Systen sequi

Patient Information Leaflet

SYSTEN SEQUI:
Systen 50; 3.2 mg, transdermal system, patch
Estradiol
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 Sequi is and what it is used for.

2. Important information before using Systen Sequi.

3. How to use Systen Sequi.

4. Possible side effects.

5. How to store Systen Sequi.

6. Contents of the pack and other information.

1. What Systen Sequi is and what it is used for
Each Systen Sequi pack contains 4 transdermal systems, Systen 50 patches, and 4 transdermal systems, Systen Conti patches.
Systen Sequi 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 group of 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 menopause.
Systen Sequi is used to:
relieve menopausal symptoms
During menopause, the amount of estrogen produced in a woman's body decreases, which may cause symptoms such as hot flushes (sudden feelings of heat in the face, neck and chest), sleep disturbances, irritability and depression. Systen Sequi relieves these menopausal symptoms. Systen Sequi may be recommended for a patient only if the symptoms significantly impair her daily life.
Experience with treatment in women over 65 years of age is limited.

2. Important information before using Systen Sequi

Medical history and regular medical examinations
HRT carries risks which should be considered when deciding whether to start or continue hormone replacement therapy.
Experience in treating women in 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 examinations, including breast examination and/or gynecological examination, if necessary.
If you start using Systen Sequi, you should have regular medical check-ups (at least once a year). During these visits, you and your doctor should consider the benefits and risks of continuing Systen Sequi treatment.
You should have regular breast examinations, as recommended by your doctor.
When not to use Systen Sequi:
If any of the conditions listed below apply to you, or if you are unsure,
tell your doctor before using Systen Sequi.
Do not start using Systen Sequi:

• 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 estrogen-dependent tumour (e.g. cancer of the endometrium);
• if you have untreated excessive growth of the endometrium (endometrial hyperplasia);
• 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. deep vein thrombosis in the legs, 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, hereditary blood disorder porphyria.

If any of the above conditions occurs for the first time during treatment with Systen Sequi, you must stop using the medicine and consult your doctor.
Warnings and precautions
Before starting treatment, inform your doctor if you have previously had any of the following conditions, as they may recur or worsen during treatment with Systen Sequi.
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 endometrium);
• increased risk of blood clots (see below "Blood clots in the veins (venous thromboembolic disease)");
• history of thromboembolic disorders or presence of risk factors for these disorders;
• increased risk of estrogen-dependent tumours, e.g. breast cancer in mother, sister or grandmother;
• hypertension;
• liver disease (e.g. liver adenoma);
• diabetes;
• gallstones;
• migraine or (severe) headaches;
• autoimmune disease affecting multiple organs (systemic lupus erythematosus);
• epilepsy;
• asthma;
• otosclerosis (ear disease 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 condition causing recurrent episodes of swelling (hereditary or acquired angioedema) or 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 during HRT, stop using Systen Sequi and contact your doctor immediately:

• if any of the conditions listed in the section "When not to use Systen Sequi" occur;
• if your skin or the whites of your eyes turn yellow (jaundice), which may be a sign of liver dysfunction;
• 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 swelling of the face, tongue and/or throat and/or difficulty swallowing or hives occur, together with breathing difficulties, suggesting angioedema;
• if symptoms of blood clots occur, such as:
  • painful swelling and redness of the lower limbs,
  • sudden chest pain,
  • difficulty breathing. For further information, see section Blood clots in the veins (venous thromboembolic disease).

Note: Systen Sequi 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 contraception may be necessary. Please discuss this with your doctor.
Hormone replacement therapy and cancer
Excessive growth of the endometrium (endometrial hyperplasia) and cancer of the endometrium
(endometrial cancer)
Using estrogen-only HRT increases the risk of excessive growth of the endometrium (endometrial hyperplasia) and endometrial cancer.
The progestagen in Systen Sequi helps reduce this additional risk.
Comparison
In 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.
In women aged 50 to 65 years with an intact uterus using estrogen-only HRT, depending on the duration of treatment and the dose of estrogen used, 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 treatment with Systen Sequi, irregular bleeding or spotting may occur. However, if irregular bleeding:

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

Breast cancer
Data confirm that taking hormone replacement therapy (HRT) in the form of estrogen-progestagen combination or estrogen-only 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 the risk may persist for 10 years or longer if HRT lasted more than 5 years.
Comparison
In 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 a 5-year period.
In women aged 50 years starting a 5-year 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 years starting a 5-year 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 years not using HRT, breast cancer is diagnosed in an average of 27 out of 1,000 women over a 10-year period.
In women aged 50 years starting a 10-year estrogen-only HRT, the number of cases will be 34 per 1,000 women (i.e. 7 additional cases).
In women aged 50 years starting a 10-year 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 of the following changes:

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

Additionally, participation in offered screening mammography programs is recommended. It is important to inform the nurse or medical staff performing the X-ray examination about your use of hormone replacement therapy, as this medicine may increase breast density, which may affect the mammography 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 estrogen-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 cause 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 hormone replacement therapy compared to women not using it.
This complication is more likely to occur during the first year of HRT than later.
Blood clots can be life-threatening and, if they travel to the lungs, can 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 during HRT, stop using Systen Sequi 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 the benefit-risk balance of HRT with their doctor.
If, after starting treatment, you experience symptoms such as painful swelling of a leg, sudden chest pain or shortness of breath, which may indicate venous thromboembolic disease, stop taking the medicine and contact your doctor immediately.
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-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 it. The number of additional stroke cases caused by 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. There is evidence of 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 administer estrogen in combination with a progestagen, as in the use of Systen Sequi. Systen Sequi should be stored out of the reach and sight of children and pets. Children and adolescents Systen Sequi should not be used in children. Systen Sequi and other medicines

Some medicines may affect the effectiveness of Systen Sequi, 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 treatment regimens with ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir, may cause increased liver function test parameters in blood laboratory tests (increased activity of the liver enzyme AlAT) in women using combined hormonal contraceptives containing ethinylestradiol. Systen Sequi contains estradiol instead of ethinylestradiol. It is

not known whether increased liver enzyme AlAT activity may occur when Systen Sequi 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 medicines you plan to take. Your doctor will provide you with appropriate advice.
Laboratory tests
If blood tests are required, inform your doctor or laboratory staff that you are taking Systen Sequi, as this medicine may affect the results of certain tests, e.g. glucose tolerance test or thyroid function tests.
Pregnancy and breastfeeding
Systen Sequi is contraindicated during pregnancy. If you become pregnant while using this medicine, stop using it immediately.
Systen Sequi is contraindicated during breastfeeding.
Driving and using machines
No studies on the effect of Systen Sequi on the ability to drive and use machines have been conducted.

3. How to use Systen Sequi

This medicine should always be used as directed by the physician. In case of doubts, 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 duration necessary to relieve symptoms. If the patient feels the dose is too high or too low, she should consult her doctor.
Dosage
Systen 50 and Systen Conti patches should be applied to the skin of the lower trunk below the waist in the following
order: first, one Systen 50 patch twice a week, every 3 or 4 days, for two consecutive weeks (during the first 2 weeks, 4 Systen 50 patches will be used), followed by one Systen Conti patch every 3 or 4 days, replacing it at the same intervals (during the next 2 weeks, 4 Systen Conti patches will be used). After 4 weeks, all patches from one package will have been used and a new package should be started.
The cycle of patch changes should be repeated continuously without interruption.
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 can be used to determine the application days, based on the first day of patch application:

To make it easier to remember the days for changing the patch, you should mark their configuration in the appropriate designated place on the packaging:

Failure to follow the described order of using Systen 50 or Systen Conti patches, mistakenly using one patch for longer than 4 days, or leaving the skin without an attached patch for any period (missing a dose), increases the likelihood of irregular bleeding, intermenstrual bleeding, or spotting.
In the treatment of menopausal symptoms, the physician will recommend the lowest effective dose.
If the patch partially or completely detaches before the scheduled change, a new Systen 50 or Systen Conti patch should be applied immediately. However, the same patch change day should be maintained.
Use of Systen Sequi 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 Sequi.
Use of Systen Sequi in elderly women
There are insufficient data to support the use of Systen Sequi in women over the age of 65.
Method of administration

Apply the patch 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 site of application. The Systen patch 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 to the same site, at least one week should elapse.
The Systen patch 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 its edge towards the center.
The patient should remove the second part of the protective liner and press the patch firmly onto the skin with the hand, again avoiding folding, and press with the hand against the skin for at least 10 seconds, warming it with hand heat to body temperature, at which the patch adheres best. 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 immediately apply a new one 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 down the toilet). Any adhesive residue remaining on the skin after patch removal can be washed off with soap and water or rubbed off gently with fingers.

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

Missed application of Systen Sequi
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
doses 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 Sequi. It may be
necessary to discontinue use of Systen Sequi 4 to 6 weeks before surgery to minimize the risk of blood
clot (see section 2. Blood clots in veins (venous thromboembolic disease)). Before resuming use of
Systen Sequi, consult a doctor.

4. Possible adverse effects

Like all medicines, this medicine can cause adverse effects, although not everyone will experience them.
Women using HRT have an increased risk of developing the following diseases compared to women not using HRT:

• breast cancer;
• endometrial hyperplasia or cancer (overgrowth or cancer of the uterine lining);
• 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 Sequi".
Below is a list of all adverse effects observed in clinical trials and reported after the marketing of Systen Sequi.

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

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

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

• depression, insomnia, emotional lability, nervousness;
• migraine, headache;
• hypertension;
• abdominal pain, gastrointestinal disturbances, diarrhoea*, flatulence*, nausea;
• itching, erythematous rash;
• joint pain, back pain, muscle pain*;
• breast pain, painful menstruation, heavy menstrual bleeding, menstrual disorders;
• pain*, swelling, malaise;
• weight gain.

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

• candidiasis;
• breast cancer, fibroadenoma of the breast;
• hypersensitivity (allergy);
• decreased libido, increased libido;
• dizziness, paraesthesia, difficulty concentrating;
• palpitations;
• breast enlargement, endometrial hyperplasia (overgrowth of the uterine lining), uterine bleeding;
• generalized oedema*, fatigue.

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

• cancer of the uterine lining (endometrium);
• mood swings;
• cerebrovascular incident, epilepsy;
• deep vein thrombosis, thrombosis*;
• pulmonary embolism;
• abdominal distension;
• gallstones;
• rash*, Stevens-Johnson syndrome;
• breast enlargement;
• peripheral oedema*, application site oedema*.

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

• dizziness;
• varicose veins;
• dyspepsia, vomiting;
• limb pain, myasthenia;
• breast tenderness, uterine contractions, vaginal infection;
• uterine fibroids, fallopian tube cyst, cervical polyps;
• increased liver enzyme activity – aminotransferases – in laboratory tests;
• gallbladder disease, jaundice;
• skin and subcutaneous tissue disorders: acne, erythema multiforme, nodular erythema, purpura, acne vulgaris, dry skin, alopecia;
• probable dementia in women over 65 years of age;
• dry eye syndrome;
• change in tear composition.

Reporting of adverse effects
If any adverse effects occur, including those not listed in this leaflet, inform your doctor or pharmacist. Adverse effects can be reported directly to the Department of Monitoring Adverse Drug Reactions 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 effects can also be reported directly to the marketing authorization holder.
Reporting adverse effects helps provide more information on the safety of this medicine.

5. How to store Systen Sequi

Store at a temperature not exceeding 25°C.
Keep Systen Sequi out of the sight and reach of children.
This recommendation applies also to used patches.
Do not use Systen Sequi after the expiry date stated on the packaging.
The expiry date (EXP) refers to the last day of the stated month.

6. Contents of the pack and other information

What Systen Sequi contains
Systen Sequi is a transdermal system, a patch composed of:
4 transdermal systems, Systen 50 patches, each containing as the active substance:

• 3.2 mg of estradiol (Estradiolum), in the form of estradiol hemihydrate;

4 transdermal systems, Systen Conti patches, each containing as active substances:

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

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 Sequi looks like and contents of the pack
8 transdermal systems, patches (4 transdermal systems, Systen 50 patches and 4 transdermal systems, Systen Conti patches), sealed in foil sachets and placed in a cardboard box.
The transdermal system, Systen 50 patch, with a surface area of 16 cm², contains 3.2 mg of estradiol and releases 50 μg of estradiol over 24 hours.
The transdermal system, Systen Conti 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, which is released nominally at 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.