Cliovelle 1 mg/0.5 mg tablets

Package leaflet: Information for the user

Cliovelle 1 mg/0.5 mg tablets
Estradiol valerate + Norethisterone acetate
Please read this leaflet carefully before taking this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any further questions, please ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm someone else even if their symptoms are the same as yours.
• If you experience any side effects, including any not listed in this leaflet, tell your doctor or pharmacist. See section 4.

Contents of the leaflet

1. What Cliovelle is and what it is used for
2. Before you take Cliovelle
3. How to take Cliovelle
4. Possible side effects
5. How to store Cliovelle
6. Contents of the pack and other information

1. What Cliovelle is and what it is used for

Cliovelle is a Hormone Replacement Therapy (HRT).
It contains two types of female hormones: an oestrogen (estrogen) and a progestagen.
Cliovelle is used in postmenopausal women, at least 1 year after the last natural menstrual period.
Cliovelle is used to:
Relieve symptoms occurring after menopause
During menopause, the amount of oestrogen produced by a woman's body decreases. This causes symptoms such as hot flushes (a feeling of warmth or heat spreading over the face, neck, and chest). Cliovelle helps relieve these symptoms. Cliovelle should only be recommended if these symptoms significantly affect your daily life.
Prevention of osteoporosis
After menopause, some women develop brittle bones (osteoporosis). All available treatment options should be discussed with your doctor. If you are at increased risk of fractures due to osteoporosis and other treatments are not suitable, Cliovelle may be used to prevent postmenopausal osteoporosis.

2. Important Information Before Using Cliovelle

Medical History and Regular Medical Examinations
Hormone replacement therapy (HRT) is associated with risks that should be considered when deciding whether to start or continue this treatment.
Experience with treating women with premature menopause (due to disease or surgical removal of the ovaries) is limited. If you are being treated for premature menopause, the risks of HRT may differ. Discuss this with your doctor.
Before starting (or resuming) HRT, your doctor should take a detailed medical history, including your personal and family medical background. Your doctor may decide to perform a physical examination, which may include breast and/or pelvic examination, if necessary.
If you start using Cliovelle, you should have regular medical check-ups (at least once a year). During these visits, discuss with your doctor the benefits and risks of continuing treatment with Cliovelle.
Regular breast examinations should be performed as recommended by your doctor.

When Not to Use Cliovelle
Do not take Cliovelle if any of the following apply to you. If you are unsure, consult your doctor before taking Cliovelle.

Do not take Cliovelle:

• if you have or have ever had breast cancer or are suspected of having it;
• if you have or are suspected of having estrogen-dependent cancer, such as endometrial (womb lining) cancer;
• if you have vaginal bleeding of unknown cause;
• if you have untreated endometrial hyperplasia (excessive thickening of the womb lining);
• if you have or have ever had venous thromboembolism (venous blood clots), such as deep vein thrombosis in the legs or pulmonary embolism in the lungs;
• if you have blood clotting disorders (such as protein C, protein S or antithrombin deficiency);
• if you currently have or recently had a condition caused by blood clots in blood vessels, such as heart attack, stroke, or angina pectoris;
• if you have or have ever had liver disease or your liver function tests have not returned to normal;
• if you have a rare inherited blood disorder called porphyria;
• if you are allergic to estradiol valerate, norethisterone acetate, or any of the other ingredients of this medicine (listed in section 6).

If any of the above conditions occur for the first time while taking Cliovelle, stop taking Cliovelle immediately and consult your doctor without delay.

Warnings and Precautions
Before starting treatment, inform your doctor if you have ever experienced any of the following conditions, as they may recur or worsen during treatment with Cliovelle. If so, you should have more frequent medical check-ups. These conditions include:

• uterine fibroids;
• endometriosis (endometrial tissue growing outside the uterus) or a history of endometrial hyperplasia;
• increased risk of venous blood clots (see "Blood clots in the veins (thrombosis)");
• increased risk of estrogen-dependent cancer (e.g. if your mother, sister, or grandmother had breast cancer);
• high blood pressure;
• liver disorders, such as benign liver tumors;
• diabetes;
• gallstones;
• migraine or severe headaches;
• an autoimmune disease affecting multiple organs (systemic lupus erythematosus, SLE);
• epilepsy;
• asthma;
• a condition affecting the inner ear (otosclerosis);
• high levels of fat (triglycerides) in the blood;
• fluid retention due to heart or kidney problems;
• hereditary or acquired angioedema.

Stop taking Cliovelle and contact your doctor immediately
if you experience any of the following while using HRT:

• any of the problems listed above under "Do not take Cliovelle";
• yellowing of the skin or whites of the eyes (jaundice), which may indicate liver disease;
• swelling of the face, tongue, and/or throat and/or difficulty swallowing, or hives with difficulty breathing, suggesting angioedema;
• significant increase in blood pressure (symptoms may include headache, fatigue, dizziness);
• first occurrence of migraine headaches;
• pregnancy;
• symptoms of blood clots such as:
  • painful swelling and redness in the legs,
  • sudden chest pain,
  • difficulty breathing. See more information under "Blood clots in the veins (thrombosis)".

Note: Cliovelle 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, additional contraception may be needed to prevent pregnancy. Please consult your doctor about this.

HRT and Cancer

Endometrial Hyperplasia and Endometrial Cancer
HRT with estrogen-only therapy increases the risk of endometrial hyperplasia (excessive thickening of the womb lining) and endometrial cancer.
The presence of a progestogen in Cliovelle protects you from this additional risk.

Irregular Bleeding
Irregular bleeding or spotting may occur during the first 3–6 months of taking Cliovelle. However, if irregular bleeding:

• lasts longer than 6 months,
• starts more than 6 months after beginning Cliovelle,
• continues after stopping Cliovelle,
  consult your doctor as soon as possible.

Breast Cancer
Evidence confirms that taking hormone replacement therapy (HRT), either estrogen-only or combined estrogen-progestogen therapy, increases the risk of breast cancer. The additional risk depends on how long HRT is used. This increased risk becomes apparent after 3 years of HRT use. After stopping HRT, the additional risk gradually decreases, but may persist for 10 years or longer if HRT was used for more than 5 years.

Comparison
Among women aged 50–54 years not using HRT, breast cancer will be diagnosed in an average of 13 to 17 per 1000 women over a 5-year period.
Among women aged 50 who start 5 years of estrogen-only HRT, the number of cases will be 16–17 per 1000 women (i.e. 0 to 3 additional cases).
Among women aged 50 who start 5 years of combined estrogen-progestogen HRT, the number of cases will be 21 per 1000 women (i.e. 4 to 8 additional cases).
Among women aged 50–59 not using HRT, breast cancer will be diagnosed in an average of 27 per 1000 women over a 10-year period.
Among women aged 50 who start 10 years of estrogen-only H0RT, the number of cases will be 34 per 1000 women (i.e. 7 additional cases).
Among women aged 50 who start 10 years of combined estrogen-progestogen HRT, the number of cases will be 48 per 1000 women (i.e. 21 additional cases).

Additionally, monitor your breasts. Contact your doctor if you notice changes such as:

• skin dimpling,
• nipple changes,
• any lumps that are palpable or visible.

Furthermore, participation in screening mammography is recommended if available. When undergoing screening mammography, inform the nurse or radiology staff performing the X-ray that you are using HRT, as this medication may increase breast density, which can affect mammogram results. Increased breast density may make it harder for mammography to detect all lumps.

Ovarian Cancer
Ovarian cancer is rare—much less common than breast cancer. Using HRT with estrogen-only or combined estrogen-progestogen therapy is associated with a slightly increased risk of ovarian cancer.
The risk of ovarian cancer depends on age. For example, among women aged 50–54 not using HRT, ovarian cancer will be diagnosed in about 2 out of 2000 women over a 5-year period.
Among women who have used HRT for 5 years, it will occur in about 3 out of 2000 women (i.e. about 1 additional case).

Effects of HRT on the Heart and Circulation

Venous Thromboembolism (Thrombosis)
The risk of venous blood clots is 1.3 to 3 times higher in women using HRT than in those not using it, especially during the first year of treatment.
Venous blood clots can be life-threatening; if a clot travels to the lungs, it may cause chest pain, breathlessness, fainting, or even death.
The likelihood of developing venous thrombosis increases with age and if any of the following apply to you.
Inform your doctor if any of the following apply to you:

• you are unable to walk for long periods due to major surgery, injury, or illness (see section 3 "Surgery");
• you are significantly overweight (BMI > 30 kg/m²);
• you have any blood clotting disorders requiring long-term anticoagulant therapy;
• any of your close relatives have ever had a blood clot in the leg, lungs, or another organ;
• you have systemic lupus erythematosus (SLE);
• you have cancer.

Symptoms of blood clots are listed under "Stop taking Cliovelle and contact your doctor immediately."

Comparison
Among women around the age of 50 not using HRT, an average of 4–7 out of 1000 can be expected to develop a venous blood clot over a 5-year period.
Among women around the age of 50 using combined estrogen-progestogen HRT for over 5 years, there will be 9–12 cases per 1000 users (i.e. 5 additional cases).

Heart Disease (Myocardial Infarction)
There is no evidence that HRT prevents heart attacks.
Women over 60 years of age using combined estrogen-progestogen HRT have a slightly increased risk of developing heart disease compared to women not using HRT.

Stroke
The risk of stroke is approximately 1.5 times higher in women using HRT than in those not using it.
The number of additional stroke cases associated with HRT increases with age.

Comparison
Among women around the age of 50 not using HRT, an average of 8 out of 1000 can be expected to have a stroke over a 5-year period. Among women around the age of 50 using HRT, there are 11 cases per 1000 users over 5 years (i.e. 3 additional cases).

Other Conditions
HRT does not protect against memory loss. Evidence suggests an increased risk of memory loss in women who start HRT after age 65. Consult your doctor.

Cliovelle and Other Medicines
Some medicines may affect the action of Cliovelle, which may lead to irregular bleeding. These include:

• medicines for epilepsy (such as phenobarbital, phenytoin, and carbamazepine);
• medicines for tuberculosis (such as rifampicin and rifabutin);
• medicines for HIV infection (such as nevirapine, efavirenz, telaprevir, ritonavir, and nelfinavir);
• herbal products containing St. John’s wort (Hypericum perforatum).

HRT may affect the action of certain other medicines:

• lamotrigine (used for epilepsy), as it may increase seizure frequency.

Treatment regimens for hepatitis C virus (HCV) infection using ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, or glecaprevir/pibrentasvir, or sofosbuvir/velpatasvir/voxilaprevir may cause increased liver function test parameters in the blood (elevated liver enzyme AlAT activity) in women using combined hormonal contraceptives containing ethinylestradiol. Cliovelle contains estradiol instead of ethinylestradiol. It is not known whether elevated AlAT liver enzyme activity may occur when Cliovelle is used concomitantly with such HCV combination therapies. Your doctor will provide appropriate advice.

Cliovelle may increase or decrease the effect of other medicines:

• the effect of cyclosporine (e.g., used to prevent transplant rejection, treat rheumatoid arthritis or psoriasis) may be increased.

Medicines containing ketoconazole (an antifungal agent) may increase the effect of Cliovelle.

Inform your doctor or pharmacist about all medicines you are currently using, have recently used, or plan to use, including over-the-counter medicines, herbal remedies, or other natural products.
Your doctor will provide appropriate advice.

Laboratory Tests
If you are undergoing blood tests, inform your doctor or laboratory staff that you are taking Cliovelle, as this medicine may affect the results of certain tests.

Pregnancy and Breast-feeding
Cliovelle is intended for use only in postmenopausal women. If you become pregnant, stop taking Cliovelle and contact your doctor.

Driving and Operating Machinery
No effects of the medicine on the ability to drive or operate machinery have been observed.

Cliovelle Contains Lactose
If you have been previously diagnosed with an intolerance to certain sugars, consult your doctor before taking this medicine.

3. How to use Cliovelle

This medicine should always be taken as directed by your doctor. If in doubt, consult your doctor or pharmacist.
Take one tablet daily, without interruption between individual packs (blister strips) of the medicine.
Take the first tablet from the blister marked with the day of the week on which you start taking Cliovelle tablets (e.g., "Mon" if starting on Monday). Then take one tablet daily, following the direction of the arrow, until the entire blister is empty. The next day, start a new blister.
Swallow the tablets with a large amount of water, preferably at the same time each day.
Your treating doctor will prescribe the lowest effective dose necessary to treat your symptoms and recommend taking it for the shortest possible duration. If you think the dose prescribed is too high or too low, discuss it with your doctor.
Taking more Cliovelle than prescribed
If you have taken an excessive dose of this medicine, contact your doctor or hospital for risk assessment and advice.
In case of overdose, symptoms may include breast tenderness, nausea or vomiting, irregular menstrual bleeding, feeling depressed, fatigue, acne, or excessive hair growth on the body and face.
If you accidentally take an extra dose, still take your next normal dose the following day.
Missing a dose of Cliovelle
If you forget to take a tablet, you may take it within 12 hours of your usual time. Otherwise, discard the missed tablet and take the next tablet at your usual time the following day.
Do not take a double dose to make up for a missed dose.
In case of surgery
If you are undergoing surgery, inform the surgeon that you are taking Cliovelle. It may be necessary to stop taking Cliovelle approximately 4 to 6 weeks before the procedure to reduce the risk of blood clots (see section 2, "Blood clots in veins (venous thrombosis)"). Ask your doctor when you can resume taking Cliovelle.
If you have any further questions about the use of this medicine, consult your doctor or pharmacist.

4. Possible adverse effects

Like all medicines, this medicine may cause adverse effects, although not everyone will experience them.
Adverse effects are mostly mild to moderate in severity and do not necessarily require discontinuation of therapy.

The following conditions are reported more frequently in women using HRT compared to women not using this therapy:

• breast cancer
• excessive growth or cancer of the uterine lining (endometrial hyperplasia or cancer)
• ovarian cancer
• blood clots in the veins of the legs or lungs (venous thromboembolic disease)
• heart disease
• stroke
• increased risk of memory loss if HRT is started after the age of 65

For more information about these adverse effects, see section 2.

The following adverse effects may occur during treatment with Cliovelle:

Very common (may affect more than 1 in 10 people)
Vaginal bleeding. Breast tenderness or pain.

Common (may affect up to 1 in 10 people)
Fungal infections of the genital area or vaginal inflammation. Fluid retention.
Depression or worsening of pre-existing depression. Migraine or worsening of existing migraine, headaches.
Nausea. Back pain. Breast swelling or tenderness. Uterine tumours (fibroids) or worsening or recurrence of uterine tumours. Peripheral oedema (swollen hands and feet). Weight gain.

Uncommon (may affect up to 1 in 100 people)
Hypersensitivity (allergic reaction). Nervousness. Superficial thrombophlebitis (inflammation of surface veins associated with blood clots). Abdominal pain, pressure or discomfort. Flatulence, bloating. Hirsutism (excessive body and facial hair), acne, hair loss. Itching. Urticaria (hives). Leg cramps.

Rare (may affect up to 1 in 1,000 people)
Pulmonary embolism (blood clots in the lungs) (see also section 2: "Important information before taking Cliovelle").
Deep vein thrombosis (DVT) with blood clots.

Very rare (may affect up to 1 in 10,000 people)
Anaphylactic reactions (sudden, serious, potentially life-threatening allergic reactions).

The following side effects have been reported with other HRTs:

• gallbladder disease
• various skin disorders:
• skin pigmentation changes, especially on the face or neck, known as chloasma (melasma)
• painful red nodules on the skin (erythema nodosum)
• rash with target-shaped redness or ulcers (erythema multiforme)
• dry eyes
• changes in tear film composition.

Reporting of adverse effects
If any adverse effects occur, including any not listed in this leaflet, inform your doctor or pharmacist.
Adverse effects can be reported directly to the Department of Monitoring Adverse Drug Reactions of the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products, Al. Jerozolimskie 181C, 02-222 Warsaw, tel.: +48 22 49-21-301, fax: +48 22 49-21-309, website: https://smz.ezdrowie.gov.pl .
Adverse effects can also be reported to the Marketing Authorisation Holder.
Reporting adverse effects helps provide more information on the safety of the medicine.

5. How to store Cliovelle tablets

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the blister pack and the outer carton.
The expiry date refers to the last day of the stated month.
Medicines must not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Contents of the package and other information

What Cliovelle contains

• The active substances are: estradiol 1 mg in the form of estradiol valerate, and norethisterone acetate 0.5 mg.
• Other components: copovidone, monohydrate lactose, magnesium stearate, and maize starch.

What Cliovelle looks like and contents of the pack
White, round, biconvex tablets with a diameter of 6 mm.
Calendar blister packs containing 28 and 84 tablets.
Blister packs containing 30 and 90 tablets.
Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer
DR. KADE Pharmazeutische Fabrik GmbH
Rigistrasse 2
12277 Berlin
Germany

For further information, please contact the representative of the Marketing Authorisation Holder:
Kadefarm Sp. z o.o.
ul. Gipsowa 18, Sierosław
62-080 Tarnowo Podgórne
Tel.: +48 61 862 99 43

This medicinal product is authorised in the Member States of the European Economic Area under the following names:
Denmark Cliovelle
Finland Cliovelle 1 mg/0.5 mg tablet
Germany Cliovelle 1 mg/0.5 mg Tabletten
Norway, Sweden Cliovelle 1 mg/0.5 mg tabletter
Poland Cliovelle 1 mg/0.5 mg tablets

Detailed information about this medicine is available on the website www.urpl.gov.pl.