INTRAROSA 6.5 mg VAGINAL OVULES

2. What you need to know before you use Intrarosa

The use of hormone replacement therapy (HRT) involves risks that need to be considered before deciding whether to start or continue treatment.

Experience in treating women with premature menopause (due to ovarian failure or surgery) is limited. If you have premature menopause, the risks of using HRT may be different. Consult your doctor.

Before starting (or resuming) HRT, your doctor will ask about your medical history and that of your family. Your doctor may decide that it is necessary to perform a physical examination, which may include a breast examination and/or an internal examination, if necessary.

Once you have started taking Intrarosa, you should see your doctor for regular check-ups (at least every 6 months). During these check-ups, you can discuss the benefits and risks of continuing with Intrarosa with your doctor.

Go for regular breast examinations, as recommended by your doctor.

Do not use Intrarosa:

if you have any of the following conditions. If you are not sure about any of the following points, consult your doctor before using Intrarosa,

• If you have or have had breast cancer, or suspect you may have it;
• If you have or have had estrogen-sensitive cancer, such as cancer of the lining of the uterus (endometrium), or suspect you may have it;
• If you have any unexplained vaginal bleeding;
• If you have excessive thickening of the lining of the uterus(endometrial hyperplasia) that is not being treated;
• If you have or have had a blood clot in a vein(thrombosis), either in the legs (deep vein thrombosis) or lungs (pulmonary embolism);
• If you have a blood clotting disorder(such as protein C, protein S, or antithrombin deficiency);
• If you have or have recently had a disease caused by blood clots in the arteries, such as a heart attack, stroke, or angina.
• If you have or have had liver diseaseand liver function tests have not yet returned to normal;
• If you have a rare blood disorder called porphyria;
• If you are allergicto prasteroneor any of the other ingredients of this medicine (listed in section 6).

If any of these disorders occur for the first time while using Intrarosa, stop treatment and consult your doctor immediately.

Warnings and precautions

When to be extra careful with Intrarosa

Tell your doctor if you have ever had any of the following problems, before starting treatment, as they may come back or get worse during treatment with Intrarosa. If so, you should see your doctor more often for check-ups:

• fibroids in the uterus;
• growth of the uterine lining outside the uterus (endometriosis) or a history of excessive thickening of the uterine lining (endometrial hyperplasia);
• a history of blood clots (see Blood clots in a vein (thrombosis));
• an increased risk of estrogen-sensitive cancer (such as having a mother, sister, or grandmother who has had breast cancer);
• high blood pressure;
• liver disorders, such as a benign liver tumor;
• diabetes;
• gallstones;
• migraine or severe headaches;

• a disease of the immune system that affects many parts of the body (systemic lupus erythematosus, SLE);
• epilepsy;

• asthma;
• a disease that affects the eardrum and hearing (otosclerosis);
• a very high level of fat in the blood (triglycerides);
• fluid retention due to heart or kidney problems.

Stop taking Intrarosa and see a doctor immediately

If you notice any of the following symptoms while using HRT:

• any of the conditions mentioned in the section Do not use Intrarosa;
• yellowing of the skin or the whites of the eyes (jaundice). These may be symptoms of liver disease;
• a large increase in blood pressure (with symptoms such as headache, tiredness, dizziness);
• migraine-type headaches, which may occur for the first time;

• swelling with pain and redness of the legs;
• sudden chest pain;
• difficulty breathing.

For more information, see Blood clots in a vein (thrombosis).

Note:Intrarosa is not a contraceptive. If it has been less than 12 months since your last menstrual period or if you are under 50, you may still need to use a contraceptive to prevent pregnancy. Ask your doctor for advice.

HRT and cancer

Intrarosa has not been studied in women with current or past cancer.

Excessive thickening of the uterine lining (endometrial hyperplasia) and cancer of the uterine lining (endometrial cancer)

Long-term use of HRT with only estrogen tablets may increase the risk of developing cancer of the uterine lining (endometrium). Intrarosa does not stimulate the growth of the endometrium, as shown by the atrophy of the uterine lining in all women treated with Intrarosa for one year in clinical trials.

It is not clear if there is any risk when Intrarosa is used for long-term treatment (more than one year). However, it has been shown that the absorption of Intrarosa into the bloodstream is very small, so it is not necessary to add a progestogen.

If you experience vaginal bleeding or spotting, it is usually not a cause for concern, but you should make an appointment with your doctor. It may be a sign that the endometrium has thickened.

The following risks are related to HRT medications that circulate in the blood. However, Intrarosa is used for local treatment of the vagina and absorption into the blood is very small. It is less likely that the disorders mentioned below will get worse or come back during treatment with Intrarosa, but you should see your doctor if you are concerned.

Breast cancer

Available data indicate that HRT that combines estrogen-progestogen, and possibly also HRT with only estrogen, increases the risk of breast cancer. The additional risk depends on how long you take HRT. The increased risk becomes apparent after a few years of HRT. However, it returns to normal within a few years (at most 5) of stopping treatment.

• Check your breasts regularly. See a doctor if you notice any changes, such as:

• dimpling of the skin;
• changes in the nipples;
• any lump that you can see or feel.

In addition, we recommend that you follow early detection programs with mammograms when they are offered to you.

Ovarian cancer

Ovarian cancer is rare, much rarer than breast cancer. The use of HRT with only estrogen has been associated with a slight increase in the risk of ovarian cancer.

The risk of ovarian cancer varies with age. For example, in women aged 50-54 who do not receive HRT, about 2 cases of ovarian cancer will be diagnosed per 2000 women over a 5-year period. In women who have received HRT for 5 years, about 3 cases will occur per 2000 HRT users (i.e., about 1 additional case).

Rare cases of ovarian and breast cancer have been reported in women treated with 6.5 mg of prasterone for 52 weeks.

Effect of HRT on the heart and circulation

Intrarosa has not been studied in women with a history of thromboembolic diseases, uncontrolled hypertension, or heart disease.

Blood clots in a vein (thrombosis)

The risk of blood clots in the veins is approximately 1.3 to 3 times higher in HRT users than in non-users, especially in the first year of treatment.

Blood clots can be serious and if one reaches the lungs, it can cause chest pain, difficulty breathing, fainting, or even death.

The likelihood of having a blood clot will be higher with increasing age and if any of the following factors apply to you. If any of these situations may apply to you, tell your doctor:

• you are unable to walk for a long time due to a major surgical procedure, injury, or illness (see also section 3, If you need to have surgery);
• you are severely overweight (BMI > 30 kg/m2);
• you have a blood clotting disorder that requires long-term treatment with medication to prevent clots;
• a close relative has had a blood clot in the legs, lungs, or other organs;
• you have systemic lupus erythematosus (SLE);
• you have cancer.

For symptoms of a blood clot, see the section Stop taking Intrarosa and see a doctor immediately.

In clinical trials, no deep vein thrombosis was observed with intravaginal prasterone, and the only case of pulmonary embolism observed indicates a lower incidence with Intrarosa than in the placebo group.

Comparison

It is estimated that, over a 5-year period, an average of 4 to 7 out of 1000 women around the age of 50 who do not receive HRT will develop a blood clot in a vein.

Heart disease (heart attack)/High blood pressure

In women who receive estrogen-only therapy, the risk of heart disease does not increase.

Stroke

The risk of having a stroke is approximately 1.5 times higher in HRT users than in non-users. The number of additional stroke cases due to HRT use increases with age.

No cases of stroke have been observed with Intrarosa in clinical trials.

Comparison

It is estimated that, over a 5-year period, an average of 8 out of 1000 women around the age of 50 who do not receive HRT will have a stroke. In women around the age of 50 who are receiving HRT, the number of cases will be 11 per 1000 HRT users over a 5-year period (i.e., 3 additional cases).

Other conditions

• HRT does not prevent memory loss. There is some evidence of a higher risk of memory loss in women who start HRT after the age of 65. Ask your doctor for advice.
• You may experience vaginal discharge due to the melting of the fatty base, and this is added to the expected increase in vaginal secretions caused by treatment. If vaginal discharge occurs, it is not necessary to interrupt the administration of Intrarosa.
• Intrarosa may affect latex condoms, diaphragms, and cervical caps.
• If you have a vaginal infection, you will need to receive a course of antibiotics before taking Intrarosa.

Children and adolescents

Intrarosa is only used in adult women.

Other medicines and Intrarosa

Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.

No data on efficacy and safety are available for women currently being treated with hormonal therapy such as androgens, HRT (estrogen alone or combined with progestogen).

The use of Intrarosa in combination with HRT (estrogen-only, estrogen-progestogen, or androgen therapy) or with vaginal estrogens is not recommended.

Pregnancy, breastfeeding, and fertility

Pregnancy and breastfeeding

Intrarosa should only be used in postmenopausal women. If you become pregnant, stop taking Intrarosa and consult your doctor.

Fertility

Intrarosa is contraindicated in women of childbearing age. It is not known if this medicine affects fertility.

Driving and using machines

Intrarosa does not normally affect the ability to drive or use machines.

3. How to use Intrarosa

Follow the instructions for administration of this medicine exactly as prescribed by your doctor or pharmacist. If you are unsure, consult your doctor or pharmacist again.

Your doctor will try to prescribe the lowest dose to treat your symptoms for as short a period as necessary. Talk to your doctor if you think this dose is too high or too low.

How much to use

Use one vaginal tablet once a day, at bedtime.

How to use Intrarosa

Insert the vaginal tablet into the vagina with your finger or with an applicator provided in the packaging.

Read the instructions for use of Intrarosa carefully at the end of the package leaflet before using this medicine.

How long to use

Once you have started using it, see your doctor at least every 6 months to check if you need to continue using Intrarosa.

If you use more Intrarosa than you should

A vaginal douche is recommended.

If you forget to use Intrarosa

If you forget to use a vaginal tablet, insert one as soon as you remember. However, if it is less than 8 hours until the next dose, skip the missed vaginal tablet.

Do not use two vaginal tablets to make up for the missed dose.

If you need to have surgery

If you are going to have surgery, tell the surgeon that you are using Intrarosa. You may need to stop using Intrarosa 4 to 6 weeks before the operation to reduce the risk of a blood clot (see section 2, Blood clots in a vein (thrombosis)). Ask your doctor when you can start using Intrarosa again.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

The following diseases are more common in women who use HRT medications that circulate in the blood, compared to women who do not use HRT. These risks apply less to treatments with estrogens administered vaginally:

• breast cancer;
• ovarian cancer;
• blood clots in the veins of the legs or lungs (venous thromboembolism);
• stroke;
• possible memory loss if HRT is started after the age of 65.

For more information on these side effects, see section 2.

The most frequently reported side effect in clinical trials was vaginal discharge. This is probably due to the melting of the fatty base, and this is added to the expected increase in vaginal secretions caused by treatment. Vaginal discharge does not require interruption of Intrarosa administration.

The following side effects were also reported:

• common (may affect up to 1 in 10 people): abnormal vaginal cytology (in most cases, ASCUS or LGSIL), weight fluctuations (increase or decrease);
• uncommon (may affect up to 1 in 100 people): benign cervical or uterine polyps, benign breast mass.

The following side effects have been reported with HRT containing estrogens, but not with Intrarosa, during clinical trials:

• gallbladder disease
• various skin disorders:

• skin pigmentation, especially on the face and neck, known as pregnancy patch(chloasma)
• red and painful skin nodules (erythema nodosum)
• rash with ulcers or redness in a target shape (erythema multiforme)

Reporting of side effects

If you experience any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly through the Spanish Medicines Monitoring System for Human Use: www.notificaRAM.es

By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storage of Intrarosa

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton and blister after EXP. The expiry date is the last day of the month indicated.

Store below 30 °C.

Do not freeze.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. This will help to protect the environment.

6. Package Contents and Additional Information

Composition of Intrarosa

• The active substance is prasterone. Each ovule contains 6.5 mg of prasterone.
• The other component is hard fat (adeps solidus).

Appearance of the Product and Package Contents

Intrarosa is a white or off-white ovule, bullet-shaped, approximately 28 mm in length and 9 mm in diameter at its widest end.

The applicator is made of LDPE and colorant at 1% (titanium dioxide).

It is presented in blister packs containing 28 ovules with 6 applicators.

Marketing Authorization Holder

Endoceutics S.A.

Rue Belliard 40

1040 Brussels

Belgium

Manufacturer

Basic Pharma Manufacturing B.V.

Burgemeester Lemmensstraat 352

6163 JT Geleen

Netherlands