Estraderm MX

Patient Information Leaflet

Estraderm MX 25 mcg/day transdermal patch, 50 mcg/day transdermal patch, 100 mcg/day transdermal patch

estradiol
Please read all of this leaflet carefully before you start using this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not give it to others, even if their symptoms are the same as yours, as it may be harmful.
• If you experience any side effects, including those not listed in this leaflet, tell your doctor or pharmacist. See section 4.

Contents of this leaflet:

1. What Estraderm MX is and what it is used for
2. What you need to know before using Estraderm MX
3. How to use Estraderm MX
4. Possible side effects
5. How to store Estraderm MX
6. Contents of the pack and other information

1. What Estraderm MX is and what it is used for

Estraderm MX is a hormone replacement therapy (HRT). It contains the active substance estradiol, which
belongs to the class of estrogens (female sex hormones). Estradiol is naturally
produced by the body, primarily by the ovaries.
The estradiol contained in Estraderm MX is identical to the estradiol produced naturally by the body.
Estraderm MX is used for:
Relief of symptoms occurring after menopause
During menopause, the amount of estrogen produced by a woman's body decreases.
This may cause symptoms such as hot flushes affecting the face, neck, and chest. Estraderm MX relieves
these postmenopausal symptoms. Estraderm MX will be prescribed to you only if your symptoms
are significantly interfering with your daily life.
Menopause occurs naturally in all women, usually between the ages of 45 and 55. It may also occur in younger women who have undergone surgical removal of the ovaries.
Prevention of osteoporosis
After menopause, some women may develop brittle bones (osteoporosis). Please consult your
doctor regarding all available treatment options.
If you are at increased risk of fractures due to osteoporosis and other medications are not suitable for you, you may use Estraderm MX to prevent postmenopausal osteoporosis.

2. What you should know before using Estraderm MX

Medical history and regular check-ups
HRT involves risks that must be considered when deciding whether to start or continue therapy.
Experience in treating women with premature menopause (due to ovarian failure or surgical intervention) is limited. In cases of premature menopause, the risks of using HRT may differ. Inform your doctor in such cases.
Before starting (or restarting) HRT, your doctor will ask about your personal and family medical history. Your doctor may decide to perform an examination, which could include a breast and/or internal pelvic examination, if necessary.
Once you have started taking Estraderm MX, visit your doctor regularly (at least once a year). During these visits, discuss with your doctor the benefits and risks of continuing treatment with Estraderm MX.
Have regular breast examinations as recommended by your doctor.

Do not use Estraderm MX
If any of the following conditions apply to you. If you have any doubts about any of the points listed, consult your doctor before using Estraderm MX.

Do not use Estraderm MX:

• if you have, have had, or your doctor suspects you have breast cancer
• if you have, or your doctor suspects you have a tumour sensitive to oestrogens, for example, cancer of the uterine lining (endometrium)
• if you have had vaginal bleeding of unknown origin
• if you have excessive thickening of the lining of the uterus (endometrial hyperplasia) and are not receiving treatment for it
• if you have or have had a blood clot in a vein (thrombosis), such as in the legs (deep vein thrombosis) or in the lungs (pulmonary embolism)
• if you have a blood clotting disorder (e.g. protein C, protein S or antithrombin deficiency)
• if you have or have recently had a disease caused by blood clots in the arteries, such as heart attack, stroke, or angina pectoris (chest pain)
• if you have severe liver problems
• if you have or have had liver disease and liver function tests have not returned to normal
• if you have a rare inherited blood disorder called "porphyria"
• if you are allergic (hypersensitive) to estradiol or any of the other ingredients of this medicine (listed in section 6)

If any of the following conditions occur for the first time while taking Estraderm MX, stop taking it immediately and contact your doctor without delay.

Warnings and precautions
Tell your doctor if you have ever had any of the following conditions before starting treatment, as they may recur or worsen during treatment with Estraderm MX. If so, you should see your doctor more frequently for check-ups:

• benign uterine tumours (fibroids in the uterus)
• growth of the uterine lining outside the uterus (endometriosis) or history of excessive growth of the uterine lining (endometrial hyperplasia)
• increased risk of developing blood clots (see “Blood clots in a vein (thrombosis)”)
• increased risk of developing oestrogen-sensitive cancers (e.g. if your mother, sister, or grandmother had breast cancer)
• high blood pressure
• liver problems, e.g. benign liver tumour
• diabetes
• gallstones
• migraine or severe headaches
• autoimmune disease affecting multiple organs (systemic lupus erythematosus, SLE)
• epilepsy
• asthma
• disease affecting the eardrum and hearing (otosclerosis)
• very high levels of fats in the blood (triglycerides)
• fluid retention due to heart or kidney problems
• hereditary or acquired angioedema, a hereditary condition characterised by sudden attacks of swelling, which may occur or worsen during treatment
• if you have risk factors for developing a blood clot in a vein, for example: you or a family member has had a blood clot in blood vessels; you are severely overweight (body mass index >30 kg/m²); you have an autoimmune disease called systemic lupus erythematosus (SLE); you have a clotting disorder; you or a family member has had recurrent miscarriages; you need to remain immobile for a long time; you have recently undergone surgery or experienced trauma
• if you are taking medicines to thin the blood (anticoagulants)
• if you have kidney problems, especially end-stage renal failure
• if you have heart problems
• if you have high levels of fats in the blood (hypertriglyceridaemia)
• if you have thyroid problems or are taking thyroid medications

Stop treatment with Estraderm MX and contact your doctor immediately
If you notice any of the following symptoms while taking HRT:

• any of the conditions listed in the section “Do not use Estraderm MX”
• yellowing of the skin or whites of the eyes (jaundice), which may indicate liver disease
• swelling of the face, tongue, and/or throat and/or difficulty swallowing, or hives together with breathing difficulties, suggesting angioedema
• marked increase in blood pressure (symptoms may include headache, fatigue, dizziness)
• new-onset migraine-like headaches
• if you become pregnant
• if you notice signs of a blood clot such as:
  • painful swelling and redness in the legs,
  • sudden chest pain,
  • difficulty breathing. For more information, see section “Blood clots in a vein (thrombosis)”.

Note: Estraderm MX 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 should use an additional contraceptive method to prevent possible pregnancy. Ask your doctor for advice.

HRT and cancer

Excessive thickening of the uterine lining (endometrial hyperplasia) and cancer of the uterine lining (endometrial cancer)
Taking oestrogen-only HRT increases the risk of excessive thickening of the uterine lining (endometrial hyperplasia) and cancer of the uterine lining (endometrial cancer).
Taking a progestogen in addition to oestrogen for at least 12 days of each 28-day cycle protects against this additional risk. Therefore, if you still have your uterus, your doctor will prescribe a progestogen separately. If your uterus has been removed (by hysterectomy), discuss with your doctor whether you can safely take this product without a progestogen.

Among untreated women with a uterus, an average of 5 cases of endometrial cancer per 1000 women aged 50–65 years will be diagnosed.
Among women with a uterus aged 50–65 years who use oestrogen-only HRT, depending on duration of use and dose of oestrogen, between 10 and 60 cases of endometrial cancer per 1000 women (between 5 and 55 additional cases) will be diagnosed.
Estraderm MX 100 micrograms contains a high dose of oestrogen compared to other oestrogen-only products used for HRT. No increased risk of endometrial cancer is known when Estraderm MX 100 micrograms is used in combination with a progestogen.

Unexpected bleeding
During treatment with Estraderm MX, you will have a monthly bleed (so-called "withdrawal bleed"). However, if in addition to monthly bleeding you experience unexpected bleeding or spotting (blood drops) that:

• continues beyond the first 6 months,
• occurs after more than 6 months of starting Estraderm MX,
• continues after stopping Estraderm MX, consult your doctor as soon as possible.

Breast cancer
Evidence shows that taking combined oestrogen-progestogen HRT or oestrogen-only HRT increases the risk of breast cancer. The additional risk depends on the duration of HRT use and becomes apparent within 3 years of use.
After stopping HRT, the additional risk decreases over time, but may persist for 10 years or more if HRT has been used for more than 5 years.

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

Regularly check your breasts. See your doctor if you notice any changes such as:

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

Additionally, it is recommended to participate in mammographic screening programmes when offered. For mammographic screening, it is important that you inform the nurse or healthcare professional performing the X-ray that you are taking HRT, as this medicine may increase breast density, which can affect the mammogram result.
When breast density is increased, a mammogram may not detect all lumps.

Ovarian cancer
Ovarian cancer is rare – much rarer than breast cancer. The use of oestrogen-only or combined oestrogen-progestogen therapy has been associated with a slight increase in the risk of ovarian cancer.
The risk of ovarian cancer varies with age. For example, among women aged 50–54 years not using HRT, about 2 women in 2,000 will be diagnosed with ovarian cancer over 5 years. For women using HRT for 5 years, there will be about 3 cases per 2,000 women treated (i.e. about 1 additional case).

Effects of HRT on the heart and circulation

Blood clots in a vein (thrombosis)
The risk of blood clots in veins is 1.3 to 3 times higher in HRT users than in non-users, especially during the first year of use.
Blood clots can be dangerous; if one travels to the lungs, it can cause chest pain, sudden shortness of breath, fainting, or even death.
The risk of developing a blood clot in a vein increases with age and if any of the following conditions apply to you. Inform your doctor if any of the following apply:

• you are unable to walk for long periods due to major surgery, accident, or illness (see also “If you are undergoing surgery”),
• you are severely overweight (BMI >30 kg/m²),
• you have a blood clotting disorder requiring long-term treatment with a medicine to prevent blood clots,
• a close relative has had a blood clot in the leg, lung, or another organ,
• you have systemic lupus erythematosus (SLE),
• you have cancer. For signs of a blood clot, see “Stop treatment with Estraderm MX and contact your doctor immediately”.

Comparison
For women around 50 years of age not taking HRT, an average of 4–7 cases per 1000 are expected to develop a blood clot in a vein over 5 years.
For women around 50 years of age taking combined oestrogen-progestogen HRT for more than 5 years, there will be 9–12 cases per 1000 users (i.e. an increase of 5 cases).
For women around 50 years of age who have had a hysterectomy and are taking oestrogen-only HRT for more than 5 years, there will be 5–8 cases per 1000 (i.e. an increase of 1 case).

Heart disease (heart attack)
There is no evidence that HRT can prevent heart attacks.
Women over 60 years of age using HRT containing oestrogen and progestogen have a slightly higher risk of developing heart disease compared to those not using HRT.
Women who have had a hysterectomy and are using oestrogen-only HRT are not at increased risk of heart disease.

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
Among women over 50 years of age not taking HRT, an average of 8 per 1000 may have a stroke over 5 years. Among women aged 50 taking HRT, there will be 11 cases per 1000 over 5 years (i.e. 3 additional cases).

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

Children and adolescents
Estraderm MX must not be used in children.

Other medicines and Estraderm MX
Some medicines may interfere with the effects of Estraderm MX, which may cause irregular bleeding. This may occur with the following medicines:

• sedatives (medicines that relax),
• medicines for epilepsy (such as phenobarbital, phenytoin, and carbamazepine),
• medicines for tuberculosis (such as rifampicin, rifabutin),
• medicines for HIV infections (such as nevirapine, efavirenz, ritonavir, and nelfinavir),
• medicine for fungal infections (ketoconazole),
• antibiotic used to treat bacterial infections (erythromycin),
• herbal preparations such as St John’s wort (Hypericum perforatum),
• medicines for hepatitis C virus (HCV) (such as the combination regimen of ombitasvir/paritaprevir/ritonavir with or without dasabuvir, and the regimen of glecaprevir/pibrentasvir) may cause elevations in liver function blood tests (increase in liver enzyme ALT) in women using combined hormonal contraceptives containing ethinylestradiol. Estraderm MX contains estradiol, not ethinylestradiol. Therefore, it is not known whether an increase in liver enzyme ALT may occur when taking Estraderm MX with this HCV combination regimen. Your doctor will advise you.

Inform your doctor or pharmacist if you are taking or have recently taken any other medicines, including those without a prescription, herbal products, or other natural remedies.

Laboratory tests
If you are due to have a blood test, inform your doctor or laboratory staff that you are taking Estraderm MX, as this medicine may alter the results of certain tests.

Pregnancy and breastfeeding
Estraderm MX is intended for use only in postmenopausal women. If you become pregnant, stop taking Estraderm MX and contact your doctor.
If you are pregnant, suspect you may be pregnant, plan to become pregnant, or are breastfeeding, consult your doctor or pharmacist before using this medicine.

Driving and using machines
Estraderm MX does not affect the ability to drive or use machinery.

3. How to use Estraderm MX

Use this medicine exactly as instructed by your doctor or pharmacist. If
you have any doubts, consult your doctor.
Your doctor will generally prescribe the lowest effective dose needed to treat your symptoms, for
the shortest possible duration. Consult your doctor if you think the dose is too strong or too weak.
You should apply the Estraderm MX patch twice a week, meaning you should change it every 3–4 days,
to ensure a continuous hormonal supply to your body.
For example, if you start treatment on a Monday or Thursday, you should always change the patch on
Thursday or Monday, respectively.
The package contains a set of adhesive labels indicating the days of the week, which will serve as a reminder.
Choose the label showing on the left the day you applied the first patch. Stick this label inside the package opening,
in the indicated spot, and discard the other labels.
Your doctor will advise whether you should use Estraderm MX continuously—applying the patch twice a week without interruption—or in a cyclic regimen, applying the patches twice a week for 21 days followed by a 7-day treatment-free interval.
Your doctor may also prescribe an additional treatment with a progestogen, a female hormone.

Use in patients with liver impairment
Estraderm MX must not be used in patients with severe liver problems (e.g. severe hepatic insufficiency).
Estraderm MX must not be used in patients who currently have or have had acute liver disease. Your doctor will not prescribe Estraderm MX until liver function has returned to normal.

How to apply the Estraderm MX patch
The package contains 8 sealed pouches, each containing a transdermal patch.

• Remove one pouch

• Open the pouch by tearing it at the marked notch; do not use scissors, to avoid damaging the patch

• Remove the patch

• Peel off first the smaller, then the larger part of the transparent protective film; handle the adhesive surface as little as possible

• Immediately apply the patch:
  o onto a clean, dry, and non-oily or cream-covered area of skin
  o never apply the patch immediately after a hot bath or shower; wait until the skin is completely cool and dry
  o onto an area of skin without redness, lesions, or irritation
  o on a body area where only small skin folds form during movement (e.g. buttocks, hips, or abdomen), and not exposed to direct sunlight (e.g. areas normally covered by clothing)
  o Do not apply the patch on the breast or near the breast area

• Press firmly over the entire surface of the patch for about 10–20 seconds

• Run your finger along the edges to ensure good adhesion. Do not test adhesion by trying to peel off the patch

• Do not apply the patch consecutively on the same skin area

Each time you change the patch, apply it to a different skin area. After one week has passed since application on a specific body site, you may reapply the patch to that same site.
If applied correctly, the patch will adhere to the skin without problems for up to 4 days. You may bathe, shower, swim, or engage in sports activities without concern.
However, if the patch becomes detached, replace it with a new one. Then continue with the regular schedule of patch application according to your previously established dates.
If you need to be exposed to sunlight, including sunbeds, ensure the patch is covered by clothing or swimwear.

If you use more Estraderm MX than you should
In case of accidental overdose of Estraderm MX, contact your doctor immediately or go to the nearest hospital.
It is unlikely to experience an overdose of estradiol when administered transdermally (via patch). However, if this should occur, the situation can be quickly resolved by removing the patch.
Symptoms of estradiol overdose may include breast tenderness, unexpected vaginal bleeding, fluid retention, and/or abdominal swelling.

If you forget to use Estraderm MX
If you forget to replace the patch on the scheduled day, do not panic—replace it as soon as possible.
Then resume your previously planned schedule.
If you forget to apply the patch one or more times, there may be an increased chance of symptom recurrence or unexpected vaginal bleeding.
Do not use a double dose to make up for a missed dose.

If you stop using Estraderm MX
Do not stop treatment with Estraderm MX without first consulting your doctor, unless you develop serious side effects.
The patch may become accidentally detached. If you applied it correctly, it should adhere to the skin without problems for 4 days. However, if you notice the patch has come off, replace it with a new one. Then continue with the regular application of a new patch according to your previously established schedule.

If you need to undergo surgery
If you are scheduled for surgery, inform your surgeon that you are using Estraderm MX.
You may need to stop taking Estraderm MX approximately 4–6 weeks before surgery to reduce the risk of blood clots (see section 2 “Blood clots in a vein (thrombosis)”). Ask your doctor when you can restart using Estraderm MX.
If you have any questions about the use of this medicine, consult your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone experiences them.
The following effects are reported more frequently in women using HRT compared to those who do not use it:

• breast cancer
• abnormal growth 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 thromboembolism)
• heart disease
• stroke
• possible memory loss if HRT is started after the age of 65
  For further information on these side effects, see section 2.

Very common side effects (may affect more than 1 in 10 people)

• breast disorders
• irregular vaginal bleeding
• reactions at the site where the patch is applied: such as bleeding, bruising, burning, discomfort, dryness, or skin reactions, e.g. eczema, erythema, oedema, inflammation, irritation, papules, rash, skin discolouration, skin spots, urticaria, blisters, itching, swelling, pain, or tingling.

Common side effects (may affect up to 1 in 10 people)

• headache
• nausea
• abdominal pain, abdominal distension

Uncommon side effects (may affect up to 1 in 100 people)

• breast tumour

Rare side effects (may affect up to 1 in 1,000 people)

• dizziness
• limb pain (hands, legs, ankles and feet)
• oedema, weight gain or weight loss

Very rare side effects (may affect up to 1 in 10,000 people)

• severe allergic reactions, even after the first use
• blockage of a blood vessel
• high blood pressure
• development or worsening of varicose veins
• changes in liver function tests
• yellowing of the skin, mucous membranes and eyes due to bile stasis (jaundice)
• skin reactions such as contact dermatitis, skin pigmentation changes, widespread itching, widespread rash

Side effects with unknown frequency (frequency cannot be estimated from the available data)

• severe allergic reactions (anaphylaxis) and angioedema (for a list of symptoms, see the section “Contact your doctor immediately if while being treated with Estraderm MX”)
• depression
• nervousness, emotional instability
• changes in sexual desire
• migraine
• gallstones (cholelithiasis)
• vomiting
• diarrhoea
• gallbladder problems
• hair loss
• dark brown skin patches with defined borders, usually on the face, forehead and temples (chloasma)
• urticaria
• back pain
• thickening of the womb lining (endometrial hyperplasia)
• benign tumour of the womb (leiomyoma)
• chest pain
• breast tenderness
• painful menstruation
• fibrocystic breast disease
• breast enlargement
• nipple discharge

The following side effects have been reported with other HRTs:

• oestrogen-dependent benign and malignant tumours, e.g. endometrial carcinoma
• formation of a blood clot in a vein of the leg and pelvic area (deep vein thrombosis) and in the lungs (pulmonary embolism)
• stroke
• myocardial infarction
• gallbladder diseases
• various skin disorders:
  • skin pigmentation changes, especially on the face or neck, known as "pregnancy mask" (chloasma)
  • painful red nodules (erythema nodosum)
  • target-like rash or lesions (erythema multiforme)
• dry eyes, changes in the tear film
• dementia

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist.
You can also report side effects directly via the national reporting system at the following website:
https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Estraderm MX

Do not store above 25 °C. Do not expose the patches to direct sunlight.
Keep this medicine out of the sight and reach of children.
Estraderm MX patches must be stored in their original packaging inside the pouches.
Do not use this medicine after the expiry date stated on the packaging after “Expiry”.
The expiry date refers to the last day of that month.
Used patches should be folded with the adhesive side inwards and disposed of in designated
containers.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. This will help protect the environment.

6. Package contents and other information

What Estraderm MX contains

Estraderm MX 25 mcg/day transdermal patch

• The active substance is estradiol. Each transdermal patch contains 0.75 mg of estradiol hemihydrate and releases 25 mcg of estradiol over 24 hours.
• The other components are acrylic-methacrylic acid copolymer, isopropyl palmitate, polyethylene terephthalate, ethylene-vinyl acetate. The protective liner, which is removed before application of the transdermal patch, is siliconized on the inner side.

Estraderm MX 50 mcg/day transdermal patch

• The active substance is estradiol. Each transdermal patch contains 1.5 mg of estradiol hemihydrate and releases 50 mcg of estradiol over 24 hours.
• The other components are acrylic-methacrylic acid copolymer, isopropyl palmitate, polyethylene terephthalate, ethylene-vinyl acetate. The protective liner, which is removed before application of the transdermal patch, is siliconized on the inner side.

Estraderm MX 100 mcg/day transdermal patch

• The active substance is estradiol. Each transdermal patch contains 3 mg of estradiol hemihydrate and releases 100 mcg of estradiol over 24 hours.
• The other components are acrylic-methacrylic acid copolymer, isopropyl palmitate, polyethylene terephthalate, ethylene-vinyl acetate. The protective liner, which is removed before application of the transdermal patch, is siliconized on the inner side.

Description of the appearance of Estraderm MX and contents of the pack
Each pack of Estraderm MX 25 mcg/day transdermal patch contains 8 sealed pouches,
each containing one transdermal patch.
Each pack of Estraderm MX 50 mcg/day transdermal patch contains 8 sealed pouches,
each containing one transdermal patch.
Each pack of Estraderm MX 100 mcg/day transdermal patch contains 8 sealed pouches,
each containing one transdermal patch.

Marketing Authorization Holder and Manufacturer
Merus Labs Luxco II S.à.R.L.
26-28, rue Edward Steichen
L-2540 Luxembourg

Manufacturer
Norgine B.V.,
Antonio Vivaldistraat 150,
1083 HP Amsterdam,
The Netherlands