main two 12-week phase III clinical studies, the safety data of Intrarosa has also beenobtained from one non comparative open-label safety study of one year.

Cases of breast and ovarian cancer have been reported in women treated with 6.5 mg of prasterone for52 weeks (see section 4.4).

Cases of abnormal Pap smears either ASCUS or LSIL have been reported with a common frequencyin women treated with Intrarosa for 52 weeks (see section 4.4).

Endometrial safety

On the 389 evaluable end-of-study endometrial biopsies performed after 52 weeks of treatment with

Intrarosa, no histological abnormalities were reported on the biopsies.

The European Medicines Agency has waived the obligation to submit the results of studies with

Intrarosa in all subsets of the paediatric population.

Prasterone administered in the vagina is an inactive precursor that enters the vaginal cells and isconverted intracellularly into cell-specific small amounts of both oestrogens and androgens dependingupon the level of enzymes expressed in each cell type. The beneficial effects on the symptoms andsigns of vulvar and vaginal atrophy are exerted through activation of the vaginal oestrogen andandrogen receptors.

In a study conducted in postmenopausal women, administration of the Intrarosa pessary once daily for7 days resulted in a mean prasterone Cmax and area under the curve from 0 to 24 hours (AUC0-24) atday 7 of 4.4 ng/mL and 56.2 ng h/mL, respectively, which were significantly higher than those in thegroup treated with placebo (Table 4; Figure 1). The Cmax and AUC0-24 of the metabolites testosteroneand estradiol were also slightly higher in women treated with the Intrarosa pessary compared to thosereceiving placebo but all remained within normal values of postmenopausal women(< 10 pg estradiol/mL; < 0.26 ng testosterone/mL) as measured by validated mass spectrometry-basedassays for both the study samples and reference values.

Table 4: Cmax and AUC0-24 of prasterone, testosterone, and estradiol on Day 7 following dailyadministration of placebo or Intrarosa (mean ± S.D.)

Placebo (N=9) Intrarosa (N=10)

Cmax (ng/mL) 1.60 (±0.95) 4.42 (±1.49)

Prasterone

AUC0-24 (ng⋅h/mL) 24.82 (±14.31) 56.17 (±28.27)

Cmax (ng/mL) 0.12 (±0.04)1 0.15 (±0.05)

Testosterone

AUC0-24 (ng⋅h/mL) 2.58 (±0.94)1 2.79 (±0.94)

Cmax (pg/mL) 3.33 (±1.31) 5.04 (±2.68)

Estradiol

AUC0-24 (pg⋅h/mL) 66.49 (±20.70) 96.93 (±52.06)1 : N=8

Figure 1: Serum concentrations of prasterone (A), testosterone (B), and estradiol (C)measured over a 24h period on Day 7 following daily administration of placeboor Intrarosa (mean ± S.D.)

The distribution of intravaginal (exogenous) prasterone is mainly local but some increase in systemicexposure is observed especially for the metabolites but within normal values.

Exogenous prasterone is metabolized in the same manner as endogenous prasterone. Systemicmetabolism has not been studied in this application.

Systemic elimination has not been studied specifically for this application.

Prasterone was not mutagenic or clastogenic in a standard battery of in vitro and in vivo studies.

Carcinogenic and reproductive and development toxicity studies were not performed.

Hard fat (adeps solidus)

Not applicable

3 years

Store below 30 °C

Do not freeze

Blister composed of an outer layer of PVC and an inner layer of LDPE.

Applicator made of LDPE and 1% colorant (Titanium dioxide).

28 pessaries are packed in a carton with 6 applicators.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Endoceutics S.A.

Rue Belliard 401040 Brussels

Belgium

EU/1/17/1255/001

Date of first authorisation: 08 january 2018

Date of latest renewal: 15 september 2022

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.