Climen

Package leaflet: Information for the user

Climen

2 mg film-coated tablets and 2 mg + 1 mg film-coated tablets
valerian estradiol (white tablets) and
valerian estradiol + cyproterone acetate (pink tablets)
Please read this leaflet carefully before using this medicine because it contains important
information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not give it to others, even if their symptoms are the same as yours, as it could be harmful.
• If you experience any side effect, including those not listed in this leaflet, contact your doctor or pharmacist. See section 4.

Contents of this leaflet

1. What Climen is and what it is used for
2. What you need to know before taking Climen
3. How to take Climen
4. Possible side effects
5. How to store Climen
6. Package contents and other information

1. What Climen is and what it is used for

Climen is a cyclic combined oestrogen-progestogen containing estradiol valerate and cyproterone acetate,
used for:
➢ hormone replacement therapy (HRT) of estrogen deficiency symptoms in postmenopausal women;
➢ prevention of osteoporosis in postmenopausal women at high risk of future fractures who have specific intolerances or contraindications to other approved medicinal products for osteoporosis prevention.
Experience with treatment in women over 65 years of age is limited.

2. What you should know before taking Climen

Medical examination and regular check-ups
Hormone replacement therapy (HRT) involves risks that must be considered when deciding whether to start or continue treatment.
Experience with treating women who have experienced early menopause (due to cessation of ovulation or surgical intervention) is limited. If you have early menopause, the risks associated with HRT may differ. Consult your doctor.
Before starting (or restarting) HRT, your doctor will ask you questions about your medical history and that of your family members. The doctor may decide to perform certain tests. These 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 visits, discuss with your doctor the benefits and risks related to continuing treatment with Climen.

Have regular breast examinations as recommended by your doctor.
Do not take Climen
if any of the conditions listed below apply to you. If you are unsure about any of the conditions described below, consult your doctor before taking Climen.
Do not take Climen:

• if you are allergic to estradiol valerate, cyproterone acetate, or any of the other ingredients of this medicine (listed in section 6);
• if you are pregnant or breastfeeding;
• if you have, have had, or suspect you have a malignant breast tumour;
• if you have had, have, or suspect you have a malignant tumour whose growth is sensitive to oestrogens, for example a tumour of the uterine lining (endometrium);
• if you currently have or have previously been treated for blood clots in a vein (thrombosis), such as those in the legs (deep vein thrombosis) or in the lungs (pulmonary embolism);
• if you have blood clotting disorders (such as deficiencies in protein C, protein S, or antithrombin);
• if you have or have recently had a disease caused by blood clots in the arteries, such as heart attack, stroke, or angina (chest pain);
• if you have or have previously had liver disease and your liver function values have not returned to normal;
• if you have vaginal bleeding of unknown cause;
• if you have untreated thickening of the uterine lining (endometrial hyperplasia);
• if you have a rare inherited blood disorder called "porphyria";
• if you have meningioma or have previously been diagnosed with meningioma (a generally benign tumour of the tissue layer between the brain and skull).

If any of these conditions occur for the first time while taking Climen, stop treatment immediately and consult your doctor.
Warnings and precautions
Talk to your doctor or pharmacist before taking Climen.
When to be particularly careful with Climen
Inform your doctor if you have previously had any of the following conditions before starting treatment, as they may recur or worsen during treatment with Climen. If so, you may need to see your doctor more frequently for check-ups:
➢ uterine fibroids;
➢ endometriosis (growth of uterine lining tissue in other locations) or history of excessive growth of the uterine lining (endometrial hyperplasia);
➢ increased risk of developing blood clots (see below “Effects of HRT on the heart and circulation – Blood clots in a vein (thrombosis)”)
➢ increased risk of oestrogen-sensitive tumours (e.g., if you have a mother, sister, or grandmother who had breast cancer);
➢ high blood pressure;
➢ liver disease such as benign liver tumour;
➢ diabetes;
➢ gallstones;
➢ migraine or severe headaches;

➢ a systemic autoimmune disease affecting multiple organs (Systemic Lupus Erythematosus or SLE);
➢ epilepsy;
➢ asthma;
➢ a condition affecting the eardrum and hearing (otosclerosis);
➢ very high levels of fats in the blood (triglycerides);
➢ fluid retention due to heart or kidney problems;
➢ benign breast conditions;
➢ chorea minor (rapid, uncoordinated, involuntary movements);
➢ if you have a benign tumour of the pituitary gland (adenoma), you must be closely monitored by your doctor, who will prescribe periodic measurements of prolactin levels;
➢ hereditary or acquired angioedema.
Stop treatment with Climen and contact your doctor immediately if:

• any condition listed in the section “Do not take Climen” occurs;
• you develop yellowing of the skin or whites of the eyes (jaundice). These may be signs of liver disease;
• you experience a marked increase in blood pressure (symptoms may include headache, fatigue, dizziness);
• you develop a new type of migraine headache;
• you become pregnant;
• you notice signs of a blood clot, such as:
  • painful swelling and redness in the legs
  • sudden chest pain
  • difficulty breathing
• swelling of the face, tongue, and/or throat and/or difficulty swallowing or hives with breathing difficulties, which are indicative of angioedema.

For further information, see the section below “Effects of HRT on the heart and circulation – Blood clots in veins (thrombosis)”.
Note: Climen is not a contraceptive. If less than 12 months have passed since your last menstrual period or if you are under 50 years of age, you may still need to use additional contraceptive measures to prevent pregnancy. Consult your doctor.
HRT and cancer
Excessive thickening of the uterine lining (endometrial hyperplasia) and cancer of the uterine lining (endometrial carcinoma)
Taking oestrogen-only HRT increases the risk of excessive thickening of the uterine lining (endometrial hyperplasia) and cancer of the uterine lining (endometrial carcinoma).
The presence of a progestogen in Climen protects against this additional risk.
Among women who still have a uterus and who do not take HRT, on average, 5 out of 1,000 will be diagnosed with endometrial carcinoma between the ages of 50 and 65. For women aged 50 to 65 who still have a uterus and who take oestrogen-only HRT, between 10 and 60 out of 1,000 will be diagnosed with endometrial carcinoma (i.e., 5 to 55 additional cases), depending on the dose and duration of treatment.

Irregular bleeding
You will experience monthly bleeding (called withdrawal bleeding) while taking Climen.
However, if you experience unexpected bleeding or spotting (bleeding between periods) in addition to monthly bleeding, and:

• it continues beyond the first 6 months
• it occurs after you have taken Climen for more than 6 months
• it continues after stopping Climen, contact your doctor as soon as possible.

Breast cancer
If you have or have had breast cancer, you must not take this medicine (see “Do not take Climen”). Evidence shows that taking combined oestrogen-progestogen hormone replacement therapy (HRT) or oestrogen-only HRT increases the risk of breast cancer. The additional risk depends on the duration of HRT use. This additional risk becomes apparent within 3 years of use. After stopping HRT, the additional risk decreases over time, but may persist for 10 years or more if HRT has been used for more than 5 years.
If you have a close relative (mother, sister, or grandmother) who has had breast cancer, your doctor may recommend more frequent check-ups.
Comparison
Among women aged 50 to 54 years who do not take HRT, breast cancer will be diagnosed in approximately 13–17 out of 1,000 women over a 5-year period. Among women aged 50 who start oestrogen-only HRT for 5 years, there will be 16–17 cases per 1,000 users (i.e., 0–3 additional cases). Among women aged 50 who start combined oestrogen-progestogen HRT for 5 years, there will be 21 cases per 1,000 treated women (i.e., 4–8 additional cases).
Among women aged 50 to 59 years who do not take HRT, breast cancer will be diagnosed in an average of 27 out of 1,000 women over a 10-year period.
Among women aged 50 who start oestrogen-only HRT for 10 years, there will be 34 cases per 1,000 users (i.e., 7 additional cases).
Among women aged 50 who start combined oestrogen-progestogen HRT for 10 years, there will be 48 cases per 1,000 users (i.e., 21 additional cases).
Regularly examine your breasts. Contact your doctor if you notice any changes such as:

• small depressions in the skin;
• changes in the nipple;
• any visible or palpable hardening.

Additionally, it is recommended to participate in mammographic screening programmes when offered. For mammographic screening, it is important that you inform the nurse/healthcare professional performing the X-ray that you are using HRT, as this treatment can increase breast density, which may affect the mammogram result. Where breast density is increased, mammography may not detect all lumps.
Ovarian cancer
Ovarian cancer is rare – much rarer than breast cancer.
The use of oestrogen-only HRT or combined oestrogen-progestogen HRT has been associated with a slight increase in the risk of ovarian cancer. The risk of ovarian cancer varies with age. For example, among women aged 50 to 54 years who do not take HRT, about 2 out of 2,000 will receive a diagnosis of

ovarian cancer over a 5-year period. For women taking HRT for 5 years, there will be about 3 cases per 2,000 treated women (i.e., about 1 additional case).
Liver tumours
After using hormonal substances such as those contained in Climen, benign liver tumours have been observed in rare cases, and even more rarely, malignant liver tumours. In isolated cases, these tumours have caused intra-abdominal bleeding, which can be life-threatening. Although these events are extremely unlikely, you must inform your doctor if you experience any unusual abdominal pain that does not disappear quickly.
Effects of HRT on the heart and circulation
Blood clots in a vein (thrombosis)
HRT can increase the risk of blood clots in veins by 1.3 to 3 times in users compared to non-users, especially during the first year of use.
Blood clots can be dangerous, and if they reach the lungs, they can cause chest pain, sudden shortness of breath, collapse, or even death.
The risk of developing a blood clot in a vein increases with age and if any of the following conditions apply to you. Inform your doctor if any of the following apply:
o you are unable to walk for a prolonged period due to major surgery, accident, or illness (see also section 3, “If you need to undergo surgery”)
o you are severely overweight (BMI > 30 kg/m²)
o you have any blood clotting disorder requiring long-term treatment with a medicine that prevents blood clots
o a close relative has had a blood clot in the leg, lung, or another organ
o you have Systemic Lupus Erythematosus (SLE)
o you have cancer.
For possible signs of a blood clot, see “Stop using Climen and contact your doctor immediately”
Comparison
For women around 50 years of age who are not taking HRT, on average, 4–7 out of 1,000 are expected to develop a blood clot in a vein over a 5-year period.
For women around 50 years of age who are taking combined oestrogen-progestogen HRT for more than 5 years, there will be 9–12 cases per 1,000 users (i.e., an increase of 5 cases).
Heart disease (heart attack)
There is no evidence that HRT can prevent heart attacks.
Women over 60 years of age who use combined oestrogen-progestogen HRT have a slightly higher probability of developing heart disease compared to women who do not take HRT.
Stroke
The risk of stroke is approximately 1.5 times higher in HRT users compared to non-users. The number of additional stroke cases due to HRT use increases with age.
Comparison

For women around 50 years of age who are not taking HRT, on average, 8 out of 1,000 may have a stroke over a 5-year period. For women around 50 years of age who are taking combined oestrogen-progestogen HRT for more than 5 years, there will be 11 cases per 1,000 users (i.e., an increase of 3 cases).
Meningioma
An increased risk of a benign brain tumour (meningioma) has been reported with high doses (equal to or greater than 25 mg) of cyproterone acetate. If you have been diagnosed with meningioma, your doctor will discontinue treatment with all medicines containing cyproterone, including Climen, as a precautionary measure (see section “Do not take Climen”).
Other conditions

• HRT does not prevent memory loss. The risk of memory loss may be higher in women who start HRT after age 65. Consult your doctor.
• If you are prone to developing patchy brown spots (chloasma) on your face, you should minimize exposure to sunlight or ultraviolet rays during treatment with Climen.
• Your doctor will monitor you closely if you have heart or kidney problems, as oestrogen intake may cause fluid retention.
• During oestrogen therapy, some women are particularly prone to developing gallstones.
• You may experience abnormal uterine bleeding.
• Oestrogens may increase levels of certain plasma proteins (TBG, corticosteroid-binding globulin, SHBG, angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).

Other medicines and Climen
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines, including over-the-counter medicines, herbal remedies, or other natural products.
Your doctor will give you the necessary instructions.
Some medicines may interfere with the effects of Climen. This may cause irregular bleeding. These include:

• medicines for epilepsy (e.g., barbiturates, phenytoin, primidone, carbamazepine, and possibly oxcarbazepine, topiramate, and felbamate);
• medicines for tuberculosis (e.g., rifampicin, rifabutin);
• medicines for HIV and hepatitis C virus infections known as protease inhibitors and non-nucleoside reverse transcriptase inhibitors (e.g., nevirapine, efavirenz, ritonavir, and nelfinavir);
• herbal preparations containing St. John's wort (Hypericum perforatum);
• medicines for the treatment of fungal infections (e.g., griseofulvina, fluconazole, itraconazole, ketoconazole, and voriconazole);
• medicines for the treatment of bacterial infections (e.g., clarithromycin, erythromycin, penicillins, and tetracyclines);
• medicines for the treatment of certain heart conditions, high blood pressure (e.g., verapamil and diltiazem);
• grapefruit juice.

HRT may interfere with the effects of other medicines:

• an antiepileptic medicine (lamotrigine), as it may increase the frequency of seizures;
• medicines against hepatitis C virus (HCV) (such as combination regimens with ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin; glecaprevir/pibrentasvir or

sofosbuvir/velpatasvir/voxilaprevir) may cause increases in blood test results related to liver function (elevated liver enzyme ALT) in women using COCs containing ethinylestradiol. Climen contains estradiol instead of ethinylestradiol. It is not known whether elevated liver ALT enzyme levels may occur when using Climen with this HCV combination regimen.
Paracetamol may increase the amount of estradiol absorbed into the blood.
If you have diabetes, your doctor may adjust your treatment regimen.
Laboratory tests
If you need blood tests, tell your doctor or laboratory staff that you are taking Climen, as this medicine may affect the results of certain tests.
Pregnancy and breastfeeding
Climen is intended for use only in postmenopausal women. If you are or suspect you are pregnant, do not take this medicine (see “Do not take Climen”). If you become pregnant, stop taking Climen and contact your doctor.
Climen is contraindicated during breastfeeding.
Driving and using machines
No effects on the ability to drive or use machines have been observed in users of Climen.
Climen contains lactose and sucrose
If your doctor has diagnosed you with an intolerance to certain sugars, contact him before taking this medicine.

3. How to take Climen

Take this medicine exactly as directed by your doctor. If you have any doubts, consult your doctor or pharmacist.
Women with amenorrhoea (of proven non-pregnant origin) and postmenopausal women may start treatment at any time.
Take one white tablet daily for the first 11 days, followed by one pink tablet daily for the next 10 days.
Treatment should begin with the first tablet from the white tablet section, the compartment of which is marked with the word "START". The subsequent daily tablets must be taken from the following compartments in the direction of the arrows printed on the pack.
In this way, all the white tablets will be taken first, followed by all the pink tablets.
To help you follow the treatment schedule correctly, the pack includes a sticker showing the days of the week. This label should be applied to the designated space on the pack, ensuring that the day of the week on which treatment is started aligns with the compartment marked "START". This will make it easier to keep track of the correct daily tablet intake.

Swallow the tablets whole, without chewing, with a drink of water, preferably at the same time each day (e.g. after breakfast or after dinner).
At the end of the pack (after 21 days of treatment), a 7-day break should be observed. During this time, women who still have their uterus will usually experience a withdrawal bleed similar to menstruation. If no bleeding occurs during the 7-day break, the next pack of Climen should not be started until pregnancy has been ruled out (see “Pregnancy and breastfeeding”). The new pack should be started after the 7-day break on the same day of the week as the previous pack.
Your doctor will prescribe the lowest effective dose needed to treat your symptoms for the shortest necessary duration.
Consult your doctor if you think the dose is too high or not strong enough.

Additional information for specific patient groups
Use in children and adolescents
Climen is not indicated for use in children and adolescents.

Use in the elderly
There are no data indicating the need for dose adjustment in elderly patients (see “Warnings and precautions”).

Use in patients with impaired liver function
No formal studies have been conducted in patients with impaired liver function. Climen is contraindicated in women with severe liver disease (see “Do not take Climen”).

Use in patients with impaired renal function
No formal studies have been conducted in patients with impaired renal function.

If you need surgery
If you are about to undergo surgery, inform your surgeon that you are taking Climen. You may need to stop taking Climen approximately 4–6 weeks before surgery to reduce the risk of blood clots (see “Blood clots in a vein”). Ask your doctor when you can resume taking Climen.

If you take more Climen than you should
Overdose may cause nausea, vomiting, and irregular bleeding. Specific treatment is not required, but consult your doctor if you are concerned.

If you forget to take Climen
If you forget to take a tablet, take it as soon as you remember. Take the next tablet at your usual time.
If more than 24 hours have passed, discard the missed tablet.
Do not take a double dose to make up for the forgotten tablet.
Missing one or more Climen tablets may increase the likelihood of breakthrough bleeding and spotting (uterine bleeding).

If you have any questions about the use of this medicine, consult your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody experiences them.
The following diseases are reported more frequently in women using HRT than in non-users:

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

For more information about these side effects, see section 2.
The following side effects have been observed with the use of Climen. These generally disappear after the first few months of treatment and can be categorized as follows:
Common side effects (may affect up to 1 in 10 users):

• weight gain/weight loss;
• headache;
• abdominal pain, nausea;
• skin rash, itching;
• uterine/vaginal bleeding, including spotting (light intermenstrual bleeding).

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

• hypersensitivity reaction;
• depressed mood;
• dizziness;
• visual disturbances;
• palpitations;
• dyspepsia (indigestion);
• erythema nodosum (a condition characterized by red, painful nodules under the skin, usually on the legs and feet, less commonly on the forearms), urticaria (skin rash similar to a nettle sting, accompanied by burning and itching);
• breast pain, breast tenderness;
• oedema.

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

• anxiety, increased/decreased libido;
• migraine;
• intolerance to contact lenses;
• flatulence (intestinal gas), vomiting;
• hirsutism (excessive hair growth), acne;
• muscle cramps;
• dysmenorrhoea (painful menstruation), vaginal discharge, symptoms mimicking premenstrual syndrome, breast enlargement;
• fatigue.

In women with hereditary angioedema, exogenous estrogens may induce or worsen symptoms of angioedema (see "Warnings and precautions").

The following side effects have been reported with other HRTs:

• gallbladder disease
• a range of skin disorders:
  • changes in skin pigmentation, especially on the face or neck, known as "melasma" (chloasma)
  • red, painful skin nodules (erythema nodosum)
  • skin rash with redness or target-shaped lesions (erythema multiforme)
  • vascular purpura (pinpoint bleeding under the skin and mucous membranes)

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, please inform your doctor or pharmacist. You may also report side effects directly via the national reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse .
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Climen

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the packaging after "Exp.". The expiry date refers to the last day of that month.
Do not dispose of medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What Climen contains

• The active substance is estradiol valerate. Each white coated tablet contains 2.0 mg of estradiol valerate;
• The other components are: lactose monohydrate, maize starch, povidone 25,000, talc, magnesium stearate, sucrose, povidone 90, macrogol 6,000, calcium carbonate, montanic acid glycol ester.
• The active substances are estradiol valerate and cyproterone acetate. Each pink coated tablet contains 2.0 mg of estradiol valerate and 1.0 mg of cyproterone acetate.
• The other components are: lactose monohydrate, maize starch, povidone 25,000, talc, magnesium stearate, sucrose, povidone 90, macrogol 6,000, calcium carbonate, montanic acid glycol ester, glycerol 85%, titanium dioxide, yellow iron oxide, red iron oxide.

Description of the appearance of Climen and contents of the pack
Climen is presented as coated tablets.
The calendar pack contains 21 coated tablets (11 white tablets and 10 pink tablets).
To keep track of administration, the Climen calendar pack includes 7 adhesive strips for the days of the week, each marked with one of the 7 days of the week.
Select the strip corresponding to the day you start taking the medicine.
For example, if you start on Wednesday, select the strip starting with "WED".
Attach the adhesive strip for the chosen day to the top of the Climen blister pack where it is indicated "Apply label here", so that the first day is above the box marked "Start".

This way you can check whether you have taken the tablet each day. Always start with the box marked "Start" and continue in the direction of the arrow until all 21 tablets have been taken.
Marketing Authorization Holder
Bayer S.p.A., Viale Certosa 130, 20156 Milan, Italy
Manufacturer
Bayer AG, Müllerstraße 178, 13353 Berlin, Germany
Bayer Weimar GmbH und Co. KG, Dobereinerstraße 20, 99427 Weimar, Germany