Cyclo-progynova

Package leaflet: Information for the user

Cyclo-Progynova, 2 mg (white tablets); 2 mg + 0,5 mg (light brown tablets), coated tablets
(Estradiol valerate; Estradiol valerate + Norgestrel)
Please read all of 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 personally. Do not pass it on to others. It may harm other people, even if their symptoms are the same as yours.
• If any of the side effects worsens, or if you experience any side effects not listed in this leaflet, inform your doctor or pharmacist immediately. See section 4.

Leaflet contents

1. What Cyclo-Progynova is and what it is used for
2. Important information before taking Cyclo-Progynova
3. How to take Cyclo-Progynova
4. Possible side effects
5. How to store Cyclo-Progynova
6. Contents of the pack and other information

1. What Cyclo-Progynova is and what it is used for

Cyclo-Progynova is a medicine used in Hormone Replacement Therapy (HRT).
It contains two different hormones: estrogen and progestagen. In postmenopausal women, the ovaries stop producing these hormones.
Why Cyclo-Progynova is used
Cyclo-Progynova is used to treat symptoms of estrogen deficiency (such as hot flushes, sleep disturbances, dizziness, vaginal dryness) resulting from natural menopause or hypogonadism, removal of reproductive organs, or primary ovarian insufficiency in women who still have their uterus.
Cyclo-Progynova is used to control irregular menstrual cycles.
Treatment of primary or secondary amenorrhea.
Cyclo-Progynova is not a contraceptive.

2. Important Information Before Using Cyclo-Progynova

Medical History and Regular Medical Examinations
Hormone replacement therapy (HRT) carries certain risks that should be considered when deciding whether to start or continue treatment.
Experience with treating women with premature menopause (due to ovarian failure or surgical removal of ovaries) is limited. In women with premature menopause, the risks associated with HRT may differ. In such cases, consult your doctor.
Before starting (or restarting) HRT, your doctor will take a detailed medical history of you and your family. Your doctor may decide that a physical examination is necessary. This may include a breast examination and/or, if needed, a gynecological examination.
After starting Cyclo-Progynova, 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 Cyclo-Progynova.
Regular breast examinations should be performed as recommended by your doctor.
Patients with pituitary adenoma require careful monitoring (including periodic prolactin level testing).

When Not to Use Cyclo-Progynova
Do not use Cyclo-Progynova if any of the following conditions apply to you. If you are unsure whether any of these conditions apply to you, consult your doctor before using Cyclo-Progynova.

Do not use Cyclo-Progynova:

• if you are allergic (hypersensitive) to the active substances or to any of the other ingredients of Cyclo-Progynova (listed in section 6);
• if you have breast cancer – diagnosed previously or suspected;
• if you have an estrogen-dependent tumor (e.g., endometrial cancer) or if such a tumor is suspected;
• if you have unexplained vaginal bleeding;
• if you have untreated endometrial hyperplasia (overgrowth of the endometrium);
• if you currently have or have previously had venous thrombosis (e.g., deep vein thrombosis in the legs) or pulmonary embolism;
• if you currently have or have recently had an arterial thrombotic disease, such as: myocardial infarction, stroke, or angina pectoris;
• if you have blood clotting disorders (such as protein C, protein S or antithrombin deficiency);
• if you have or have previously had liver disease and liver function parameters have not returned to normal;
• if you are pregnant or breastfeeding;
• if you have an increased risk of venous or arterial thromboembolic disease;
• if you have a rare, inherited blood pigment disorder called "porphyria".

If any of the above conditions develops for the first time during treatment with Cyclo-Progynova, stop taking the medicine immediately and contact your doctor.

Warnings and Precautions
Before starting Cyclo-Progynova, discuss this with your doctor, pharmacist, or nurse.
When to exercise special caution when using Cyclo-Progynova:
If you have ever had any of the following clinical conditions, inform your doctor before starting treatment, as these conditions may recur or worsen during treatment with Cyclo-Progynova. In such cases, more frequent medical check-ups are recommended:

• uterine fibroids;
• endometriosis (endometrial tissue growing outside the uterus) or a history of endometrial hyperplasia;
• increased risk of venous thrombosis (see below: "Venous thrombosis");
• increased risk of developing estrogen-dependent tumors, e.g., breast cancer in mother, sister, or grandmother;
• high blood pressure;
• liver disease, such as benign liver tumor;
• diabetes;
• gallstones;
• migraine or severe headaches;
• autoimmune disease that may affect multiple organs (systemic lupus erythematosus, SLE);
• hereditary or acquired angioedema;
• epilepsy;
• asthma;
• otosclerosis (a disorder of the ear affecting hearing);
• very high levels of blood lipids (triglycerides);
• fluid retention associated with heart or kidney failure;
• chorea minor.

Stop taking Cyclo-Progynova and contact your doctor immediately
if you experience any of the following symptoms during HRT:

• any of the conditions listed in section "When not to use Cyclo-Progynova";
• yellowing of the skin or whites of the eyes (jaundice) – this may indicate liver disease;
• a significant increase in blood pressure (symptoms may include headache, fatigue, dizziness);
• new onset of migraine-like headaches;
• pregnancy;
• symptoms suggesting venous thrombosis, such as:
  • painful swelling and redness in the leg;
  • sudden chest pain;
  • shortness of breath;
  • swelling of the face, tongue and/or throat and/or difficulty swallowing or hives, combined with breathing difficulties, suggesting angioedema.

Note: Cyclo-Progynova is not a contraceptive. Women who have not completed 12 months since their last menstrual period or who are under 50 years of age may still require additional contraception to prevent pregnancy. Consult your doctor for advice.

HRT and Cancer

Endometrial Hyperplasia and Endometrial Cancer
Using estrogen-only HRT increases the risk of endometrial hyperplasia and endometrial cancer.
The progestagen in Cyclo-Progynova protects against this additional risk.
In women with an intact uterus who do not use HRT, about 5 out of 1,000 women will be diagnosed with endometrial cancer between the ages of 50 and 65. Depending on the duration and dose of estrogen therapy, between 10 and 60 out of 1,000 women aged 50 to 65 who have an intact uterus and use estrogen-only HRT will be diagnosed with endometrial cancer (i.e., an additional 5 to 55 cases per 1,000).

Unusual Bleeding
While taking Cyclo-Progynova, you will have regular monthly bleeding (withdrawal bleeding). However, if you experience unexpected bleeding or spotting between periods that:

• persists beyond the first 6 months of treatment,
• occurs after more than 6 months of using Cyclo-Progynova,
• continues after stopping HRT,

contact your doctor as soon as possible.

Breast Cancer
Evidence confirms that using hormone replacement therapy (HRT), whether estrogen-only or combined estrogen-progestagen products, is associated with an increased risk of breast cancer, which increases with the duration of therapy. The 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.

• You should regularly examine your breasts. Contact your doctor if you notice any of the following changes:
  • skin indentation;
  • changes in the nipple;
  • any visible or palpable lumps.

Additionally, participation in screening mammography is recommended if available. When undergoing screening mammography, inform the nurse or radiology staff that you are using HRT, as this medication may increase breast density, potentially affecting mammogram results. In areas of increased breast density, mammography may not detect all lumps.

Comparison:
Among women aged 50–54 not using HRT, breast cancer will be diagnosed in an average of 13 to 17 out of 1,000 women over 5 years.
Among women aged 50 starting 5-year estrogen-only HRT, the number of cases will be 16–17 per 1,000 (i.e., 0 to 3 additional cases).
Among women aged 50 starting 5-year combined estrogen-progestagen HRT, the number of cases will be 21 per 1,000 (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 out of 1,000 women over 10 years.
Among women aged 50 starting 10-year estrogen-only H0, the number of cases will be 34 per 1,000 (i.e., 7 additional cases).
Among women aged 50 starting 10-year combined estrogen-progestagen HRT, the number of cases will be 48 per 1,000 (i.e., 21 additional cases).

Ovarian Cancer
Ovarian cancer is rare—much less common than breast cancer. Using estrogen-only HRT or combined estrogen-progestagen HRT 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 2,000 women over 5 years. Among women using HRT for 5 years, it will occur in about 3 out of 2,000 users (i.e., about 1 additional case).

Effects of HRT on the Heart and Circulatory System

Venous Thrombosis (Thrombosis)
The risk of venous thrombosis is about 1.3 to 3 times higher in women using HRT, especially during the first year of treatment, compared to women not using HRT.
Thrombosis can be life-threatening, particularly if a clot travels to the lungs, causing chest pain, shortness of breath, fainting, or even death.
The risk of thrombosis increases with age and if any of the following conditions apply to you. Inform your doctor:

• if you are unable to walk for prolonged periods due to major surgery, injury, or illness (see also section 3 "Surgical procedures");
• if you are significantly overweight (BMI > 30 kg/m²);
• if you have blood clotting disorders requiring long-term anticoagulant therapy;
• if close relatives have had venous thrombosis in the legs, lungs, or other organs;
• if you have systemic lupus erythematosus (SLE);
• if you have cancer.

Symptoms suggesting venous thrombosis are listed in the section "Stop taking Cyclo-Progynova and contact your doctor immediately."

Comparison:
Among women around age 50 not using HRT, about 4 to 7 out of 1,000 can be expected to develop venous thrombosis over 5 years.
Among women around age 50 using combined estrogen-progestagen HRT for more than 5 years, 9 to 12 out of 1,000 will develop venous thrombosis (i.e., 5 additional cases).

Heart Disease (Myocardial Infarction)
HRT has not been shown to prevent heart attacks.
In women over 60 years of age using combined estrogen-progestagen HRT, the risk of heart disease is slightly higher than in women not using HRT.

Stroke
The risk of stroke in women using HRT is about 1.5 times higher than in women not using HRT. The number of additional stroke cases related to HRT use increases with age.

Comparison:
Among women around age 50 not using HRT, about 8 out of 1,000 are expected to have a stroke over 5 years. Among women around age 50 using HRT, this number is 11 per 1,000 over 5 years (i.e., 3 additional cases).

Other Diseases

• If you have kidney or heart disease, you should remain under medical supervision, as estrogens may cause fluid retention. In severe renal insufficiency, blood levels of the active substances in Cyclo-Progynova will be elevated.
• If you have elevated triglyceride levels (a type of fat in the blood), you should remain under medical supervision, as levels may increase further and potentially lead to pancreatitis.
• If you have hereditary angioedema, using Cyclo-Progynova may worsen symptoms.
• If you are prone to developing brown patches (melasma) on the face, avoid sunlight or ultraviolet radiation during treatment with Cyclo-Progynova.
• HRT does not prevent memory loss. Some evidence suggests increased memory loss in women starting HRT after age 65. For more information, talk to your doctor.

Estrogens increase the total circulating levels of thyroid hormones, corticosteroids, and sex hormones. This may be relevant when interpreting laboratory test results.

Cyclo-Progynova and Other Medicines
Inform your doctor about all medicines you are currently taking or have recently taken, including those obtained without a prescription, herbal remedies, or other natural supplements.
Some medicines (listed below) may affect the action of Cyclo-Progynova, potentially leading to irregular bleeding:

• antiepileptic drugs (e.g., barbiturates, phenytoin, primidone, carbamazepine, and possibly oxcarbazepine, topiramate, felbamate);
• drugs used to treat tuberculosis (e.g., rifampicin, rifabutin);
• drugs used to treat HIV and hepatitis C virus infections (protease inhibitors and non-nucleoside reverse transcriptase inhibitors, e.g., nevirapine, efavirenz, nelfinavir, ritonavir);
• St. John's wort (Hypericum perforatum);
• antifungal drugs (e.g., griseofulvin, itraconazole, ketoconazole, voriconazole, fluconazole);
• antibiotics used to treat bacterial infections (e.g., clarithromycin, erythromycin);
• drugs used to treat certain heart conditions and high blood pressure (e.g., verapamil, diltiazem);
• grapefruit juice.

If you take paracetamol, the effect of Cyclo-Progynova may be enhanced.
HRT may affect the action of other medicines:

• antiepileptic drugs (lamotrigine), as seizures may increase in frequency;
• drugs used to treat hepatitis C virus (HCV) (e.g., ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, glecaprevir/pibrentasvir, or sofosbuvir/velpatasvir/voxilaprevir), as they may cause increased liver function parameters in blood tests (elevated alanine aminotransferase [AlAT] enzyme activity) in women using combined hormonal contraceptives containing ethinylestradiol. Cyclo-Progynova contains estradiol instead of ethinylestradiol. It is unknown whether elevated AlAT enzyme activity may occur when Cyclo-Progynova is used concurrently with these HCV treatment regimens.

Laboratory Tests
If you need to have blood tests, inform your doctor or laboratory staff that you are taking Cyclo-Progynova, as this medicine may affect the results of certain tests.
Inform your doctor or pharmacist about all medicines you are currently or recently taking, including over-the-counter medicines, herbal remedies, and other natural supplements.
Your doctor will provide appropriate advice.

Pregnancy and Breastfeeding
Cyclo-Progynova is intended for postmenopausal women. If you become pregnant, stop taking Cyclo-Progynova immediately and contact your doctor.
Small amounts of sex hormones may pass into breast milk. Hormone replacement therapy is not recommended during breastfeeding.

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

Cyclo-Progynova Contains Monohydrate Lactose and Sucrose
This product contains monohydrate lactose and sucrose. If you have been previously diagnosed with an intolerance to certain sugars, consult your doctor before taking this medicine.

3. How to use Cyclo-Progynova

This medicine should always be used as directed by the physician. If in doubt, consult the doctor or pharmacist. The physician will decide how long Cyclo-Progynova should be taken.
If the patient is still menstruating, treatment should begin on the fifth day of menstruation. In any other case, the attending physician may advise immediate initiation of therapy.
The physician will prescribe the lowest possible dose for the shortest possible duration that provides relief of symptoms. If the patient feels the dose is too high or too low, she should consult her doctor.
One white tablet should be taken daily for the first 11 days, followed by one light brown tablet daily for the next 10 days, preferably at the same time each day. The tablets should be swallowed whole with a small amount of liquid.
One pack provides a 21-day course of treatment.
After the 21-day cycle of tablet intake, a 7-day break should be taken.
Withdrawal bleeding usually occurs during the 7-day break, a few days after taking the last tablet.

Use in children and adolescents
Cyclo-Progynova is not indicated for use in children and adolescents.

Elderly patients
There are no data suggesting the need for dose adjustment in elderly patients.

Patients with liver disorders
Adequate studies on the use of Cyclo-Progynova in patients with liver function disorders have not been conducted. The medicine is contraindicated in women with severe liver disease (see section "When not to use Cyclo-Progynova").

Patients with kidney disorders
Adequate studies on the use of Cyclo-Progynova in patients with kidney function disorders have not been conducted.

Missed dose of Cyclo-Progynova
If a patient forgets to take a tablet at the usual time and less than 24 hours have passed, the missed tablet should be taken as soon as possible, and the next tablet should be taken at the usual time. However, if more than 24 hours have passed, the missed tablet should be left in the blister and treatment should continue with the remaining tablets at the usual daily time. If several tablets are missed, bleeding may occur.

Use of a higher than recommended dose of Cyclo-Progynova
Overdose may cause nausea, vomiting, and irregular bleeding. Specific treatment is not required, but in case of any doubts, medical advice should be sought.

In case of surgical procedure
If the patient is scheduled for surgery, she should inform the surgeon about taking Cyclo-Progynova. It may be necessary to discontinue Cyclo-Progynova approximately 4–6 weeks before the planned operation to reduce the risk of thrombosis (see section 2 "Venous thromboembolism (thrombosis)"). The patient should ask the doctor when she can resume taking Cyclo-Progynova.

4. Possible adverse effects

Like all medicines, this medicine may cause adverse effects, although not everyone will experience them.
Serious adverse effects associated with hormone replacement therapy (HRT) are described in the section "Warnings and precautions".
The following diseases are reported more frequently in women taking HRT than in women not taking HRT:

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

Detailed information about these adverse effects is provided in section 2.
The following symptoms may be related to the use of hormone replacement therapy or, in some cases, may be symptoms of menopause. These symptoms have also been observed in patients using other oral hormone replacement therapies.

Common adverse effects (in 1 to 10 out of every 100 patients):

• increase or decrease in body weight,
• abdominal pain, nausea,
• rash, itching of the skin,
• bleeding or spotting from the vagina.

Uncommon adverse effects (in 1 to 10 out of every 1,000 patients):

• hypersensitivity reactions,
• depressed mood,
• dizziness,
• visual disturbances,
• rapid heartbeat (palpitations),
• indigestion,
• nodular erythema, urticaria,
• breast pain, breast tenderness,
• swelling.

Rare adverse effects (in 1 to 10 out of every 10,000 patients):

• anxiety,
• decreased or increased sexual desire (libido),
• migraine,
• intolerance to contact lenses,
• bloating, vomiting,
• male-pattern body hair growth in women (hirsutism), acne,
• muscle cramps,
• painful menstruation, vaginal discharge, premenstrual syndrome, breast swelling,
• fatigue.

With the use of other HRT medicines, the following adverse effects have occurred:

• gallbladder disease,
• various skin disorders: o skin pigmentation, especially on the face or neck, known as "melasma" (chloasma); o painful red skin nodules (erythema nodosum); o rash with target-like redness or ulcerations (erythema multiforme).

Cyclo-Progynova may cause or worsen symptoms of hereditary angioedema (see section "Warnings and precautions").
If any of the adverse effects worsen or if any adverse effects not listed in this leaflet occur, consult your doctor or pharmacist.

Reporting of adverse effects
If you experience any adverse effects, including those 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 181 C
02-222 Warsaw
Phone: +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 authorization holder.
Reporting adverse effects helps to provide more information on the safety of this medicine.

5. How to store Cyclo-Progynova

Do not use this medicine after the expiry date stated on the packaging.
Keep the medicine out of sight and reach of children.
Storage: No special requirements.
Medicines must not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer in use. This will help protect the environment.

6. Contents of the pack and other information

What Cyclo-Progynova contains

• The active substances are: estradiol valerate (Estradioli valeras) and norgestrel (Norgestrelum). Each white coated tablet contains 2 mg of estradiol valerate. Each light brown coated tablet contains 2 mg of estradiol valerate and 0.5 mg of norgestrel.
• Other components of the medicine are:
  White tablets:
  Core: lactose monohydrate, maize starch, povidone K25, talc, magnesium stearate;
  Coating: sucrose, povidone K90, macrogol 6000, calcium carbonate, talc, Montana wax.

Light brown tablets:
Core: lactose monohydrate, maize starch, povidone K25, talc, magnesium stearate;
Coating: sucrose, povidone K90, macrogol 6000, calcium carbonate, talc, glycerol 85%, titanium dioxide (E 171), yellow iron oxide (E 172), red iron oxide (E 172), Montana wax.

What Cyclo-Progynova looks like and contents of the pack
Each Cyclo-Progynova blister pack contains 11 white tablets and 10 light brown coated tablets.
The blister contains 21 coated tablets.
The package may contain 1 or 3 blisters.

Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder
Bayer AG
Kaiser-Wilhelm-Allee 1
51373 Leverkusen
Germany

Manufacturer
Bayer Weimar GmbH und Co. KG
Döbereinerstrasse 20
99427 Weimar
Germany

For further information, please contact the local representative of the Marketing Authorisation Holder:
Bayer Sp. z o.o.
Al. Jerozolimskie 158
02-326 Warsaw
Phone: (22) 5723500
Fax: (22) 5723555