Systen 50

Package leaflet: Information for the user

SYSTEN 50
3.2 mg, transdermal system, patch
Estradiol
Please read all of 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 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 them, even if their symptoms are the same as yours.
• If you experience any side effects, including any not listed in this leaflet, please tell your doctor or pharmacist. See section 4.

Leaflet contents:

1. What Systen 50 is and what it is used for
2. Important information before using Systen 50
3. How to use Systen 50
4. Possible side effects
5. How to store Systen 50
6. Contents of the pack and other information

1. What Systen 50 is and what it is used for

Systen 50 is a medicine used in hormone replacement therapy (HRT). It contains estradiol (a female hormone belonging to the group of estrogens) and is a transdermal system in the form of a patch applied to the skin.
The estradiol contained in Systen 50 is identical to the hormone naturally produced by the ovaries in women before the menopause.
Systen 50 is used to:
Relieve menopausal symptoms
During menopause, the amount of estrogen produced by a woman's body decreases, which may cause symptoms such as hot flushes (sensation of heat in the face, neck and chest), sleep disturbances, irritability and depression. Systen 50 relieves these menopausal symptoms.
Systen 50 may be prescribed only if 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, Systen 50 may be used to prevent postmenopausal osteoporosis.
Experience in treating women over 65 years of age is limited.

2. Important information before using Systen 50

Medical history and regular medical check-ups
HRT carries risks that should be considered when deciding whether to start or continue hormone replacement therapy.
Experience in treating women with premature menopause (due to ovarian failure or surgical removal of the ovaries) is limited. If you are experiencing premature menopause, the risks associated with HRT may differ. Please discuss this with your doctor.
Before starting (or resuming) HRT, your doctor should take a full medical and family history. Your doctor may decide to perform examinations, including breast and/or gynaecological examinations, if necessary.
If you start using Systen 50, you should have regular medical check-ups (at least once a year). During these visits, you should discuss with your doctor the benefits and risks of continuing Systen 50.
You should have regular breast examinations as recommended by your doctor.

When not to use Systen 50
If you have any of the conditions listed below, or are unsure, please tell your doctor before using Systen 50.
Do not start using Systen 50:

• if you are allergic to estradiol or any of the other ingredients of this medicine (listed in section 6);
• if you have or have had breast cancer or there is suspicion of it;
• if you have or are suspected of having an estrogen-dependent tumour (e.g. cancer of the endometrium);
• if you have untreated endometrial hyperplasia (excessive growth of the lining of the womb);
• if you have vaginal bleeding of unknown cause;
• if you are pregnant or breastfeeding;
• if you have or have had liver disease and liver function test results have not returned to normal;
• if you have or have had blood clots in the veins (venous thromboembolic disease), e.g. in the deep veins of the legs (deep vein thrombosis), or in the lungs (pulmonary embolism);
• if you have blood clotting disorders (deficiency of protein C, protein S or antithrombin);
• if you have or have had arterial thromboembolic disorders (e.g. stroke, angina pectoris, myocardial infarction);
• if you have the rare inherited blood disorder – porphyria.

If any of the above conditions occur for the first time while using Systen 50, stop using the medicine and consult your doctor immediately.

Warnings and precautions
Before starting treatment, inform your doctor if you have ever had any of the following conditions, as they may recur or worsen during treatment with Systen 50.
In such cases, your doctor may decide that you require more frequent monitoring:

• uterine fibroids;
• endometriosis (presence of endometrial tissue outside the uterus) or previous endometrial hyperplasia (excessive growth of the lining of the womb);
• increased risk of blood clots (see below: “Blood clots in the veins (venous thromboembolic disease)”);
• increased risk of estrogen-dependent tumours, e.g. breast cancer in mother, sister or grandmother;
• high blood pressure;
• liver disease (e.g. liver adenoma);
• diabetes;
• gallstones;
• migraine or (severe) headaches;
• systemic lupus erythematosus (an autoimmune disease affecting multiple organs);
• epilepsy;
• bronchial asthma;
• otosclerosis (an ear disorder leading to progressive hearing loss);
• mastopathy;
• high levels of triglycerides in the blood;
• fluid retention due to impaired heart or kidney function;
• hypothyroidism (a condition in which the thyroid gland does not produce enough thyroid hormones) and you are receiving thyroid hormone replacement therapy;
• hereditary or acquired angioedema (a condition causing recurrent episodes of swelling) or a history of sudden swelling of the hands, face, feet, lips, eyes, tongue, throat (airway obstruction) or gastrointestinal tract.

If any of the following conditions occur while using HRT, stop using Systen 50 and contact your doctor immediately:

• if any of the conditions listed under “When not to use Systen 50” occur;
• if your skin or the whites of your eyes turn yellow (jaundice), which may indicate liver problems;
• a significant increase in blood pressure (symptoms may include headache, fatigue and dizziness);
• if you experience a migraine-type headache for the first time;
• if you become pregnant;
• if you develop swelling of the face, tongue and/or throat and/or difficulty swallowing or hives, combined with breathing difficulties, suggesting angioedema;
• if you experience symptoms of blood clots such as:
  • painful swelling and redness in the legs,
  • sudden chest pain,
  • difficulty breathing. For further information, see section Blood clots in the veins (venous thromboembolic disease).

Note: Systen 50 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 need to use an additional method of contraception. Please discuss this with your doctor.

Hormone replacement therapy and cancer

Endometrial hyperplasia and endometrial cancer
In women with an intact uterus, the risk of endometrial hyperplasia and endometrial cancer increases when estrogens are used alone for prolonged periods. Studies have shown that women using estrogen-only therapy have a 2- to 12-fold increased risk of developing endometrial cancer compared to women not using these medicines, depending on the duration of treatment and estrogen dose (see section 4). The increased risk may persist for at least 10 years after stopping treatment.
Cyclic addition of a progestogen for 12 days per month in a 28-day treatment cycle, or continuous combination of estrogen with a progestogen, in women with an intact uterus, prevents the increased risk associated with estrogen-only HRT.
During the first months of treatment, breakthrough bleeding or spotting may occur. If such symptoms occur after a period of treatment or persist after stopping treatment, inform your doctor, who may perform further investigations.
In women with an intact uterus who cannot tolerate progestogens, unopposed estrogen therapy may be considered, with the recommendation of long-term monitoring and regular endometrial examinations including biopsies, performed annually or more frequently if bleeding or spotting occurs.
Unopposed estrogen stimulation may lead to pre-cancerous or cancerous changes in residual endometriosis foci. Therefore, in women who have had a hysterectomy due to endometriosis, particularly if residual endometriosis foci are known to be present, progestogen should be added to estrogen replacement therapy.
The safety of transdermal systems delivering more than 50 μg per day, when combined with a progestogen, has not been studied.

Unexpected bleeding
While using Systen 50, you will have a monthly withdrawal bleed. If you experience unexpected bleeding or spotting unrelated to the monthly bleed that:

• persists beyond the first 6 months of treatment;
• occurs after using Systen 50 for more than 6 months;
• continues despite stopping Systen 50;
  you should contact your doctor as soon as possible.

Breast cancer
Evidence shows that using hormone replacement therapy (HRT) as a combination of estrogen and progestogen, or estrogen alone, increases the risk of developing breast cancer. The additional risk depends on how long you use 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 used for more than 5 years.

Comparison:
In women aged 50 to 54 years not using 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 estrogen-progestogen 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 years not using 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 estrogen-progestogen 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 of the following changes:

• skin dimpling;
• changes in the nipple;
• any visible or palpable lumps.

Additionally, participation in available mammographic screening programmes is recommended. It is important to inform the nurse or radiology technician performing the mammogram that you are using hormone replacement therapy, as this medicine may increase breast density, which may affect the mammogram result. Not all lumps may be detected during mammography in areas of increased breast density.

Ovarian cancer
Ovarian cancer is less common than breast cancer. Some epidemiological studies have shown an increased risk of ovarian cancer in women after hysterectomy who have used estrogen-only HRT for a long time (at least 5 to 10 years). Some studies, including the WHI study, suggest that long-term use of combined HRT may lead to a similar or slightly lower risk.

Hormone replacement therapy and effects on the heart and circulation

Blood clots in the veins (venous thromboembolic disease)
HRT is associated with an increased risk of venous thromboembolic disease, i.e. deep vein thrombosis or pulmonary embolism.
Studies have shown a 2- to 3-fold increased risk of venous thromboembolic disease in women taking HRT compared to women not using HRT.
This complication is more likely to occur during the first year of HRT use than later.
Blood clots can be life-threatening and, if they travel to the lungs, may cause chest pain, shortness of breath, loss of consciousness, or even death.
The risk of blood clots in the veins is higher if you are older or if any of the following risk factors are present. Please inform your doctor if:

• you are unable to walk for a prolonged period due to severe injury or surgery (see section 3. If surgery is planned);
• you are obese (body mass index - BMI >30 kg/m²);
• you have thromboembolic disorders requiring long-term anticoagulant therapy;
• a close family member has previously had blood clots in the legs, lungs, or other organs;
• you have systemic lupus erythematosus.

If you experience symptoms of blood clots, see If any of the following conditions occur while using HRT, stop using Systen 50 and contact your doctor immediately.
There is no consensus on the possible role of varicose veins in venous thromboembolic disease.
Women already receiving anticoagulant treatment should discuss with their doctor the benefit-risk balance of using HRT.

Hormone replacement therapy and ischaemic heart disease
There is no evidence that HRT prevents myocardial infarction.
In women over 60 years of age using estrogen-progestogen HRT, the risk of ischaemic heart disease is slightly higher than in women not using HRT.
In women who have had a hysterectomy and are using estrogen-only HRT, there is no increased risk of developing ischaemic heart disease.

Hormone replacement therapy and stroke
The risk of stroke is about 1.5 times higher in women using HRT compared to women not using HRT. The number of additional stroke cases due to HRT use will increase with age.

Comparison:
In women aged 50 to 59 years not using HRT, the average number of stroke cases over 5 years is estimated at 8 per 1,000 women. In women aged 50 to 59 years using HRT, the number of cases over 5 years will be 11 per 1,000 women (i.e. 3 additional cases).

Conditions requiring monitoring during estrogen therapy:

• liver disorders or mild liver insufficiency;
• history of cholestatic jaundice;
• HRT does not improve cognitive function. Evidence suggests an increased risk of probable dementia in women starting continuous combined or estrogen-only therapy after the age of 65.

In women with an intact uterus using unopposed estrogen therapy, an increased risk of endometrial hyperplasia and endometrial cancer has been observed. Therefore, to reduce the risk of hyperplasia and endometrial cancer in women with an intact uterus, it is recommended to use estrogen in combination with a progestogen, as in the case of Systen 50.

Systen 50 should be stored out of the reach and sight of children and pets.

Children and adolescents
Systen 50 must not be used in children.

Systen 50 and other medicines
Some medicines may affect the effectiveness of Systen 50, which may lead to irregular bleeding. These include:

• antiepileptic medicines (such as: phenobarbital, phenytoin and carbamazepine),
• anti-tuberculosis medicines (such as: rifampicin, rifabutin),
• medicines used to treat HIV infection (such as: nevirapine, efavirenz, ritonavir and nelfinavir),
• medicines used to treat hepatitis C virus infection (such as: telaprevir),
• herbal products containing St. John's wort (Hypericum perforatum).

Estrogen-containing HRT may affect the action of other medicines:

• the antiepileptic medicine lamotrigine, as it may increase the frequency of seizures.
• medicines used to treat hepatitis C virus (HCV), such as treatment regimens with ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, glecaprevir/pibrentasvir, or sofosbuvir/velpatasvir/voxilaprevir, which may cause increased liver function test parameters in blood (elevated liver enzyme AlAT activity) in women using combined hormonal contraceptives containing ethinylestradiol. Systen 50 contains estradiol instead of ethinylestradiol. It is not known whether elevated AlAT liver enzyme activity may occur when Systen 50 is used concomitantly with such HCV combination treatment regimens.

Please tell your doctor about all medicines you are currently taking or have recently taken, as well as any medicines you plan to take, including over-the-counter medicines, herbal remedies and natural products. Your doctor will provide appropriate advice.

Laboratory tests
If you need to have a blood test, inform your doctor or laboratory staff that you are using Systen 50, as it may affect the results of certain tests, e.g. glucose tolerance test or thyroid function tests.

Pregnancy and breastfeeding
Systen 50 is contraindicated during pregnancy. If you become pregnant while using this medicine, stop it immediately.
Systen 50 must not be used during breastfeeding.

Driving and using machines
No studies on the effect of Systen 50 on the ability to drive and use machines have been conducted.

3. How to use Systen 50

This medicine should always be used as directed by the doctor. If in doubt, consult the doctor.
HRT should only be continued as long as the benefits of relieving severe symptoms outweigh the risks of HRT use.
The doctor should prescribe the lowest effective dose for the shortest possible duration needed to relieve symptoms. If the patient feels that the dose is too high or too low, she should consult her doctor.
Dosage
The doctor will adjust the dose according to the individual woman's response to treatment.
Systen 50 should be used twice a week.
The patches should be changed every 3 or 4 days. The medicine should be used in a three-week cycle followed by a seven-day treatment-free interval. During this time, vaginal bleeding may occur. For example, if the first patch is applied on Monday, it should be replaced on Thursday, and then again the following Monday. The following table may be used to determine application days, based on the first day of patch application:

To help remember the patch change days, mark their configuration in the appropriate designated space on the packaging:

Continuous treatment with Systen 50 may be indicated in women who have had a hysterectomy or in whom severe estrogen deficiency symptoms occur during the treatment-free interval.
Treatment should be initiated with one Systen 50 patch.
The dose of the medicinal product should be adjusted according to the severity of estrogen overdose symptoms (adverse reactions) or lack of therapeutic effect.
For maintenance treatment, the physician will recommend the lowest effective dose.
In women who have had a hysterectomy, a dose exceeding 100 μg of estradiol per day should not be used.
In women with an intact uterus, a dose exceeding 50 μg of estradiol per day should not be used.
In women who have had a hysterectomy, except for those previously diagnosed with endometriosis, adding a progestagen to estrogen replacement therapy is not indicated.
For the treatment of postmenopausal symptoms, the physician will recommend the lowest effective dose.
If the product partially or completely detaches, a new patch should be applied as soon as possible. However, the same patch change day should be maintained.
In all women with an intact uterus, administration of a progestagen is recommended as follows:

• for 12 to 14 consecutive days of the calendar month during continuous use of Systen 50

or

• for the last 12 to 14 days (i.e., starting on day 8 or 10 of the cycle) of a 21-day cycle of Systen 50 treatment.

In both cases, vaginal bleeding usually occurs approximately 12 days after the first progestagen dose.
In patients previously diagnosed with endometrial hyperplasia (including women who have had a hysterectomy), a progestagen should be added periodically during treatment with Systen 50. Bleeding will occur after the addition of a progestagen to the treatment.
In women with an intact uterus undergoing combined HRT, using one patch for longer than 4 days or remaining without a patch applied for any period (missed dose), increases the likelihood of intermenstrual bleeding or spotting.
Use of Systen 50 in patients with renal and/or hepatic impairment
There are insufficient data on dosing in patients with severe hepatic or renal impairment.
Estrogens may cause fluid retention; therefore, patients with cardiac or renal insufficiency should be closely monitored during treatment with Systen 50.
Use of Systen 50 in elderly women
There are insufficient data to support the use of Systen 50 in women over 65 years of age.
Method of administration

The patch should be applied to clean, dry, healthy and intact skin on the trunk below the waist. Creams, body balm or powder may interfere with the adhesive layer of the patch and should not be used at the application site. Systen 50 should not be applied to the skin of the breasts or the area around them. The application site should be rotated. To reapply the patch at the same site, at least one week should elapse.
Systen 50 should be used immediately after opening the sachet.
After opening the sachet containing the patch, remove one part of the protective film.
Then, without folding, apply the exposed part of the patch to the intended site, starting from its edge towards the center.
The patient should remove the second part of the protective film and press the patch firmly onto the skin with the hand, avoiding folding, and press it against the skin for at least 10 seconds, warming it with hand heat to body temperature, which is crucial for optimal adhesion. During application, the patient should not touch the adhesive surface of the patch directly with fingers.
It is not necessary to remove the patch during bathing or showering. However, it is recommended to remove the patch before using a sauna and to immediately apply a new one afterwards. To remove the patch, grasp its edge and gently peel it off the skin. After use, the patch should be folded in half and disposed of in a waste container (do not flush down the toilet). Any adhesive residue remaining on the skin after removal can be washed off with soap and water or gently rubbed off with fingers.

Use of a higher than recommended dose of Systen 50
If a higher than recommended dose of the medicine is used, consult a doctor or pharmacist immediately.
Symptoms of overdose may include: breast pain and tenderness, nausea, intermenstrual bleeding, abdominal
cramps and bloating. These symptoms resolve without specific treatment after removal of the patch.

Missed application of Systen 50
If a patient forgets to change the patch, the missed patch should be applied as soon as possible.
However, the original schedule for changing to a new patch should be maintained. Repeated missed
applications may increase the likelihood of intermenstrual bleeding and spotting.

If surgery is planned
If surgery is planned, the patient should inform the surgeon that she is using Systen 50. It may be necessary
to discontinue Systen 50 4 to 6 weeks before surgery to minimize the risk of blood clots (see section 2.
Venous thromboembolism (venous thromboembolic disease)). Before restarting Systen 50, consult a doctor.

4. Possible adverse reactions

Like all medicines, this medicine can cause adverse reactions, although not everyone experiences them.
In women using HRT, there is an increased risk of developing the following diseases compared to
women not using HRT:

• 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);
• ischaemic heart disease;
• stroke;
• probable dementia if HRT is initiated after the age of 65.

For further information, see section 2, "Important information before using Systen 50".
Below is a list of adverse reactions observed in clinical trials and reported after marketing of the transdermal system, Systen 50 patch.

Very common (may affect more than 1 in 10 users):

• itching at the application site, rash at the application site.

Common (may affect up to 1 in 10 users):

• low mood,
• migraine, dizziness, headache,
• abdominal pain, diarrhoea, nausea,
• itching, rash,
• joint pain,
• breast pain, uterine bleeding,
• pain, erythema at the application site, swelling at the application site, reaction at the application site,
• weight gain.

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

• genital fungal infection (candidiasis),
• hypersensitivity (allergy),
• palpitations,
• flatulence,
• muscle pain,
• breast enlargement, menstrual disorders,
• oedema, generalized oedema, peripheral oedema.

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

• breast cancer,
• epilepsy,
• thrombosis,
• abdominal distension,
• gallstones.

Frequency not known (frequency cannot be estimated from the available data):

• cancer of the uterine lining (endometrium),
• cerebrovascular incident,
• myocardial infarction,
• deep vein thrombosis,
• pulmonary embolism,
• angioedema.

The type, frequency, and severity of adverse reactions in women with an intact uterus treated with Systen 50 in combination with a progestagen may vary depending on the type and dose of the progestagen used concomitantly with Systen 50.

Other adverse reactions associated with oral estrogen-progestagen replacement therapy:

• dizziness;
• indigestion, vomiting;
• limb pain, myasthenia;
• breast tenderness, uterine cramps, vaginal infection;
• uterine fibroids, ovarian cyst;
• increased liver enzyme activity – aminotransferases – in laboratory tests;
• gallbladder disease, jaundice;
• skin and subcutaneous tissue disorders: acne, erythema multiforme, erythema nodosum, purpura, acneiform eruptions, dry skin, alopecia;
• probable dementia in women over 65 years of age;
• dry eye syndrome;
• change in tear composition.

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

5. How to store Systen 50

Store at a temperature not exceeding 25°C.
Keep the medicine out of the sight and reach of children.
This recommendation also applies to used transdermal systems, patches.
Do not use this medicine after the expiry date stated on the packaging.
The expiry date (EXP) refers to the last day of the stated month.
Medicines must not be disposed of via wastewater. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Contents of the pack and other information

What Systen 50 contains
Each transdermal system, Systen 50 patch, contains as the active substance 3.2 mg of estradiol
(Estradiolum), in the form of estradiol hemihydrate.
The other components of the medicine are:

• Adhesive layer
• Absorbent gum
• Polyester film

What Systen 50 looks like and contents of the pack
6 or 8 transdermal systems, patches, individually sealed in foil sachets, packed in a cardboard box.
The Systen 50 transdermal patch with a surface area of 16 cm² contains 3.2 mg of estradiol and releases 50 μg of estradiol over 24 hours.
Marketing Authorisation Holder:
Theramex Ireland Limited
3rd Floor, Kilmore House,
Park Lane, Spencer Dock,
Dublin 1
D01 YE64
Ireland
Manufacturer:
Aesica Pharmaceuticals GmbH
Alfred-Nobel-Str. 10
40789 Monheim am Rhein
Germany

For further information about this medicine, please contact the local representative of the Marketing Authorisation Holder Theramex at the telephone number: 22 307 71 66.