CLIMEN Coated Tablets

Introduction

Package Leaflet: Information for the User

Climen Coated Tablets

Estradiol Valerate / Cyproterone Acetate

Package Leaflet Contents:

1. What is Climen and what is it used for
2. What you need to know before taking Climen
3. How to take Climen
   1. Possible side effects
   2. Storage of Climen
   3. Package Contents and Additional Information

1. What is Climen and what is it used for

Climen is indicated for:

• Hormone Replacement Therapy (HRT) for:

• Treatment of menopausal symptoms (the period of time when reproductive function and menstruation cease in a woman), natural or surgically induced, e.g. hot flashes, night sweats, urogenital disorders (atrophic vulvovaginitis), depressive mood.

• Prevention of osteoporosis (bone mass loss) if you are at high risk of suffering future fractures and cannot use other medications for this purpose. Consult your doctor about all available treatment options.

Climen should not be used to prevent heart disease or to enhance intellectual capacity.

Climen is not a contraceptive and does not restore fertility.

2. What you need to know before starting to take Climen

Follow your doctor's instructions carefully.

Read the following information before using Climen.

Medical history and regular check-ups

The use of HRT involves risks that must be taken into account when deciding whether to start or continue treatment.

Experience in treating women with premature menopause (due to ovarian failure or surgical intervention) 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 you about your personal and family medical history. Your doctor may decide to perform a physical examination. This may include a breast examination and/or an internal examination, if necessary.

Once you have started treatment with Climen, you should visit your doctor for regular check-ups (at least once a year). During these check-ups, discuss the benefits and risks of continuing Climen with your doctor.

Breast examinations should be performed regularly, as recommended by your doctor.

Do not take Climen

if any of the following cases apply to you. If you are unsure about any of the following points, consult your doctorbefore taking Climen. Do not take Climen:

• If you have or have had breast canceror if you suspect you may have it.
• If you have known or suspected premalignant lesionsinfluenced by sex hormones or hormone-dependent tumors.
• If you have a cancer that depends on the action of estrogens, such as cancer of the lining of the uterus (endometrium), or if you suspect you may have it.
• If you have a meningioma or have been diagnosed with a meningioma (a usually benign tumor of the tissue layer between the brain and the skull) at any time.
• If you are pregnant or suspect you may be pregnant or if you are breastfeeding.

• If you have abnormal vaginal bleeding.

• If you have excessive thickening of the lining of the uterus(endometrial hyperplasia) and are not being treated.

• If you have or have had the formation of a blood clot in a vein(thrombosis), e.g., in the legs (deep vein thrombosis) or lungs (pulmonary embolism).
• If you have a high risk of suffering from arterial or venous thrombosis (blood clot).

• If you have any disorder that affects blood clotting(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 pectoris.

• If you have or have had a liver disease, and your liver function tests have not returned to normal.
• If you have a rare blood disorder called "porphyria" that is inherited from parents to children (hereditary).

• If you are allergic to estradiol valerate, cyproterone acetate, or any of the other components of this medication (listed in section 6).

If any of these diseases occur for the first time while you are taking Climen, stop treatment and consult your doctor immediately.

Warnings and precautions

Consult your doctor or pharmacist before starting to take Climen.

Visit your doctor regularly and at least once a year. Discuss with your doctor at each visit the need to adjust or continue treatment. Your doctor will check if you have a high risk of suffering from thrombosis due to a combination of risk factors or a very high risk factor. In the case of a combination of risk factors, the risk may be higher than a simple addition of 2 individual risks. If the risk is too high, your doctor will not prescribe HRT.

For the treatment of climacteric symptoms, HRT should only be initiated when symptoms affect the quality of life of the woman. In all cases, a careful assessment of the risks and benefits should be made at least annually, and HRT should only be continued while the benefits outweigh the risks. The administration of the lowest dose and the shortest treatment duration should always be considered.

A increased risk of a benign brain tumor (meningioma) has been reported with high doses (25 mg and higher) of cyproterone acetate. If you are diagnosed with a meningioma, your doctor will stop treatment with all medications containing cyproterone acetate, including Climen, as a precautionary measure (see section "Do not take Climen").

Be careful with Climen:

Before starting treatment, inform your doctor if you have ever had any of the following problems, as they may return or worsen during treatment with Climen. If so, you should visit your doctor more frequently for check-ups:

• Gynecological disorders of any kind, such as irregular, frequent, or persistent uterine bleeding, fibroids (a type of uterine tumor), endometriosis (appearance of endometrial tissue outside its usual location), or a history of endometrial hyperplasia (excessive thickening of the uterine lining).
• Increased risk of developing blood clots (see "Blood clots in a vein (thrombosis)")
• Increased risk of developing a hormone-dependent cancer (e.g., having a mother, sister, or grandmother who has had breast cancer)
• Changes or alterations in the breasts.

• High levels of certain fats (triglycerides) in the blood or a family history of this disorder due to the risk of developing pancreatitis (inflammation of the pancreas).

• High blood pressure.

• Liver disorders, such as a benign liver tumor.

• Diabetes.

• Gallstones.

• Migraines or severe headaches.

• A disease of the immune system that affects many organs of the body (systemic lupus erythematosus, SLE).

• Epilepsy.

• Multiple sclerosis (a disease of the nervous system).

• Asthma.

• A disease that affects the eardrum and ear (otosclerosis).

• Fluid retention due to heart or kidney problems
• Chorea minor (a disease of the nervous system).
• Hereditary and acquired angioedema.

Stop taking Climen and go to the doctor immediately

If you notice any of the following disorders when taking HRT:

• any of the disorders mentioned in the section "Do not take Climen",
• yellowing of the skin or whites of the eyes (jaundice). This may be a sign of liver disease,
• swelling of the face, tongue, or throat, and difficulty swallowing or urticaria accompanied by difficulty breathing, which suggest angioedema,
• a significant increase in blood pressure (symptoms may be headache, fatigue, dizziness),
• migraine-like headaches when they appear for the first time,
• • painful swelling and redness of the legs
  • sudden chest pain
  • difficulty breathing

For symptoms of a blood clot, see "Stop taking Climen and go to the doctor immediately"

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

Be careful not to exceed the recommended doses.

During treatment with HRT, some serious diseases may occur more frequently, such as blood clots (thrombosis) and certain types of tumors.

HRT and cancer

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

HRT with estrogen alone increases the risk of excessive thickening of the uterine lining (endometrial hyperplasia) and cancer of the uterine lining (endometrial cancer).

The progestogen in Climen protects you from this increased risk.

In women with an intact uterus who do not use HRT, an average of 5 out of 1,000 women, aged 50-65, will be diagnosed with endometrial cancer. In women with an intact uterus who use HRT with estrogen alone, an average of 10-60 out of 1,000 women, aged 50-65, will be diagnosed with endometrial cancer (i.e., 5-55 additional cases), depending on the dose and duration of treatment.

Unexpected bleeding

You will have menstrual bleeding once a month (also called withdrawal bleeding) while taking Climen. However, if you have irregular bleeding or spotting in addition to your menstrual period, which:

• continues for longer than the first 6 months;
• starts after you have been taking Climen for more than 6 months;
• continues after you have finished treatment with Climen;

consult your doctor as soon as possible.

Breast cancer

Existing data show that the use of hormone replacement therapy (HRT) with combined estrogen-progestogen or estrogen-only increases the risk of breast cancer. The additional risk depends on the duration of HRT use. The additional risk becomes apparent after 3 years of use. After stopping HRT, the additional risk will decrease over time, but the risk may persist for 10 years or more if HRT has been used for more than 5 years.

Your doctor will guide you on how to detect anomalies in your breast and will perform periodic check-ups throughout treatment.

Comparison

In women aged 50-54 who are not using HRT, an average of 13-17 out of 1,000 will be diagnosed with breast cancer over a 5-year period.

In women aged 50 who start hormone replacement therapy with estrogen-only for 5 years, there will be 16-17 cases per 1,000 users (i.e., 0-3 additional cases).

In women aged 50 who start taking HRT with estrogen-progestogen for 5 years, there will be 21 cases per 1,000 users (i.e., 4-8 cases).

In women aged 50-59 who are not taking HRT, an average of 27 cases of breast cancer will be diagnosed per 1,000 women over a 10-year period.

In women aged 50 who start hormone replacement therapy with estrogen-only for more than 10 years, there will be 34 cases per 1,000 users (i.e., 7 additional cases).

In women aged 50 who start taking HRT with estrogen-progestogen for 10 years, there will be 48 cases per 1,000 users (i.e., 21 additional cases).

Check your breasts regularly. Consult your doctor if you detect any changes such as:

• dimpling of the skin
• changes in the nipple
• any lump that you can see or feel

In addition, it is recommended that you participate in breast cancer screening programs when offered. For breast cancer screening, it is important to inform the nurse/healthcare professional performing the X-ray that you are taking HRT, as these medications can increase breast density, which can affect the result of the mammogram. When breast density increases, the mammogram may not detect all lumps.

Ovarian cancer

Ovarian cancer occurs less frequently than breast cancer. The use of HRT with estrogen-only or combined estrogen-progestogen has been associated with a slightly increased risk of ovarian cancer.

The risk of ovarian cancer varies with age. For example, in women aged 50-54 who are not taking HRT, there are approximately 2 cases of ovarian cancer per 2,000 women over a 5-year period. In women treated with HRT for 5 years, there are approximately 3 cases per 2,000 patients (i.e., approximately 1 additional case).

Effects of HRT on the heart and circulation

Blood clots in a vein (thrombosis)

The risk of blood clots in the veinsis approximately 1.3 to 3 times higher in HRT users compared to non-users, especially during the first year of use. The risk of thrombosis also increases with age.

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

You are more likely to have a blood clot in the veins with age and if any of the following apply to you. Inform your doctor if any of these situations apply to you:

• You are unable to walk for a long time due to major surgery, 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 a medication used to prevent blood clots
• Any of your close relatives have had a blood clot in the leg, lung, or any other organ
• You have systemic lupus erythematosus (SLE)
• You have cancer.

For symptoms of a blood clot, see "Stop taking Climen and go to the doctor immediately"

Comparison

In women in their fifties who are not taking HRT, an average of 4-7 out of 1,000 will have a blood clot in a vein over a 5-year period.

In women in their fifties who have been taking HRT with estrogen-progestogen for more than 5 years, there will be 9-12 cases per 1,000 users (i.e., 5 additional cases).

Arterial thromboembolism

In large clinical trials with combined estrogen-conjugated and medroxyprogesterone acetate (MPA), a possible increase in the risk of cardiovascular disease was observed in the first year of use and an increase in the risk of stroke. It is unknown whether these findings can be extended to other HRT compounds that contain different estrogens and progestogens, such as Climen.

Coronary heart disease (heart attack)

It has not been demonstrated that HRT prevents heart attacks. You should not use HRT to prevent cardiovascular diseases.

Women over 60 years old who use HRT with estrogen-progestogen are slightly more likely to develop heart disease than those who do not take HRT.

Stroke

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

Comparison

In women in their fifties who are not taking HRT, an average of 8 out of 1,000 will have a stroke over a 5-year period. For women in their fifties who are taking HRT, there will be 11 cases per 1,000 users over a 5-year period (i.e., 3 additional cases).

Dementia

There is limited evidence from clinical studies that hormone replacement therapy may increase the risk of significant loss of intellectual abilities, such as memory loss (dementia), if treatment is started at 65 years or older. The risk may decrease if treatment is started in early menopause, as observed in other studies. It is unknown whether these findings can be extended to other HRT products.

Other diseases

If you are diabetic, you should be carefully monitored while taking HRT, as it may have an effect on carbohydrate metabolism (peripheral insulin resistance and glucose tolerance).

If it is suspected that you have a prolactinoma (a non-cancerous tumor that causes an increase in prolactin secretion), it must be ruled out before starting treatment. If you have a prolactinoma, close medical supervision is necessary (including periodic measurement of prolactin levels).

If you develop chloasma (skin discoloration in patches with irregular contours of dark yellow color, mainly on the face) during treatment with hormone replacement therapy (HRT), especially if you have a history of chloasma during pregnancy, you should avoid sun exposure or ultraviolet rays while taking HRT.

Inform your doctor if you have a kidney or heart function disorder. Estrogens can cause fluid retention, and therefore, patients with kidney function disorders should be carefully monitored.

You should evaluate with your doctor the possible alternative treatments available for your specific situation and how long treatment should be continued. This should be reviewed periodically throughout treatment.

If you have a uterine fibroid (a type of uterine tumor), it may increase in size due to the influence of estrogens. In that case, treatment should be discontinued.

If you suffer from reactivation of endometriosis, it is recommended that you discontinue treatment.

Climen is not a contraceptive and should not be used as such; it also does not restore fertility.

To avoid pregnancy, non-hormonal contraceptive measures should be used when necessary (with the exception of rhythm and temperature methods). If there are indications of pregnancy, you should stop taking the pills until pregnancy has been ruled out (see section "Pregnancy, breastfeeding, and fertility").

HRT does not prevent memory loss. There is some evidence of a higher risk of memory loss in women who start using HRT after the age of 65. Ask your doctor for advice.

In women with hereditary angioedema (swelling or allergic edema that usually appears on the face), exogenous estrogens such as those in Climen may induce or worsen symptoms.

Additional information in special populations

Children and adolescents

Climen is not indicated for use in children and adolescents.

Elderly population

There are no data available on the use of Climen in this population.

3. How to take Climen

Follow exactly the administration instructions for this medication indicated by your doctor or pharmacist. In case of doubt, consult your doctor or pharmacist again.

Remember to take your medication.

• Adult women, including the elderly

If you still have menstrual cycles, treatment should begin on the fifth day of the cycle (first day of menstrual bleeding = first day of the cycle).

If you have amenorrhea (absence of menstruation) or very infrequent periods or are postmenopausal, you can start treatment at any time, once pregnancy has been previously ruled out.

Dosage

Take one white tablet once a day for the first 11 days, followed by one pink tablet once a day for 10 days. After these 21 days of treatment, there will be a 7-day interval without taking tablets.

Administration

Each package allows for 21 days of treatment. After the 7-day interval without medication, you should start a new package of Climen on the same day of the week you started with the previous one. The tablets should be taken without chewing, with some liquid.

To help you follow the order of taking the medication, 7 self-adhesive strips with the 7 days of the week are provided.

Choose the strip that starts with the day you take the first tablet. For example, if you take your first tablet on a Wednesday, use the strip that starts with "WED".

Stick the strip on the top of the Climen blister pack, where it says "Place strip here", so that the first day is above the tablet marked with the word "Start". Now you will have a day marked above each tablet and you can visually check if you have taken the tablet on a given day.

Take one tablet every day, following the direction of the arrows, until you finish the 21 tablets in the blister pack. This way, you will take one white tablet daily for the first 11 days and then one pink tablet daily for the next 10 days.

The time of day you take the tablet is irrelevant, but once you have chosen a specific time, you should maintain it every day.

During the 7-day interval without taking tablets, bleeding usually occurs a few days after stopping the last tablet.

For both the start and continuation of treatment for climacteric symptoms, the minimum effective dose should be used for the shortest possible treatment time.

If you think the effect of Climen is too strong or too weak, tell your doctor or pharmacist.

Your doctor will indicate the duration of your treatment with Climen. Do not stop treatment before, as it may not have the desired effect.

If you take more Climen than you should

In case of overdose or accidental ingestion, consult your doctor or pharmacist or call the Toxicology Information Service. Phone 915 620 420, indicating the medication and the amount used.

Overdose may cause nausea, vomiting, and irregular bleeding. No specific treatment is necessary, but you should consult your doctor if you are concerned.

If you forget to take Climen

Do not take a double dose to make up for forgotten doses.

If you have forgotten to take a tablet and less than 24 hours have passed, take the tablet as soon as possible and take the next tablet at your usual time. If more than 24 hours have passed, leave the forgotten tablet in the blister pack. Continue taking the remaining tablets at your usual schedule every day. If treatment is suspended for a longer period, irregular bleeding may occur.

If you need surgery

If you are going to undergo surgery, inform the surgeon that you are taking Climen. You may need to interrupt treatment with Climen for 4 to 6 weeks before surgery to reduce the risk of blood clots (see also section 2 "Blood clots in a vein"). Ask your doctor when you can resume treatment with Climen.

If you have any other questions about the use of this medication, ask your doctor or pharmacist.

4. Possible side effects

Like all medications, this medication can cause side effects, although not everyone will experience them.

The following diseases occur more frequently in women using HRT compared to women not taking HRT:

• breast cancer
• abnormal growth or cancer of the lining of the uterus (endometrial hyperplasia or cancer)
• ovarian cancer
• blood clots in the veins of the legs or lungs (venous thromboembolism)
• coronary heart disease
• stroke
• possible memory loss if HRT is started after the age of 65.

For more information on these side effects, see section 2

In addition to the side effects listed in the section "Be careful with Climen", the following possible side effects are listed, according to the part of the body they affect and their frequency of occurrence, which have been reported in users of different oral HRT preparations:

• Frequent side effects(may affect up to 1 in 10 users):

• Weight gain, weight loss.
• Headache (headache).
• Abdominal pain, nausea.
• Skin rash, itching (pruritus).
• Vaginal bleeding, including spotting.

• Uncommon side effects(may affect up to 1 in 100 users):

• Hypersensitivity reaction (allergic).
• Depressive mood.
• Dizziness.
• Visual disturbances.
• Palpitations.
• Dyspepsia (difficult digestion).
• Erythema nodosum (a type of skin inflammation with the appearance of nodules on the legs).
• Urticaria (hives).
• Breast pain, breast tension.
• Edema (fluid retention).

• Rare side effects(may affect up to 1 in 1,000 users):

• Anxiety, increased libido (sexual desire), decreased libido.
• Migraine.
• Intolerance to contact lenses.
• Swelling, vomiting.
• Hirsutism (excessive hair growth), acne.
• Muscle cramps.
• Dysmenorrhea (painful menstruation), vaginal discharge, premenstrual syndrome, breast enlargement.
• Fatigue.

In women with hereditary angioedema (allergic-type swelling or edema that usually appears on the face), exogenous estrogens such as those contained in Climen may induce or worsen symptoms (see "Be careful with Climen").

The following side effects have been reported in relation to other medications used in HRT:

• Estrogen-dependent tumors, benign or malignant, e.g., endometrial cancer.
• Venous thromboembolism, e.g., deep vein thrombosis in legs or pelvis and pulmonary embolism, worsening of varicose veins, hypertension (see sections "Do not take Climen" and "Be careful with Climen").
• Myocardial infarction.
• Stroke.
• Subcutaneous and skin disorders:
• skin discoloration, especially on the face or neck, known as "pregnancy spots" (chloasma) (skin spots),
• skin rash with redness in a target shape or blisters (erythema multiforme) (a type of skin inflammation),
• painful red nodules on the skin (erythema nodosum),
• vascular purpura (red spots on the skin),
• contact dermatitis, changes in pigmentation,
• generalized itching and
• exanthema (skin rash).
• Gallbladder disorder.
• Possible dementia in women over 65 years old (see section "Be careful with Climen").

Reporting side effects

If you experience any type of side effect, consult your doctor or pharmacist, even if it is a possible side effect that does not appear in this leaflet. You can also report them directly through the Spanish Pharmacovigilance System for Human Use Medicines: www.notificaRAM.es. By reporting side effects, you can contribute to providing more information on the safety of this medication.

5. Conservation of Climen

Keep this medication out of sight and reach of children.

No special storage conditions are required.

Do not use this medication after the expiration date that appears on the package after CAD. The expiration date is the last day of the month indicated.

Medications should not be thrown down the drain or into the trash. Deposit the packages and medications you no longer need in the SIGRE collection point at the pharmacy. If in doubt, ask your pharmacist how to dispose of the packages and medications you no longer need. This way, you will help protect the environment.

6. Package contents and additional information

Climen composition

• The active ingredients are estradiol valerate and cyproterone acetate.

Each white coated tablet contains 2.0 mg of estradiol valerate.

Each pink coated tablet contains 2.0 mg of estradiol valerate and 1.0 mg of cyproterone acetate.

• The other components (excipients) are lactose monohydrate, cornstarch, povidone 25, talc, magnesium stearate, sucrose, povidone 90, macrogol 6,000, calcium carbonate, montan glycol, glycerol 85% (E-422), titanium dioxide (E-171), yellow iron oxide (E-172), red iron oxide (E-172).

Product appearance and package contents

Climen is presented as coated tablets in a blister pack. Each blister pack contains 21 tablets (11 white tablets and 10 pink tablets).

Marketing authorization holder and manufacturer

Bayer Hispania, S.L.

Av. Baix Llobregat, 3-5

08970 Sant Joan Despí (Barcelona)

Spain

Manufacturer

Delpharm Lille SAS

Parc d'Activités Roubaix-Est

22 Rue de Toufflers - CS 50070

59452 Lys-Lez-Lannoy

France

or

Bayer AG

Müllerstraße 178

13353 Berlin

Germany

or

Bayer Weimar GmbH und Co. KG

Döbereinerstraße 20

99427 Weimar

Germany

Date of last revision of this leaflet:January 2024

Detailed information about this medication is available on the website of the Spanish Agency for Medicines and Health Products (AEMPS) http://www.aemps.gob.es/.