Patient Information Leaflet

Juvinelle, 1 mg + 2 mg, tablets
Estradiol valerate + Dienogest
Please read this leaflet carefully before using the medicine, as it contains important information for you.

Keep this leaflet, as you may need to read it again.
If you have any questions, please consult your doctor or pharmacist.
This medicine has been prescribed for a specific individual. Do not pass it on to others. The medicine may harm someone else, even if their symptoms are the same.
If you experience any adverse effects, including any not listed in this leaflet, tell your doctor or pharmacist. See section 4.

Table of Contents

What Juvinelle is and what it is used for
Important information before taking Juvinelle
How to take Juvinelle
Possible side effects
How to store Juvinelle
Contents of the pack and other information

1 What Juvinelle is and what it is used for
Juvinelle is a medicine used in hormone replacement therapy (HRT).
It contains two types of female hormones, an estrogen and a progestagen. Juvinelle is indicated for use in postmenopausal women who have been at least 12 months since their last natural menstrual period.
Juvinelle is used to relieve postmenopausal symptoms.
During menopause, the amount of estrogen produced by a woman's body decreases. This may lead to symptoms such as hot flushes (a feeling of warmth spreading over the face, neck, and chest). Juvinelle helps relieve these postmenopausal symptoms. Juvinelle is prescribed only when symptoms significantly affect the patient's daily life.

2 Important information before taking Juvinelle
Medical history and regular check-ups
HRT involves certain risks that should be considered when deciding whether to start or continue treatment.
Experience with HRT use in women with premature menopause (due to ovarian failure or surgical procedures) is limited. In women with premature menopause, the risks of HRT may differ. Please consult your doctor.
Before starting (or restarting) HRT, your doctor will take a medical history, including that of your family. Your doctor may perform a physical examination, including breast and (or) pelvic examination, if necessary.
After starting Juvinelle, you should attend regular check-up visits (at least once a year). During these visits, discuss with your doctor the benefits and risks of continuing Juvinelle treatment.
You should undergo regular breast examinations as recommended by your doctor.

When not to take Juvinelle
If any of the following apply to you, or if you are unsure about any of the following, you should consult your doctor before taking Juvinelle.
Do not take Juvinelle:

if you currently have or have had breast cancer, or if breast cancer is suspected,
if you have or have had a malignant estrogen-dependent tumor, such as cancer of the lining of the womb (endometrium), or if such a tumor is suspected,
if you have vaginal bleeding of unknown cause,
if you have untreated endometrial hyperplasia (excessive thickening of the womb lining),
if you currently have or have had venous thromboembolic disease (e.g. deep vein thrombosis in the legs or pulmonary embolism),
if you have blood clotting disorders (such as protein C, protein S or antithrombin deficiency),
if you currently have or have recently had an arterial disease caused by blood clots, such as myocardial infarction, stroke, or angina pectoris,
if you currently have liver disease and liver function tests have not returned to normal,
if you have the rare inherited blood disorder called porphyria,
if you are allergic to estrogens, progestagens, 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 Juvinelle, stop taking the medicine immediately and contact your doctor without delay.

Warnings and precautions
Before starting Juvinelle, discuss this with your doctor or pharmacist.
Inform your doctor if you currently have or have had any of the following conditions, as they may recur or worsen during treatment with Juvinelle. In such cases, more frequent monitoring may be required:

uterine fibroids,
endometriosis (endometrial tissue growing outside the uterus) or previous episodes of endometrial hyperplasia,
increased risk of thromboembolic disorders or personal history of such disorders (see section 2 "Blood clots in veins (thrombosis)"),
increased risk of estrogen-dependent cancer (e.g. if your mother, sister, or grandmother had breast cancer),
high blood pressure,
liver function disorders, e.g. benign liver tumor,
diabetes,
gallstones,
migraine or severe headaches,
autoimmune disease affecting multiple organs (systemic lupus erythematosus, SLE),
epilepsy,
asthma,
otosclerosis (a disease affecting the eardrum and hearing),
very high levels of fats (triglycerides) in the blood,
fluid retention due to heart or kidney problems,
hereditary or acquired angioedema.

Stop taking Juvinelle and contact your doctor immediately
If, while taking HRT, you notice any of the following symptoms:

any of the conditions listed in section 2 "When not to take Juvinelle",
yellowing of the skin or whites of the eyes (jaundice) or liver function disorders,
swelling of the face, tongue, and (or) throat and (or) difficulty swallowing or hives, accompanied by breathing difficulties, suggesting angioedema,
significantly increased blood pressure (possible symptoms include headache, fatigue, dizziness),
new-onset migraine-type headaches,
pregnancy,
signs of blood clot formation, such as:
- painful swelling and redness in the legs
- sudden chest pain
- difficulty breathing. More information is available in section 2 "Blood clots in veins (thrombosis)".

Note: Juvinelle 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 contraceptive measures may be necessary. Please consult your doctor.

HRT and cancer
Endometrial hyperplasia and endometrial cancer
Using estrogen-only HRT increases the risk of endometrial hyperplasia (excessive thickening of the womb lining) and endometrial cancer. The presence of a progestagen in Juvinelle protects against this additional risk.

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

continues beyond the first 6 months,
starts after you have been taking Juvinelle for more than 6 months,
continues after stopping Juvinelle,
you should see your doctor immediately.

Breast cancer
Evidence shows that taking hormone replacement therapy (HRT), either combined estrogen-progestagen or estrogen-only, increases the risk of developing breast cancer. The additional risk depends on how long you take HRT. This additional 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 taken for more than 5 years.

Comparison
In women aged 50 to 54 years who do not take HRT, breast cancer will be diagnosed in an average of 13 to 17 out of 1,000 women over a 5-year period.
In women aged 50 who start a 5-year course of estrogen-only HRT, the number of cases will be 16–17 per 1,000 women (i.e. 0 to 3 additional cases).
In women aged 50 who start a 5-year course of combined estrogen-progestagen HRT, the number of cases will be 21 per 1,000 women (i.e. 4 to 8 additional cases).
In women aged 50 to 59 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.
In women aged 50 who start a 10-year course of estrogen-only HRT, the number of cases will be 34 per 1,000 women (i.e. 7 additional cases).
In women aged 50 who start a 10-year course of combined estrogen-progestagen HRT, the number of cases will be 48 per 1,000 women (i.e. 21 additional cases).

You should examine your breasts regularly. Contact your doctor if you notice any changes such as:

skin indentations,
changes in the nipple,
any visible or palpable lumps.

Additionally, participation in screening mammography is recommended if offered. For screening mammography, it is important to inform the medical staff performing the X-ray that you are taking HRT, as this medicine may increase breast density, which could affect mammography results. Increased breast density may make it harder to detect all lumps.

Ovarian cancer
Ovarian cancer is rare—much rarer than breast cancer. HRT containing either estrogens alone or combined with progestagens is associated with a slightly increased risk of ovarian cancer.
The risk of ovarian cancer depends on age. For example, in women aged 50 to 54 who do not take HRT, ovarian cancer will be diagnosed in about 2 out of 2,000 women over a 5-year period.
In women who have taken HRT for 5 years, it will occur in about 3 out of 2,000 women (i.e. about 1 additional case).

Effects of HRT on the heart and circulation
Blood clots in veins (thrombosis)
The risk of developing venous thromboembolic disease is about 1.3 to 3 times higher in women taking HRT, especially during the first year of treatment, compared to women who do not take HRT.
Blood clots can be dangerous. If a clot travels to the lungs, it may cause chest pain, shortness of breath, fainting, or even death.
The likelihood of venous blood clots increases with age and depending on the presence of the following risk factors. Inform your doctor if any of the following apply:

you are unable to walk for a prolonged period due to major surgery, injury, or illness (see also section 3 "If surgery is required"),
you are obese (body mass index BMI > 30 kg/m²),
you have blood clotting disorders and require long-term anticoagulant therapy,
a close relative has had a blood clot in the leg, lung, or another organ,
you have systemic lupus erythematosus (SLE),
you have cancer.

Information about symptoms of blood clots is provided in section 2 "Stop taking Juvinelle and contact your doctor immediately".

Comparison
In women aged 50 to 59 who do not take HRT, a venous blood clot will occur in an average of 4 to 7 out of 1,000 women over 5 years.
In women aged 50 to 59 who have taken combined estrogen-progestagen HRT for more than 5 years, a venous blood clot will occur in 9 to 12 out of 1,000 women (i.e. 5 additional cases).

Heart disease (myocardial infarction)
There is no scientific evidence that HRT prevents myocardial infarction. Women over 60 who take combined estrogen-progestagen HRT have a slightly higher risk of heart disease than women who do not use HRT.

Stroke
The risk of stroke is about 1.5 times higher in women taking HRT than in those who do not. The number of additional stroke cases due to HRT use increases with age.

Comparison
In women aged 50 to 59 who do not take HRT, a stroke will occur in an average of 8 out of 1,000 women over 5 years. In women aged 50–59 who take HRT, there will be 11 such cases per 1,000 women over 5 years (i.e. 3 additional cases).

Other conditions
HRT does not prevent memory loss. There is evidence of an increased risk of memory loss in women who start HRT after age 65. Please consult your doctor.

Juvinelle and other medicines
Tell your doctor or pharmacist about all medicines you are currently taking, have recently taken, or plan to take.
Some medicines may affect the action of Juvinelle. This may lead to irregular bleeding. These include:

medicines used to treat epilepsy (e.g. phenobarbital, phenytoin, carbamazepine),
medicines used to treat tuberculosis (e.g. rifampicin, rifabutin),
medicines used to treat HIV infection (e.g. nevirapine, efavirenz, ritonavir, nelfinavir),
herbal products containing St. John's wort (Hypericum perforatum).

HRT may affect the action of certain other medicines:

the antiepileptic drug lamotrigine, as it may increase seizure frequency.
Treatment regimens for hepatitis C virus (HCV) infection using ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, glecaprevir/pibrentasvir, or sofosbuvir/velpatasvir/voxilaprevir may cause increased liver function parameters in blood tests (elevated alanine aminotransferase enzyme activity, AlAT) in women taking combined hormonal contraceptives containing ethinylestradiol. Juvinelle contains estradiol valerate instead of ethinylestradiol. It is not known whether elevated AlAT enzyme activity may occur when Juvinelle is taken concurrently with such combination HCV antiviral regimens. Your doctor will provide appropriate advice.

Tell your doctor or pharmacist about all medicines you are currently taking or have recently taken, medicines you plan to take, as well as over-the-counter medicines, herbal products, or other natural remedies.

Laboratory tests
If blood tests are required, inform the laboratory staff that you are taking Juvinelle, as it may affect the results of certain tests.

Pregnancy and breastfeeding
Juvinelle is intended for use only in postmenopausal women. If you become pregnant, stop taking Juvinelle and contact your doctor.

Driving and operating machinery
No effect of Juvinelle on the ability to drive or operate machinery has been observed.

Juvinelle contains lactose
If you have previously been diagnosed with intolerance to certain sugars, you should consult your doctor before taking this medicine.

3 How to take Juvinelle
Always take this medicine exactly as your doctor or pharmacist has told you. If you are unsure, consult your doctor or pharmacist.
Your doctor will prescribe the lowest effective dose needed to treat your symptoms for the shortest possible duration. If you feel the effect of the medicine is too weak or too strong, inform your doctor.

Take one tablet daily, preferably at the same time each day.
Swallow the tablet whole with water.
Juvinelle can be taken with or without food.
Start the next calendar pack the day after finishing the current one.
Do not take breaks between packs.

If you are currently taking another HRT medicine
Continue taking your current medicine until the end of the pack and all tablets for the month have been taken. Take the first Juvinelle tablet the next day. Do not interrupt treatment between your previous medicine and Juvinelle.

If you have previously used HRT with a weekly break
Start the pack the day after the end of the break.

If starting HRT for the first time
You may start taking Juvinelle on any day.

Taking more Juvinelle than recommended
If you take too much Juvinelle, you may experience nausea, vomiting, or vaginal bleeding. No specific treatment is required, but if you are concerned, contact your doctor or pharmacist.

If you forget to take Juvinelle
If you forget to take a tablet and less than 24 hours have passed since it was due, take it as soon as possible. Take the next tablet at your usual time.
If more than 24 hours have passed since the tablet was due, leave the missed tablet in the pack. Take the next tablets at your usual time each day. Do not take a double dose to make up for a missed dose.
Missing tablets for several days may cause bleeding.

Stopping Juvinelle
Menopausal symptoms such as hot flushes, difficulty sleeping, nervousness, dizziness, or vaginal dryness may return. After stopping Juvinelle, bone loss will resume.

If surgery is required
If you are scheduled for surgery, inform your surgeon that you are taking Juvinelle. You may need to stop taking Juvinelle approximately 4–6 weeks before the planned surgery to reduce the risk of blood clots (see section 2 "Blood clots in veins (thrombosis)"). Ask your doctor when you can resume taking Juvinelle.
If you have any further questions about using this medicine, consult your doctor or pharmacist.

4 Possible side effects
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Irregular bleeding may occur during the first months of Juvinelle treatment. This is usually temporary and resolves with continued treatment. If bleeding persists, contact your doctor.
The following conditions occur more frequently in women taking HRT than in those who do not:

breast cancer,
abnormal growth or cancer of the womb lining (endometrial hyperplasia or endometrial cancer),
ovarian cancer,
blood clots in the legs or lungs (venous thromboembolic disorders),
heart disease,
stroke,
risk of memory loss, if HRT is started after age 65.

More information about these side effects is provided in section 2 "Important information before taking Juvinelle".
The following side effects have been reported with Juvinelle:

Common (may affect up to 1 in 10 people)

headache,
nausea,
breast pain, vaginal bleeding, hot flushes.

Uncommon (may affect up to 1 in 100 people)

weight gain,
drowsiness, nervousness, loss of appetite leading to weight loss, aggression, depression,
decreased libido, inability to achieve orgasm,
dizziness, migraine, hyperactivity, tingling sensation,
high blood pressure, venous thrombosis (may present as leg pain) (see also section 2 "Blood clots in veins (thrombosis)"), nosebleeds,
bloating, abdominal pain, constipation, diarrhea, dry mouth, vomiting,
gallbladder pain,
excessive sweating, acne, skin itching, dry skin with red, scaly areas (psoriasis),
muscle pain, leg cramps,
uterine lining disorders, painful menstruation, genital itching,
vaginal candidiasis,
fatigue, generalized fluid retention, facial swelling,
edema.

With other HRT products, the following side effects have been reported:

gallbladder disease,
various skin disorders:
- skin discoloration, especially on the face or neck, known as chloasma (melasma),
- painful red skin nodules (erythema nodosum),
- rash with lesions or redness resembling a target (erythema multiforme).

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

5 How to store Juvinelle
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the outer packaging and blister: “Expiry date” or “EXP”. The expiry date refers to the last day of the stated month.
Do not store above 25°C.
Do not dispose of medicines via the sewage system or household waste. Ask your pharmacist how to dispose of medicines you no longer use. These measures help protect the environment.

6 Contents of the pack and other information
What Juvinelle contains

The active substances are estradiol valerate and dienogest. One tablet contains 1 mg estradiol valerate (equivalent to 0.76 mg estradiol) and 2 mg dienogest.
Other ingredients: monohydrate lactose, maize starch, povidone (K 25), magnesium stearate, anhydrous colloidal silicon dioxide, iron oxide red (E172).

What Juvinelle looks like and contents of the pack
Juvinelle is a pinkish, round tablet with a diameter of 6 mm.
Calendar blister packs containing 28 and 3 x 28 tablets.
Not all pack sizes may be marketed.

Marketing authorization holder and manufacturer
DR. KADE Pharmazeutische Fabrik GmbH
Rigistrasse 2
12277 Berlin
Germany
For further information, contact the representative of the marketing authorization holder:
Kadefarm Sp. z o.o.
Sierosław, ul. Gipsowa 18
62-080 Tarnowo Podgórne, Poland
Tel.: + 48 61 862 99 43
e-mail: [email protected]
Detailed information on this medicine is available on the website www.urpl.gov.pl.