Package leaflet: Information for the patient

Warning! Keep this leaflet. The information on the immediate packaging is in a foreign language.
Divigel 0.1% (Delidose)
1.0 mg/1.0 g, gel
Estradiolum
Divigel 0.1% and Delidose are different brand names of the same medicine.
Please read the entire leaflet carefully before using the medicine, as it contains
important information for the patient.

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

Table of contents of the leaflet

What is Divigel 0.1% and what is it used for
Important information before using Divigel 0.1%
How to use Divigel 0.1%
Possible side effects
How to store Divigel 0.1%
Contents of the pack and other information

1. What is Divigel 0.1% and what is it used for

Divigel 0.1% is a medicine intended for use in hormone replacement therapy (HRT).
The medicine contains the female hormone estrogen.
Divigel 0.1% is used to:
Relieve symptoms occurring after menopause.
During menopause, the amount of estrogen produced by a woman's body decreases.
This may result in symptoms such as hot flushes affecting the face, neck, and chest
("hot flushes").
Divigel 0.1% relieves these postmenopausal symptoms. Divigel 0.1% is prescribed only when symptoms significantly impair the patient's daily life.
Prevention of osteoporosis
After menopause, some women develop brittle bones (osteoporosis). If a patient is at increased risk of fractures due to osteoporosis and other medicines are not suitable, Divigel 0.1% may be used to prevent postmenopausal osteoporosis. Please consult your doctor.
Experience in treating women over 65 years of age is limited.

2. Important information before using Divigel 0.1%

Medical history and regular check-ups
Hormone replacement therapy (HRT) carries risks that should be considered when deciding whether to start or continue treatment.
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Cases of HRT use in women with premature menopause (due to ovarian failure or surgical procedures) are rare. In women with premature menopause, the risks associated with HRT may differ.
Please consult your doctor.
Before starting (or restarting) HRT, your doctor will take a detailed medical history, including that of your family. Your doctor may perform a physical examination, including breast and/or pelvic examination, if necessary.
After starting Divigel 0.1%, you should attend regular follow-up visits (at least once a year). During these visits, discuss with your doctor the benefits and risks of continuing Divigel 0.1%.
You should undergo regular breast examinations as recommended by your doctor.

When not to use Divigel 0.1%
If any of the following apply to you, or if you have any doubts about any of the following points, you should consult your doctor before using Divigel 0.1%.
Do not use Divigel 0.1%:

if you are allergic to estradiol or any of the other ingredients of this medicine (listed in section 6),
if you currently have or have had breast cancer or if breast cancer is suspected,
if you have or have had an estrogen-dependent malignant tumor, such as endometrial cancer, or if such a tumor is suspected,
if you have vaginal bleeding of unknown cause,
if you have untreated endometrial hyperplasia (excessive thickening of the lining of the uterus),
if you have or have had venous thromboembolic disease (e.g. deep vein thrombosis in the legs or pulmonary embolism),
if you have blood clotting disorders (such as protein C, protein S or antithrombin deficiency),
if you currently have or recently had an arterial thrombotic disease, such as myocardial infarction, stroke, or angina pectoris,
if you have or have had liver disease and liver function tests have not returned to normal,
if you have the rare hereditary blood disorder called porphyria.

If any of the above conditions develops for the first time while using Divigel 0.1%, you must stop treatment immediately and contact your doctor without delay.

Warnings and precautions
Before starting Divigel 0.1%, discuss this with your doctor or pharmacist.
Inform your doctor if you currently have or have had in the past any of the following conditions, as they may recur or worsen during treatment with Divigel 0.1%. In such cases, more frequent monitoring may be required:

uterine fibroids (benign tumors),
endometriosis (endometrial tissue growing outside the uterus) or previous history of endometrial hyperplasia,
increased risk of venous thromboembolic disorders or personal history of such conditions (see "Blood clots in veins (thrombosis)"),
increased risk of estrogen-dependent cancer (e.g. if your mother, sister, or grandmother had breast cancer),

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high blood pressure,
liver function disorders, such as benign liver tumor,
diabetes, with or without vascular complications,
gallstones,
severe headaches or migraine-type headaches,
autoimmune disease affecting multiple organs (systemic lupus erythematosus, SLE),
epilepsy,
asthma,
a disease affecting the eardrum and hearing (otosclerosis),
very high levels of fats (triglycerides) in your blood,
fluid retention due to heart or kidney dysfunction,
hereditary or acquired angioedema (a condition characterized by swelling, usually of the face, limbs, or joints).

You must stop using Divigel 0.1% and contact your doctor immediately
if, while using HRT, you notice any of the following symptoms:

any of the conditions listed in the section "When not to use Divigel 0.1%",
yellowing of the skin or whites of the eyes (jaundice) or signs of liver dysfunction,
swelling of the face, tongue, and/or throat and/or difficulty swallowing, or hives with breathing difficulties, which may indicate angioedema,
significantly increased blood pressure (possible symptoms: headache, fatigue, dizziness),
recurrence of migraine-type headaches,
pregnancy,
signs of blood clot formation, such as:
painful swelling and redness in the legs,
sudden chest pain,
difficulty breathing. More information is available in the section "Blood clots in veins (thrombosis)".

Note: Divigel 0.1% is not a contraceptive. If less than 12 months have passed since your last menstrual period, or if you are under 50 years of age, additional contraceptive measures may be needed to prevent pregnancy. Please consult your doctor.

HRT and malignant tumors
Endometrial hyperplasia and endometrial cancer
Using estrogen-only HRT increases the risk of endometrial hyperplasia and endometrial cancer. Taking a progestogen for at least 12 days in each 28-day cycle protects against this increased risk. Your doctor will prescribe a separate progestogen if you still have your uterus. If your uterus has been removed (hysterectomy), discuss with your doctor whether it is safe to use this medicine without a progestogen.
In women with an intact uterus who do not use HRT, endometrial cancer is diagnosed in an average of 5 out of 1,000 women aged 50 to 65 over time.
In women aged 50 to 65 with an intact uterus who use estrogen-only HRT, endometrial cancer is diagnosed in 10–60 out of 1,000 women (i.e. 5 to 55 additional cases), depending on dose and duration of treatment.

Vaginal bleeding of unknown cause
While using Divigel 0.1%, you will have a monthly bleed (withdrawal bleeding). However, if you experience vaginal bleeding or spotting (light bleeding) unrelated to withdrawal bleeding that:

lasts longer than the first 6 months,

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occurs after you have been using Divigel 0.1% for more than 6 months,
continues after stopping Divigel 0.1%,
you should see your doctor immediately.

Breast cancer
Evidence confirms that using hormone replacement therapy (HRT), either estrogen-progestogen combination or estrogen-only, increases the risk of breast cancer. The additional risk depends on how long HRT is used. 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 who do not use HRT, breast cancer is diagnosed in an average of 13 to 17 out of 1,000 women over 5 years.
Among 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).
Among 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).
Among women aged 50 to 59 who do not use HRT, breast cancer is diagnosed in an average of 27 out of 1,000 women over 10 years.
Among 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).
Among 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 regularly examine your breasts. Contact your doctor if you notice any changes such as:

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

Additionally, participation in available screening mammography programs is recommended. It is important to inform the medical staff performing the mammogram that you are using HRT, as this medicine may increase radiological breast density, which can affect mammogram results. In areas of increased density, mammography may not detect all nodules.

Ovarian cancer
Ovarian cancer is rare—much rarer than breast cancer. Using HRT, whether estrogen-only or combined estrogen-progestogen, is associated with a slightly increased risk of ovarian cancer. The risk of ovarian cancer increases with age. For example, among women aged 50–54 who do not use HRT, ovarian cancer is diagnosed in 2 out of 2,000 women over 5 years. Among women who have used HRT for 5 years, it occurs in about 3 out of 2,000 women (i.e. about 1 additional case).

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

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

Symptoms of blood clots are described in the section "You must stop using Divigel 0.1% and contact your doctor immediately."

Comparison
Among women aged 50 to 59 who do not use HRT, venous thrombosis occurs in an average of 4–7 out of 1,000 women over 5 years.
Among women aged 50 to 59 who have used combined estrogen-progestogen HRT for over 5 years, venous thrombosis occurs in 9–12 out of 1,000 women (i.e. 5 additional cases).
Among women aged 50 to 59 with a hysterectomy who have used estrogen-only HRT for 5 years, venous thrombosis occurs in 5–8 out of 1,000 women (i.e. 1 additional case).

Coronary heart disease (myocardial infarction)
There is no scientific evidence that HRT prevents myocardial infarction.
Women over 60 years of age using combined estrogen-progestogen HRT have a slightly higher risk of heart disease than women not using HRT.
In women who have had a hysterectomy and use estrogen-only therapy, there is no increased risk of heart disease.

Ischemic stroke
The risk of ischemic stroke is approximately 1.5 times higher in women using HRT than in those who do not. The number of additional stroke cases due to HRT use increases with age.

Comparison
Among women aged 50 to 59 who do not use HRT, ischemic stroke occurs in an average of 8 out of 1,000 women over 5 years. Among women aged 50–59 using HRT, 11 out of 1,000 women will experience a stroke over 5 years (i.e. 3 additional cases).

Other conditions

HRT does not improve cognitive function (memory loss, perception disorders). Evidence suggests an increased risk of dementia in women who start HRT after age 65. Consult your doctor.
Women prone to skin pigmentation (chloasma) should limit exposure to sunlight or ultraviolet radiation while using Divigel 0.1%.

Divigel 0.1% and other medicines
Some medicines may affect the action of Divigel 0.1%, potentially causing irregular bleeding. These include:

medicines used to treat epilepsy (e.g. phenobarbital, phenytoin, carbamazepine),
medicines used to treat tuberculosis (e.g. rifampicin, rifabutin),
medicines used to treat HIV infection and hepatitis C virus (so-called protease inhibitors and non-nucleoside reverse transcriptase inhibitors, e.g. nevirapine, efavirenz, ritonavir, nelfinavir),

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herbal products containing St. John's wort (Hypericum perforatum),
medicines used to treat hepatitis C virus (HCV) (such as the combination regimen of ombitasvir/paritaprevir/ritonavir with or without dasabuvir, or the combination regimen of glecaprevir/pibrentasvir), as they may cause increased liver function test values [increased activity of the liver enzyme alanine aminotransferase (AlAT)] in women using combined hormonal contraceptives containing ethinylestradiol. It is not known whether AlAT enzyme activity may increase when Divigel is used concurrently with these HCV treatment regimens. Your doctor will advise you on this matter.

Inform your doctor or pharmacist about all medicines you are currently taking or have recently taken, including over-the-counter medicines, herbal products, or other natural remedies.

Laboratory tests
If a blood test is required, inform the laboratory staff that you are using Divigel 0.1%, as it may affect the results of certain tests.

Pregnancy and breastfeeding
Divigel 0.1% must not be used during pregnancy or while breastfeeding.
Divigel 0.1% is intended for use only in postmenopausal women. If you become pregnant, stop using Divigel 0.1% and contact your doctor.

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

Divigel 0.1% contains propylene glycol
This medicine contains 62.5 mg to 187.5 mg of propylene glycol in each 0.5–1.5 g dose. It may cause skin irritation.

Divigel 0.1% contains alcohol (ethanol 96%)
This medicine contains 271 mg to 835 mg of alcohol (ethanol) in each 0.5–1.5 g dose. It may cause stinging on damaged skin.

3. How to use Divigel 0.1%

This medicine should always be used as directed by your doctor. If in doubt, consult your doctor.

Divigel 0.1% is a gel for topical application to the skin. Divigel 0.1% may be used either continuously or cyclically. The usual starting dose is 1 mg of estradiol (1 g of gel) per day, although the choice of initial dose may depend on the severity of symptoms experienced by the patient.

Your doctor may adjust the dose after 2 or 3 cycles, ranging from 0.5 g to 1.5 g per day, corresponding to 0.5 mg to 1.5 mg of estradiol per day. Your doctor will prescribe the lowest possible dose needed to treat symptoms, for the shortest possible duration. If the patient feels that the effect of the medicine is too weak or too strong, the doctor should be informed.

In women with an intact uterus, it is necessary to combine treatment with Divigel 0.1% with an appropriate dose of a progestogen for an adequate period, for at least 12–14 consecutive days each month, to prevent estrogen-stimulated endometrial hyperplasia. Withdrawal bleeding (similar to menstrual bleeding) usually occurs after each course of progestogen.

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Method of administration

Apply Divigel 0.1% once daily to the skin of the lower trunk or alternately to the right or left thigh. The application area should be 1 to 2 times the size of the palm of the hand. Divigel 0.1% should not be applied to the breasts, face, irritated skin, or into the vagina. After application, allow the gel to dry for several minutes, and avoid washing the application site for one hour. Avoid contact of the gel with the eyes.

After applying the gel, wash your hands thoroughly with soap and water.
Cover the application site with clothing immediately after the gel has dried.
Take a shower before any anticipated close physical contact with another person.
If another person (e.g. a child or partner) or a pet accidentally comes into contact with the application site, wash the affected skin areas immediately with soap and water.

If these precautions are not followed, estradiol gel may be transferred to others (e.g. a child or partner) or to pets through direct skin contact, which may cause adverse effects. In case of any adverse effects, contact your doctor or veterinarian.

For women not currently using HRT, or women switching from another continuous combined HRT, treatment with Divigel 0.1% may be started on any day. For women switching from sequential HRT, treatment should begin the day after completion of the previous 28-day treatment cycle.

If the effect of Divigel 0.1% seems too strong or too weak, consult your doctor.

If surgery is required

Inform the surgeon that you are using Divigel 0.1%. It may be necessary to stop using Divigel 0.1% for 4 to 6 weeks before surgery to reduce the risk of thrombosis (see section 2 “Venous thromboembolism (VTE)”). Consult your doctor about when it is safe to restart Divigel 0.1%.

Use of more than the recommended dose of Divigel 0.1%

Overdose of estrogens may cause nausea, headache, and vaginal bleeding. Numerous reports of young children accidentally ingesting large doses of oral contraceptives containing estrogens have not indicated serious symptoms of overdose.

Generally, estrogens are well tolerated even at high doses. Acute toxicity studies have not shown a risk of serious adverse effects following accidental ingestion of multiple times the daily therapeutic dose. Some women may experience nausea, vomiting, and withdrawal bleeding. Symptoms of overdose typically include breast tenderness, abdominal or pelvic swelling, restlessness, and irritability. These symptoms usually resolve after discontinuation of treatment or dose reduction.

Overdose following transdermal application is unlikely. There is no specific antidote; symptomatic treatment should be initiated. The gel should be washed off.

Missed dose of Divigel 0.1%

If a patient forgets to apply one dose, the missed dose should be applied as soon as possible, provided the delay is no more than 12 hours. If the dose is delayed by more than 12 hours, the missed dose should be skipped and treatment should continue according to the usual schedule.

Missing a dose may increase the likelihood of irregular vaginal bleeding or spotting.

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Patients should ensure they have an adequate supply of medicine when travelling for an extended period.

Do not use a double dose to make up for a missed dose.

In case of accidental ingestion of the gel

If someone accidentally swallows the gel, there is generally no cause for major concern. However, contact a doctor.

Stopping Divigel 0.1%

If a patient stops treatment with Divigel 0.1%, symptoms of estrogen deficiency will return after some time.

If you have any further questions about the use of this medicine, consult your doctor or pharmacist.

4. Possible adverse effects

Like all medicines, this medicine can cause adverse effects, although not everybody will experience them.
The most commonly occurring adverse effects are usually mild and disappear during treatment.
Bleeding and spotting from the genital tract may occur, especially during the first few months of
treatment.
The following diseases are reported more frequently in women using HRT than in women who do
not use HRT:

breast cancer,
abnormal growth or cancer of the womb lining (endometrial hyperplasia or endometrial cancer),
ovarian cancer,
blood clots in the veins of the legs or lungs (venous thromboembolic disorders),
heart diseases,
stroke,
risk of dementia, if HRT is started at the age of over 65 years. More information on the above adverse effects is provided in section 2.

During the first months of treatment, breakthrough bleeding, spotting and breast tenderness may occur. These symptoms are usually temporary and disappear when treatment continues.
During treatment with Divigel 0.1%, the following adverse effects may occur:
Common (affects less than 1 in 10 people):

weight gain,
weight loss,
headache, dizziness,
nausea, vomiting, stomach cramps, flatulence,
hot flushes, vulvovaginal disorders, menstrual cycle disorders,
skin irritation, itching at the application site, pain, increased sweating,
breast tenderness or pain,
bleeding or spotting, irregular menstruation,
depression, nervousness, lethargy (lack of energy, unresponsiveness to most stimuli),
oedema,
hot flushes.

Uncommon (affects less than 1 in 100 people):
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mood changes, decreased libido, anxiety, insomnia, apathy, emotional lability, difficulty concentrating, euphoria, restlessness,
migraine, numbness, convulsions,
visual disturbances, dry eyes,
hypertension, superficial thrombophlebitis, purpura,
shortness of breath, nasal congestion,
benign breast or endometrial tumour,
increased appetite, high blood cholesterol levels,
palpitations,
constipation, dyspepsia, diarrhoea, anorectal disorders,
acne, alopecia, dry skin, nail disorders, skin nodules, hirsutism, erythema nodosum, urticaria,
joint disorders, muscle cramps,
increased frequency of urination and/or increased need to urinate, urinary incontinence, cystitis, discoloured urine, haematuria,
breast tenderness or oedema, endometrial hyperplasia, uterine disorders,
fatigue, abnormal laboratory test results, malaise, fever, influenza, generalised discomfort,
hypersensitivity.

Rare (affects less than 1 in 1,000 people):

venous thromboembolic disease (e.g. deep vein thrombosis of the legs or pelvis, or pulmonary embolism),
liver function disorders and bile flow disorders,
rash,
intolerance to contact lenses,
painful menstruation, premenstrual syndrome.

Adverse effects reported after marketing of the medicinal product:
Not known (frequency cannot be estimated from the available data):

uterine fibroids,
worsening of hereditary or acquired angioedema,
cerebrovascular disorders (cerebral ischaemic episodes),
abdominal pain, bloating,
liver disorders causing yellowing of the skin (cholestatic jaundice),
contact dermatitis, rash.

Other adverse effects observed during HRT use include:
breast cancer, cancer of the corpus uteri, coronary artery disease, gallbladder disease, myocardial infarction and stroke, skin and subcutaneous tissue disorders: chloasma, erythema multiforme, dementia.
The following adverse effects have been observed with other HRTs:

gallbladder disorders,
various skin disorders:
skin pigmentation, especially on the face or neck, known as “pregnancy mask” (chloasma gravidarum),
painful skin nodules ( Erythema nodosum ),
rash with erythematous ring-shaped lesions or ulceration ( Erythema multiforme ).

Reporting of adverse effects
If you experience any adverse effects, including any not listed in this leaflet, tell your doctor, pharmacist or nurse. Adverse effects can also 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
Reporting adverse effects helps provide more information on the safety of this medicine.
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5. How to store Divigel 0.1%

Keep this medicine out of the sight and reach of children.
Do not store above 25°C.
Do not use this medicine after the expiry date stated on the container. The expiry date refers to the last day of the stated month.
Medicines must not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. This will help protect the environment.

6. Contents of the pack and other information

What Divigel 0.1% contains
One sachet of Divigel 0.1% 1.0 g contains:

The active substance is estradiol in the form of estradiol hemihydrate 1.0 mg.
The other components are: carbomer 974 P, tromethamine, propylene glycol, ethanol 96%, purified water.

What Divigel 0.1% looks like and contents of the pack
1.0 g of gel in a sachet contains a single dose.
The pack contains 28 or 91 aluminium/PE/polyester laminate sachets in a cardboard box.
For further information, please contact the marketing authorisation holder or the parallel importer.
Marketing Authorisation Holder in France, country of export:
Orion Corporation
Orionintie 1
FI-02200 Espoo
Finland
Manufacturer:
Orion Corporation Orion Pharma
Tengströminkatu 8
FI-20360 Turku
Finland
Parallel Importer:
Delfarma Sp. z o.o.
ul. Św. Teresy od Dzieciątka Jezus 111
91-222 Łódź
Repackaged in:
Delfarma Sp. z o.o.
ul. Św. Teresy od Dzieciątka Jezus 111
91-222 Łódź
Marketing authorisation number in France, country of export: 34009 342 399 4 6
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342 399-4
342 400-2
34009 342 400 2 7
Parallel Import Authorisation Number: 253/18
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