Systen conti

Package leaflet: Information for the user

SYSTEN CONTI
3.2 mg + 11.2 mg, transdermal system, patch
Estradiol + Norethisterone acetate
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, 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, tell your doctor or pharmacist. See section 4.

Contents of the leaflet:

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

1. What Systen Conti is and what it is used for
Systen Conti is a medicine used in hormone replacement therapy (HRT). It is a transdermal system in the form of a patch applied to the skin. It contains estradiol, a female hormone belonging to the estrogens, and norethisterone acetate, which is a progestagen. The estradiol contained in the medicine is identical to the hormone naturally produced by the ovaries in women before the menopause.
Systen Conti is used:
to relieve menopausal symptoms
During the menopause, the amount of estrogen produced by a woman's body decreases, which may cause symptoms such as hot flushes in the face, neck and chest, sleep problems, irritability and depression. Systen Conti relieves these menopausal symptoms. Systen Conti may be prescribed to a woman only if her symptoms significantly affect her daily life.
Experience in treating women over 65 years of age is limited.

2. Important information before using Systen Conti

Medical history and regular medical check-ups
HRT carries risks which 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 intervention) is limited. If you are experiencing premature menopause, the risks associated with HRT may differ. Please discuss this with your doctor.
Before starting (or restarting) HRT, your doctor should take a full medical and family history. Your doctor may decide to perform tests, including a breast examination and (or) a gynaecological examination, if necessary.
If you start using Systen Conti, 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 Conti treatment.
You should have regular breast examinations, as recommended by your doctor.

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

• if you are allergic to estradiol, norethisterone acetate, 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 oestrogen-dependent tumour (e.g. endometrial cancer);
• 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 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 develops for the first time while using Systen Conti, stop using the medicine and consult your doctor.

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 Conti.
In such cases, your doctor may decide that you require more frequent monitoring:

• fibroids of the uterus;
• 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 oestrogen-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 blood triglyceride levels;
• fluid retention due to impaired heart or kidney function;
• hypothyroidism (a condition in which the thyroid gland does not produce enough hormones) and you are receiving thyroid hormone replacement therapy;
• hereditary or acquired angioedema (a condition causing recurrent episodes of swelling) or history of sudden swelling of 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 Conti and contact your doctor immediately:

• if any of the conditions listed under “When not to use Systen Conti” occur;
• if your skin or the whites of your eyes turn yellow (jaundice), which may be a sign of liver problems;
• significant increase in blood pressure (symptoms may include: headache, fatigue and dizziness);
• if you experience a migraine-type headache for the first time;
• if pregnancy is diagnosed;
• if you develop swelling of the face, tongue and (or) throat and (or) difficulty swallowing or hives, together 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 Conti 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
Using oestrogen-only HRT increases the risk of endometrial hyperplasia (excessive growth of the lining of the womb) and endometrial cancer.
The progestagen in Systen Conti helps reduce this additional risk.
Comparison
Among women aged 50 to 65 years with an intact uterus who do not use HRT, endometrial cancer is diagnosed in an average of 5 out of 1,000 women.
Among women aged 50 to 65 years with an intact uterus who use oestrogen-only HRT, depending on the duration of treatment and oestrogen dose, endometrial cancer is diagnosed in 10 to 60 out of 1,000 women (i.e. 5 to 55 additional cases).

Irregular bleeding
During the first 3 to 6 months of using Systen Conti, irregular bleeding or spotting may occur. However, if irregular bleeding:

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

Breast cancer
Evidence confirms that using hormone replacement therapy (HRT) containing oestrogen alone or in combination with a progestagen increases the risk of 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
Among women aged 50 to 54 years not using HRT, breast cancer is diagnosed in an average of 13 to 17 out of 1,000 women over 5 years.
Among women aged 50 years starting a 5-year oestrogen-only HRT, the number of cases will be 16–17 per 1,000 women (i.e. 0 to 3 additional cases).
Among women aged 50 years starting a 5-year combined oestrogen-progestagen HRT, the number of cases will be 21 per 1,000 women (i.e. 4 to 8 additional cases).
Among women aged 50 to 59 years not using HRT, breast cancer is diagnosed in an average of 27 out of 1,000 women over 10 years.
Among women aged 50 years starting a 10-year oestrogen-only HRT, the number of cases will be 34 per 1,000 women (i.e. 7 additional cases).
Among women aged 50 years starting a 10-year combined oestrogen-progestagen HRT, the number of cases will be 48 per 1,000 women (i.e. 21 additional cases).
You should regularly examine your breasts. 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 offered screening mammography programmes is recommended. It is important to inform the nurse or medical staff performing the X-ray examination 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. In some epidemiological studies, long-term (at least 5 to 10 years) use of oestrogen-only HRT in women after hysterectomy has been associated with an increased risk of ovarian cancer. 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 venous blood clots is higher if you are older or if any of the following risk factors apply. Inform your doctor if:

• you are unable to walk for a prolonged period due to severe injury or surgical procedures (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 Conti and contact your doctor immediately.
The potential role of varicose veins in venous thromboembolic disease is not clearly established.
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 combined oestrogen-progestagen HRT, the risk of ischaemic heart disease is slightly higher than in women not using HRT.

Hormone replacement therapy and stroke
The risk of stroke is approximately 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
Among 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. Among 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 oestrogen 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 over 65 years of age starting continuous combined or oestrogen-only HRT.

In women with an intact uterus using unopposed oestrogen therapy, an increased risk of endometrial hyperplasia and endometrial cancer has been observed. Therefore, to reduce the risk of endometrial hyperplasia and cancer in women with an intact uterus, oestrogen should be given in combination with a progestagen, as in the case of Systen Conti.

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

Children and adolescents
Systen Conti should not be used in children.

Systen Conti and other medicines
Tell your doctor or pharmacist about all medicines you are currently taking or have recently taken, as well as any you plan to take.
Some medicines may affect the effectiveness of Systen Conti, 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 in HIV infection (such as: nevirapine, efavirenz, ritonavir and nelfinavir),
• medicines used in the treatment of hepatitis C virus (such as: telaprevir),
• herbal products containing St John's wort (Hypericum perforatum).

Hormone replacement therapy may affect the action of other medicines:

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

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

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

Pregnancy and breastfeeding
Systen Conti is contraindicated during pregnancy. If you become pregnant while using this medicine, stop using it immediately.
Systen Conti is contraindicated during breastfeeding.

Driving and operating machinery
No studies have been conducted on the effect of Systen Conti on the ability to drive or operate machinery.

3. How to use Systen Conti

This medicine should always be used as directed by the physician. If in doubt, consult
your doctor.
HRT should only be continued as long as the benefits derived from relieving severe
symptoms outweigh the risks associated with HRT use.
The physician should prescribe the lowest effective dose for the shortest duration necessary
to alleviate symptoms. If the patient feels the dose is too high
or too low, she should consult her doctor.
Dosage
The physician will adjust the dose according to the individual woman's response to treatment.
Systen Conti should be used continuously (without breaks) by applying patches to the skin of the trunk below the waist twice weekly. Patches should be changed every 3 or 4 days. 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 make it easier to remember the days for changing the patch, please mark their configuration in the appropriate space provided for this purpose on the packaging:

In the treatment of menopausal symptoms, the physician will prescribe the lowest effective dose.
If the patch partially or completely detaches before the scheduled change, a new patch should be applied immediately. However, the same patch change day should be maintained.
Wearing an attached patch for longer than 4 days or remaining without an attached patch for any period (omission of a dose) increases the likelihood of irregular bleeding, intermenstrual bleeding, or spotting.

Use of Systen Conti in patients with impaired renal and/or hepatic function
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 Conti.

Use of Systen Conti in elderly women
There are insufficient data to support the use of Systen Conti in women over the age of 65.

Method of administration

The patch should be applied to clean, dry, healthy and intact skin on the trunk below the waist. Creams, body lotions or powders may interfere with the adhesive layer of the patch and should not be used at the application site. Systen Conti should not be applied to the skin of the breasts or in the breast area. The application site should be rotated. To reapply the patch at the same site, at least one week should elapse.
Systen Conti should be used immediately after opening the sachet.
After opening the sachet containing the patch, remove one part of the protective liner.
Then, avoiding folding, apply the exposed part of the patch to the chosen site, starting from the edge toward the center.
The patient should remove the second part of the protective liner and press the patch firmly onto the skin with the hand, avoiding folding, and then press the patch onto the skin with the hand 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 apply a new one immediately after sauna use. 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 the trash (do not flush into the toilet). Any adhesive residue remaining on the skin after patch removal can be washed off with soap and water or rubbed off with fingers.

Use of a higher than recommended dose of Systen Conti
If a higher than recommended dose of the medicinal product is used, consult a doctor or
pharmacist immediately.
Symptoms of overdose during concomitant treatment with estrogen and progestagen may include: nausea,
intermenstrual bleeding, breast pain and tenderness, abdominal cramps and bloating. These symptoms
subside without specific treatment after removal of the transdermal system.

Missed application of Systen Conti
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. Repeatedly missing doses
may increase the likelihood of intermenstrual bleeding and spotting.

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

4. Possible adverse reactions

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

• breast cancer;
• overgrowth or cancer of the lining of the womb (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 started after the age of 65.

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

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

• erythema at application site, itching at application site, rash at application site, reaction at application site.

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

• hypersensitivity;
• depression, insomnia, anxiety, nervousness;
• sensory disturbances – paraesthesia, headache;
• palpitations;
• hypertension, varicose veins, vasodilation;
• abdominal pain, diarrhoea*, nausea;
• erythematous rash;
• joint pain, back pain;
• breast pain, cervical polyp, overgrowth of the lining of the womb (endometrial hyperplasia), vaginal discharge, painful menstruation, heavy menstrual bleeding, menstrual disorders, uterine bleeding;
• pain, swelling, swelling at application site*, fatigue;
• weight gain.

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

• candidiasis;
• decreased libido;
• migraine;
• flatulence*;
• itching, rash*;
• muscle pain*;
• generalized oedema, peripheral oedema*.

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

• epilepsy*;
• thrombosis*.

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

• breast tumour, cancer of the lining of the womb (endometrium);
• mood swings;
• cerebrovascular incident, dizziness;
• deep vein thrombosis;
• pulmonary embolism;
• abdominal distension;
• gallstones;
• Stevens-Johnson syndrome;
• breast enlargement.

* Additional adverse reactions reported in clinical trials of Systen 50 (containing only estradiol).
Other adverse reactions associated with oral estrogen-progestogen replacement therapy:

• dizziness;
• dyspepsia, vomiting;
• limb pain, myasthenia;
• breast tenderness, uterine contractions, vaginal infection;
• uterine fibroids, ovarian cyst;
• increased activity of liver enzymes – aminotransferases – in blood tests;
• gallbladder disease, jaundice;
• skin and subcutaneous tissue disorders: acne, erythema multiforme, nodular erythema, purpura, acne, 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 not listed in this leaflet, inform your doctor or pharmacist. Adverse reactions 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.: +48 22 49 21 301, Fax: +48 22 49 21 309, Website: https://smz.ezdrowie.gov.pl. Adverse reactions can also be reported directly to the marketing authorization holder. Reporting adverse reactions helps provide more information on the safety of this medicine.

5. How to store Systen Conti

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 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 no longer in use.
This will help protect the environment.

6. Contents of the package and other information

What Systen Conti contains
The Systen Conti transdermal system patch contains as active substances:

• 3.2 mg of estradiol (Estradiolum), in the form of estradiol hemihydrate;
• 11.2 mg of norethisterone acetate (Norethisteroni acetas).

The other components of the medicinal product are:

• Adhesive layer: acrylic copolymer, guar gum.
• Protective layer (outer protective layer): polyester.
• Backing layer (to be removed): polyethylene terephthalate.

What Systen Conti looks like and contents of the pack
8 transdermal systems (patches) in sachets, placed in a cardboard box.
The Systen Conti transdermal system patch has a surface area of 16 cm² and contains 3.2 mg of estradiol, corresponding to a nominal release of 50 μg of estradiol over 24 hours, and 11.2 mg of norethisterone acetate, corresponding to a nominal release of 170 μg 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, please contact the local representative of the marketing authorisation holder at telephone number: 22 307 71 66.