Package leaflet: Information for the patient

Progynova 2 mg coated tablets

Estradiol valerate
Please read all of this leaflet carefully before you start taking 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 other people, even if their symptoms are the same as yours, as it may be harmful.
If you experience any side effects, including those not listed in this leaflet, talk to your doctor or pharmacist. See section 4.

Contents of this leaflet:

What Progynova is and what it is used for
What you need to know before taking Progynova
How to take Progynova
Possible side effects
How to store Progynova
Contents of the pack and other information

1. What Progynova is and what it is used for

Progynova is a medicine used in hormone replacement therapy (HRT).
Progynova contains oestrogen (estradiol valerate), a female sex hormone belonging to the group
of medicines for Hormone Replacement Therapy (HRT).
This medicine is used for the treatment of symptoms associated with post-menopause.
During menopause, the amount of oestrogen produced by a woman's body decreases. This may lead to
the onset of symptoms such as hot flushes, night sweats, insomnia, depressive states, headaches,
and dizziness.
Progynova relieves these post-menopausal symptoms. In addition, it may reduce manifestations of atrophy of the
skin and mucous membranes (especially in the urogenital tract).
This medicine will be prescribed to you only if your symptoms seriously interfere with your daily activities.

2. What you should know before taking Progynova

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 premature menopause (due to cessation of ovulation or surgical intervention) is limited. If you have premature menopause, the risks associated with HRT may differ. Consult your doctor.
Before starting (or restarting) HRT, your doctor will ask you questions about your personal and family medical history. 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 Progynova, 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 Progynova.
Have regular breast examinations as recommended by your doctor.

Do not take Progynova
Do not take Progynova 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 Progynova.

If you are allergic to estradiol valerate or to 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 or suspect you have a malignant tumour whose growth is sensitive to oestrogens, for example, a tumour of the uterine lining (endometrium);
If you have, or have previously had, blood clots in a vein (thrombosis), such as in the legs (deep vein thrombosis) or in the lungs (pulmonary embolism);
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 endometrial hyperplasia (thickening of the uterine lining) that has not been treated;
If you have a rare inherited blood disorder called "porphyria";
If you have blood clotting disorders (such as protein C, protein S or antithrombin deficiency).

If any of these conditions develop for the first time while you are taking Progynova, stop treatment immediately and consult your doctor.

Warnings and precautions
Talk to your doctor or pharmacist before taking Progynova.

When to be particularly careful with Progynova
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 Progynova. If so, you should see your doctor more frequently for check-ups:

Uterine fibroids;
Endometriosis (growth of uterine tissue outside the uterus) 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 (a condition causing seizures);
Asthma;
A condition affecting the eardrum and hearing (otosclerosis);
Very high levels of fat in the blood (triglycerides);
Fluid retention due to heart or kidney problems;
Benign breast conditions;
Chorea minor (a disorder characterised by involuntary, uncoordinated movements);
If you have a benign tumour (adenoma) of the anterior pituitary gland, you must be closely monitored by your doctor, who will prescribe periodic prolactin level measurements;
Hereditary or acquired angioedema.

Stop treatment with Progynova and contact your doctor immediately if:

Any of the conditions listed in the section “Do not take Progynova” occur;
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 experience 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 more information, see the section “Effects of HRT on the heart and circulation – Blood clots in the veins (thrombosis)”.

Note: Progynova 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 of cancer of the uterine lining (endometrial carcinoma).
Adding a progestogen to oestrogen for at least 12 days of each 28-day cycle protects against this additional risk. Your doctor will prescribe a progestogen separately if you still have your uterus. If you have had your uterus removed (hysterectomy), discuss with your doctor whether you can safely use this medicine without a progestogen.
In women who still have their uterus and who do not use HRT, on average, 5 out of 1000 will be diagnosed with endometrial carcinoma between the ages of 50 and 65. For women aged 50 to 65 who still have their uterus and who use oestrogen-only HRT, 10 to 60 out of 1000 will be diagnosed with endometrial carcinoma (i.e. an increase of 5 to 55 cases), depending on the dose and duration of treatment.
The occurrence of intermenstrual bleeding or spotting (light bleeding between periods), especially during the first treatment cycles, should not concern you.
Contact your doctor if intermenstrual bleeding or spotting continues after the first few months of treatment, appears after several months of treatment, or persists after stopping treatment: these symptoms may indicate endometrial thickening.

Breast cancer
If you have or have had breast cancer, you must not take this medicine (see “Do not take Progynova”).
Evidence shows that taking combined oestrogen-progestogen 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 will decrease over time, but may persist for 10 years or more if HRT has been used for more than 5 years.

Comparison:
In women aged 50 to 54 years who do not use HRT, breast cancer will be diagnosed in approximately 13–17 out of 1000 over a 5-year period.
In women aged 50 who start oestrogen-only HRT for 5 years, there will be 16–17 cases per 1000 users (i.e. 0–3 additional cases).
In women aged 50 who start combined oestrogen-progestogen HRT for 5 years, there will be 21 cases per 1000 treated women (i.e. 4–8 additional cases).
In women aged 50 to 59 years who do not use HRT, breast cancer will be diagnosed in an average of 27 out of 1000 over a 10-year period.
In women aged 50 who start oestrogen-only HRT for 10 years, there will be 34 cases per 1000 users (i.e. 7 additional cases).
In women aged 50 who start combined oestrogen-progestogen HRT for 10 years, there will be 48 cases per 1000 users (i.e. 21 additional cases).

Check your breasts regularly. Inform your doctor if you notice any changes such as:

Dimpling of the skin;
Changes in the nipples;
Any lump that you can see or feel.

In addition, 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, a mammogram may not detect all lumps.

Ovarian cancer
Ovarian cancer is rare – much rarer than breast cancer.
The use of oestrogen-only or combined oestrogen-progestogen therapy has been associated with a slight increase in the risk of ovarian cancer. The risk of ovarian cancer varies with age. For example, in women aged 50 to 54 years who do not use HRT, about 2 out of 2000 will be diagnosed with ovarian cancer within 5 years. For women using HRT for 5 years, there will be about 3 cases per 2000 treated women (i.e. about 1 additional case).

Liver tumours
Rarely, benign liver tumours and even more rarely malignant liver tumours have been observed after using hormonal substances such as those contained in Progynova. In isolated cases, these tumours may lead to intra-abdominal bleeding, which can be life-threatening. Although these events are extremely unlikely, you should inform your doctor if you experience any unusual abdominal pain that does not go away quickly.

Effects of HRT on the heart and circulation

Blood clots in a vein (thrombosis)
HRT can increase the risk of venous blood clots by 1.3 to 3 times compared to non-users, especially during the first year of use.
Blood clots can be dangerous; if they reach the lungs, they can cause chest pain, sudden breathlessness, collapse, or even death.
The risk of developing a venous blood clot increases with age and if any of the following conditions apply to you. Inform your doctor if any of the following apply to you:

You are unable to walk for a prolonged period due to major surgery, accident or illness (see also section 3, “If you are undergoing surgery”)
You are severely overweight (BMI > 30 kg/m²)
You have a blood clotting disorder requiring long-term treatment with a medicine that prevents blood clots
A close relative has had a blood clot in the leg, lung or another organ
You have Systemic Lupus Erythematosus (SLE)
You have cancer

For possible signs of a blood clot, see “Stop taking Progynova and contact your doctor immediately”.

Comparison:
For women around 50 years of age who are not taking HRT, on average, 4–7 out of 1000 are expected to develop a venous blood clot over a 5-year period.
For women around 50 years of age taking combined oestrogen-progestogen HRT for more than 5 years, there will be 9–12 cases per 1000 users (i.e. an increase of 5 cases).
For women around 50 years of age whose uterus has been removed and who are taking oestrogen-only HRT for more than 5 years, there will be 5–8 cases per 1000 (i.e. an increase of 1 case).

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 use HRT.
For women whose uterus has been removed and who are taking oestrogen-only HRT, there is no increased risk of developing heart disease.

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 1000 have a chance of having a stroke over a 5-year period. For women around 50 years of age taking combined oestrogen-progestogen HRT for more than 5 years, there will be 11 cases per 1000 users (i.e. an increase of 3 cases).

Other conditions

HRT does not prevent memory loss. The risk of memory loss may be higher in women who start using HRT after age 65. Consult your doctor.
If you are prone to developing facial pigmentation (chloasma), you should minimise exposure to sunlight or ultraviolet radiation during treatment with Progynova.
Some women may be particularly prone to developing gallstones during oestrogen therapy.
Abnormal uterine bleeding may occur.

Other medicines and Progynova
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 Progynova. This may cause irregular bleeding. These include:

Medicines for epilepsy (e.g. barbiturates, phenytoin, primidone, carbamazepine and probably oxcarbazepine, topiramate and felbamate);
Medicines for tuberculosis (e.g. rifampicin, rifabutin);
Medicines for HIV and hepatitis C virus infections (protease inhibitors and non-nucleoside reverse transcriptase inhibitors such as nevirapine, efavirenz, ritonavir and nelfinavir);
Herbal preparations containing St John’s wort (Hypericum perforatum);
Medicines for fungal infections (such as griseofulvin, fluconazole, itraconazole, ketoconazole and voriconazole);
Medicines for bacterial infections (such as clarithromycin, erythromycin, penicillins and tetracyclines);
Medicines for certain heart conditions, high blood pressure (such as verapamil and diltiazem);
Grapefruit juice.

HRT may interfere with the effects of other medicines:

The antiepileptic medicine lamotrigine, as it may increase the frequency of seizures;
Medicines against hepatitis C virus (HCV) (such as 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 (increase in liver enzyme ALT) in women using COCs containing ethinylestradiol. Progynova contains estradiol instead of ethinylestradiol. It is not known whether an increase in liver ALT enzyme may occur when Progynova is used with this HCV combination regimen.

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 Progynova, as this medicine may affect the results of certain tests.

Pregnancy and breastfeeding
Progynova 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 Progynova”). If you become pregnant, stop taking Progynova and contact your doctor.
Progynova is contraindicated during breastfeeding.

Driving and using machines
No effects on the ability to drive or use machines have been observed in users of Progynova.

Progynova 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 Progynova

Take this medicine exactly as directed by your doctor or pharmacist. If you have any doubts, consult your doctor or pharmacist.
Each pack covers 20 days of treatment. Take one Progynova tablet daily.
If you still have menstrual periods, start taking Progynova within the 5th day of menstruation.
In all other cases, your doctor may advise you to start treatment immediately.
If you still have a uterus (if you have not had a hysterectomy), your doctor will prescribe another hormone (a progestin) and will instruct you on how to take it. Your doctor will also advise you whether you should take the tablets continuously (without interruption) or with a break.
It does not matter at what time of day you take the tablet, but once you have chosen a specific time, you should try to take the tablets at the same time every day. The tablet can be swallowed with a small amount of liquid.
Follow the instructions for use carefully; otherwise, you may not receive the full benefit of treatment with

Progynova.

Your doctor will prescribe the lowest effective dose to treat your symptoms for the shortest necessary duration.
Consult your doctor if you think the dose is too strong or not strong enough.

Use in children and adolescents
Progynova 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.

Use in patients with hepatic impairment (liver function)
No formal studies have been conducted in patients with hepatic impairment. Progynova is contraindicated in women with severe liver disease (see "Do not take Progynova").

Use in patients with renal impairment (kidney function)
No formal studies have been conducted in patients with renal impairment.

If you need surgery
If you are about to undergo surgery, inform your surgeon that you are taking Progynova. It may be necessary to stop taking it approximately 4–6 weeks before the operation to reduce the risk of blood clots (see "Blood clots in a vein"). Ask your doctor when you can restart taking Progynova.

If you take more Progynova 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 Progynova
If you have forgotten to take a tablet, take it as soon as possible.
Take the next tablet at your usual time. Do not take a double dose to make up for the forgotten tablet.
If more than 24 hours have passed, do not take any additional tablets.
Do not take a double dose to make up for the forgotten tablet.
Missing one or more tablets may increase the likelihood of breakthrough bleeding and spotting.

If you stop taking Progynova
If you discontinue treatment with Progynova, menopausal symptoms due to estrogen deficiency may return.

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 everyone gets them.
The following conditions are more frequently reported in women using systemic oestrogen-containing medicines (systemic oestrogen therapy) compared to women not using such therapy:

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 thromboembolism);
heart disease;
stroke;
possible memory loss if oestrogen therapy is started after the age of 65.

For further information about these side effects, see section 2.
The following side effects have been observed with the use of Progynova. These effects usually disappear after the first few months of treatment and are listed below by frequency:

Common side effects (may affect up to 1 in 100 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 1,000 users):

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

Rare side effects (may affect up to 1 in 10,000 users):

anxiety,
increased/decreased libido (sexual desire),
migraine (pain localized to one side of the head),
intolerance to contact lenses,
flatulence (intestinal gas),
vomiting,
hirsutism (excessive hair growth),
acne,
muscle cramps,
dysmenorrhoea (painful menstruation),
vaginal discharge,
symptoms resembling 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 systemic oestrogen therapies:

gallbladder disease,
a range of skin disorders:
- skin pigmentation changes, 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 haemorrhages of the skin and mucous membranes).

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist. You can also report side effects directly via the national reporting system at http://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 Progynova

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.
This medicine does not require any special storage conditions.
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 Progynova contains

The active substance is estradiol valerate. Each tablet contains 2.0 mg of estradiol valerate.
The other ingredients are: lactose monohydrate, maize starch, povidone 25, talc, magnesium stearate, sucrose, povidone 90, macrogol 6000, calcium carbonate, wax E.

Description of the appearance of Progynova and contents of the pack
Progynova is a white coated tablet, available in packs of 20 tablets.
Marketing Authorization Holder
Bayer S.p.A. - Viale Certosa, 130 - 20156 Milan, Italy
Manufacturer
Bayer Weimar GmbH und Co. KG, Döbereinerstraße 20, 99427 Weimar, Germany

ProgyNova