Divigel 0,1%

Leaflet accompanying the packaging: patient information

Warning! The leaflet should be kept. Information on the immediate packaging in a foreign language.

Divigel 0.1% (Delidose)

1.0 mg/1.0 g, gel

Estradiol
Divigel 0.1% and Delidose are different trade names for the same medicine.

Read the leaflet carefully before using the medicine, as it contains important information for the patient.

• The leaflet should be kept so that it can be re-read if necessary.
• In case of any doubts, the doctor or pharmacist should be consulted.
• This medicine has been prescribed specifically for one person. It should not be passed on to others. The medicine may harm another person, even if the symptoms of their illness are the same.
• If the patient experiences any side effects, including any side effects not listed in this leaflet, they should tell their doctor, pharmacist, or nurse. See section 4.

Table of contents of the leaflet

• 1. What is Divigel 0.1% and what is it used for
• 2. Important information before using Divigel 0.1%
• 3. How to use Divigel 0.1%
• 4. Possible side effects
• 5. How to store Divigel 0.1%
• 6. Contents of the packaging 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 that occur after menopause.

During menopause, the amount of estrogen produced by the woman's body decreases.
This can lead to symptoms such as a feeling of heat on the face, neck, and chest
(“hot flashes”).
Divigel 0.1% relieves these symptoms (occurring after menopause). Divigel 0.1% is prescribed only in cases where the symptoms significantly affect the patient's daily life.

Prevention of osteoporosis

After menopause, some women develop brittle bones (osteoporosis). If the patient is at increased risk of fractures due to osteoporosis and other medicines are not suitable, Divigel 0.1% can be used to prevent osteoporosis after menopause. The doctor should be consulted.
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

The use of HRT is associated with a risk that should be considered when deciding to start or continue therapy.
There are few cases of therapy use in women with premature menopause (caused by ovarian failure or surgical procedures). In the case of women with premature menopause, the risk of using HRT may be different.
The doctor should be consulted.
Before starting (or reusing) HRT, the doctor will conduct a medical interview about the patient and their family. The doctor may perform a physical examination, including a breast examination and (or) internal organs, if necessary.
After starting Divigel 0.1%, regular check-ups (at least once a year) should be attended. During these visits, the benefits and risks of continued use of Divigel 0.1% should be discussed with the doctor.
According to the doctor's recommendations, regular breast examinations should be performed.

When not to use Divigel 0.1%

If any of the following points apply to the patient or if the patient has any doubts about any of the following points, they should consult a doctorbefore using Divigel 0.1%.
Divigel 0.1% should not be used:

• if the patient is allergicto estradiolor any of the other ingredients of this medicine (listed in section 6),
• if the patient currently has or has had breast canceror if there is a suspicion of it,
• if the patient has malignant tumor sensitive to estrogen, such as endometrial cancer (endometrium) or if there is a suspicion of it,
• if there is unexplained vaginal bleeding,
• if there is un-treated excessive thickening of the endometrium(endometrial hyperplasia),
• if the patient has or has had venous thromboembolic disease(deep vein thrombosis, e.g. of the lower limbs or lungs, e.g. pulmonary embolism),
• if the patient has blood coagulation disorders(such as protein C, protein S, or antithrombin deficiency),
• if the patient has or has recently had a disease caused by arterial thrombosis, such as heart attack, stroke, or angina pectoris,
• if the patient has or has had liver diseaseand liver test results have not returned to normal,
• if the patient has a rare inherited blood disorder called porphyria.

If any of the above factors occur for the first time while using Divigel 0.1%, its use should be stopped immediately and the doctor should be contacted without delay.

Warnings and precautions

Before starting Divigel 0.1%, it should be discussed with a doctor or pharmacist.
The doctor should be informed if the patient currently has or has had any of the following conditions, as they may recur or worsen during treatment with Divigel 0.1%. In such cases, the patient should be monitored more frequently:

• uterine fibroids (benign tumors),
• endometriosis (endometrial growth outside the uterus) or previous cases of excessive endometrial growth (endometrial hyperplasia),
• increased risk of thromboembolic disorders or a history of them (see "Thrombosis in the veins (thrombosis)"),
• increased risk of estrogen-sensitive tumors (e.g. if the patient's mother, sister, or grandmother had breast cancer),

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• high blood pressure,
• liver function disorders, such as a benign liver tumor,
• diabetes with vascular changes or without,
• gallstones,
• severe headaches or migraines,
• an immune system disease that affects many organs in the body (systemic lupus erythematosus, SLE),
• epilepsy,
• asthma,
• a disease that affects the eardrum and hearing (otosclerosis),
• very high levels of fats (triglycerides) in the patient's body,
• fluid retention due to heart or kidney dysfunction,
• inherited or acquired angioedema (a disease characterized by swelling, usually of the face, limbs, and joints).

Stop using Divigel 0.1% and contact a doctor immediately

If the patient notices any of the following symptoms while using HRT:

• any of the diseases listed in the "When not to use Divigel 0.1%" section,
• jaundice (yellowing of the skin or eyes) or liver function disorders,
• swelling of the face, tongue, and (or) throat, and (or) difficulty swallowing or hives, along with difficulty breathing, which may indicate angioedema,
• significant increase in blood pressure (possible symptoms include headaches, fatigue, dizziness),
• recurrence of migraine headaches,
• pregnancy,
• signs of thrombosis, such as:
• painful swelling and redness of the lower limbs,
• sudden chest pain,
• difficulty breathing.

Note:Divigel 0.1% is not a contraceptive. If it has been less than 12 months since the last menstrual period or if the patient is under 50 years old, additional contraceptive measures may be necessary to prevent pregnancy. The doctor should be consulted.

HRT and malignant tumors

Excessive thickening of the endometrium (endometrial hyperplasia) and malignant tumor of the endometrium (endometrial cancer)

The use of estrogen-only HRT increases the risk of excessive thickening of the endometrium (endometrial hyperplasia) and malignant tumor of the endometrium (endometrial cancer). The additional use of progestogen for at least 12 days in each 28-day cycle protects the patient from this increased risk. The doctor will prescribe progestogen separately if the patient has a preserved uterus. If the uterus has been removed (hysterectomy), the doctor should be consulted to discuss whether the use of this medicine without progestogen is safe.
In the case of women with a preserved uterus who do not use HRT, endometrial cancer is diagnosed in approximately 5 out of 1,000 women between the ages of 50 and 65. In women between the ages of 50 and 65 with a preserved uterus who use estrogen-only HRT, endometrial cancer is diagnosed in 10-60 out of 1,000 women (i.e. 5-55 additional cases), depending on the dose and duration of treatment.

Unexplained vaginal bleeding

During the use of Divigel 0.1%, the patient will experience monthly bleeding (so-called withdrawal bleeding). However, if unexplained bleeding or spotting occurs, which:

• lasts longer than the first 6 months,

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• occurs when the patient has been using Divigel 0.1% for more than 6 months,
• persists after stopping Divigel 0.1%, the doctor should be contacted immediately.

Breast cancer

Data confirm that taking hormone replacement therapy (HRT) in the form of a combination of estrogen and progestogen or estrogen alone increases the risk of breast cancer. The additional risk depends on how long the patient uses HRT. This additional risk becomes apparent after 3 years of HRT use. After stopping HRT, the additional risk will decrease over time, but the risk may persist for 10 years or longer if HRT lasted more than 5 years.
Comparison
In the case of women between the ages of 50 and 54 who do not use HRT, breast cancer will be diagnosed in approximately 13-17 out of 1,000 women over a period of 5 years.
In the case of women aged 50 who start 5-year estrogen-only HRT, the number of cases will be 16-17 out of 1,000 patients (i.e. 0-3 additional cases).
In the case of women aged 50 who start 5-year combined estrogen-progestogen HRT, the number of cases will be 21 out of 1,000 patients (i.e. 4-8 additional cases).
In the case of women between the ages of 50 and 59 who do not use HRT, breast cancer will be diagnosed in approximately 27 out of 1,000 women over a period of 10 years.
In the case of women aged 50 who start 10-year estrogen-only HRT, the number of cases will be 34 out of 1,000 patients (i.e. 7 additional cases).
In the case of women aged 50 who start 10-year combined estrogen-progestogen HRT, the number of cases will be 48 out of 1,000 patients (i.e. 21 additional cases).

Regular breast examinations should be performed. The doctor should be contacted if any changes occur, such as:

• wrinkles on the skin,
• changes in the breast area,
• any visible or palpable thickening.

In addition, participation in offered breast cancer screening programs is recommended.
It is essential to inform the medical staff performing the mammography about HRT use, as this medicine may cause an increase in the radiological density of the breast, which may affect the mammography result. In areas with increased density, mammography may not detect all tumors.

Ovarian cancer

Ovarian cancer is rare - much rarer than breast cancer. The use of HRT containing only estrogens or a combination of estrogens and progestogens is associated with a slightly increased risk of ovarian cancer. The risk of ovarian cancer depends on age. For example, in women between the ages of 50 and 54 who do not use HRT, ovarian cancer will be diagnosed over a period of 5 years in 2 out of 2,000 women. In women who have used HRT for 5 years, ovarian cancer will occur in approximately 3 out of 2,000 patients (i.e. 1 additional case).

Effect of HRT on the heart and circulation

Thrombosis in the veins (thrombosis)

The risk of venous thrombosisis approximately 1.3 to 3 times higher in women using HRT, especially in the first year of treatment, than in women who do not use it.
If a thrombus enters the lungs, it can cause chest pain, shortness of breath, fainting, or even death.
The likelihood of thrombosis in the veins increases with age and depends on the presence of the following factors. The doctor should be informed if any of the following situations occur:
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• the patient is unable to walk for an extended period due to extensive surgery, injury, or illness (see also section 3 "If surgery is necessary"),
• the patient is obese (Body Mass Index, BMI >30 kg/m),
• the patient has blood coagulation disorders and requires long-term treatment with anticoagulant medication,
• any close relatives have had a thrombus in the lower limb, lung, or other organ,
• the patient is pregnant and (or) postpartum,
• the patient has systemic lupus erythematosus (SLE),
• the patient has cancer.

Symptoms of thrombosis can be found in the "Stop using Divigel 0.1% and contact a doctor immediately" section.
Comparison
In the case of women between the ages of 50 and 59 who do not use HRT, venous thrombosis will occur in approximately 4-7 out of 1,000 women over a period of 5 years.
In women between the ages of 50 and 59 who have used combined estrogen-progestogen HRT for more than 5 years, venous thrombosis will occur in 9-12 out of 1,000 women (i.e. 5 additional cases).
In women between the ages of 50 and 59 with a removed uterus who have used estrogen-only HRT for 5 years, thrombosis will occur in 5-8 out of 1,000 women (i.e. 1 additional case).

Coronary heart disease (myocardial infarction)

There is no scientific evidence to confirm that HRT can prevent myocardial infarctions.
Women over 60 years old who use combined estrogen-progestogen HRT are slightly more likely to develop heart disease than women who do not use HRT.
In the case of 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 use it. The number of additional cases of stroke due to HRT use increases with age.
Comparison
In the case of women between the ages of 50 and 59 who do not use HRT, ischemic stroke will occur in approximately 8 out of 1,000 women over a period of 5 years. In women between the ages of 50 and 59 who use HRT, ischemic stroke will occur in 11 out of 1,000 women over a period of 5 years (i.e. 3 additional cases).

Other conditions

• HRT does not improve cognitive function (memory loss, perception disorders, attention disorders). There is evidence of an increased risk of dementia in women who start HRT at an age over 65. The doctor should be consulted.
• Women with a tendency to skin discoloration (chloasma) should limit their exposure to sunlight or ultraviolet radiation while using Divigel 0.1%.

Divigel 0.1% and other medicines

Certain medicines may affect the action of Divigel 0.1%. This may lead to irregular bleeding. This applies to the following medicines:

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

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• herbal products containing St. John's Wort(Hypericum perforatum),
• medicines used to treat hepatitis C(such as the combination therapy of ombitasvir/paritaprevir/ritonavir with dasabuvir or without dasabuvir, and the combination therapy of glecaprevir/pibrentasvir), as they may cause an increase in liver enzyme test results [increase in alanine aminotransferase (ALT) activity] in women using combined hormonal contraceptives containing ethinyl estradiol. It is not known whether the concomitant use of Divigel with these hepatitis C therapies may increase ALT activity. The doctor will advise on this.

The doctor or pharmacist should be informed about all medicines the patient is currently taking, plans to take, or is taking without a prescription, as well as about herbal products or other natural products.

Laboratory tests

If a blood test is necessary, the laboratory staff should be informed about the use of Divigel 0.1%, as it may affect the results of some tests.

Pregnancy and breastfeeding

The use of Divigel 0.1% is contraindicated in pregnancy and breastfeeding.
Divigel 0.1% is intended for use only in postmenopausal women. In case of pregnancy, the use of Divigel 0.1% should be stopped and the doctor should be contacted.

Driving and using machines

No studies have been conducted on the effect on the ability to drive and use machines.

Divigel 0.1% contains propylene glycol

The medicine contains between 62.5 mg and 187.5 mg of propylene glycol in each 0.5-1.5 g dose. The medicine may cause skin irritation.

Divigel 0.1% contains alcohol (96% ethanol)

The medicine contains between 271 mg and 835 mg of alcohol (ethanol) in each 0.5-1.5 g dose. It may cause a burning sensation on damaged skin.

3. How to use Divigel 0.1%

This medicine should always be used as directed by the doctor. In case of doubts, the doctor should be consulted.
Divigel 0.1% is a gel for application to the skin. Divigel 0.1% can be used for continuous or cyclical treatment. The usual starting dose is 1 mg of estradiol (1 g of gel) per day, but the choice of starting dose may depend on the severity of symptoms in the patient.
The dose may be modified by the doctor after 2 or 3 cycles from 0.5 g to 1.5 g per day, which corresponds to 0.5 mg to 1.5 mg of estradiol per day. The doctor will prescribe the smallest possible dose necessary for treatment, for the shortest possible period. If the patient thinks the effect of the medicine is too weak or too strong, they should inform the doctor.
In women with a preserved uterus, it is necessary to combine the use of Divigel 0.1% with an appropriate dose of progestogen, for an appropriate period, at least for 12-14 consecutive days in the month, to counteract the estrogen-stimulated growth of the endometrium.
After each series of progestogen, withdrawal bleeding (such as menstrual bleeding) usually occurs.
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Method of administration
The dose of Divigel 0.1% is applied once a day to the skin of the lower torso or the right or left thigh, alternately. The application area should be 1 to 2 times larger than the palm of the hand. Divigel 0.1% should not be applied to the breasts, face, or irritated skin, or into the vagina. After application, the gel should be left to dry for a few minutes, and the application site should not be washed for one hour. Contact between the gel and eyes should be avoided.

• After applying the gel, the hands should be washed with soap and water.
• The application site should be covered with clothing immediately after the applied gel has dried.
• A shower should be taken before a situation where skin-to-skin contact with another person is expected.
• If another person (e.g. a child or spouse) or an animal accidentally touches the application site, the skin should be washed with soap and water as soon as possible.

If the precautions are not followed, the estradiol gel may be transferred to other people (e.g. a child or spouse) or animals through direct skin-to-skin contact, which may cause side effects. In case of any side effects, the doctor or veterinarian should be contacted.
In women who do not use HRT or in women who switch from another medicine to combined HRT used continuously, treatment with Divigel 0.1% can be started on any day. In women who switch from sequential HRT, treatment should be started the day after the end of the previous 28-day treatment cycle.
If the patient thinks the effect of Divigel 0.1% is too weak or too strong, they should consult the doctor.

If surgery is necessary

Before surgery, the surgeon should be informed about the use of Divigel 0.1%. It may be necessary to stop using Divigel 0.1% 4 to 6 weeks before surgery to reduce the risk of thrombosis (see section 2 "Thrombosis in the veins (thrombosis)"). The doctor should be consulted regarding when Divigel 0.1% can be used again.

Using a higher dose of Divigel 0.1% than recommended

Overdose of estrogens may cause nausea, headaches, and bleeding from the genital tract.
Several reports of ingestion of large doses of oral contraceptives containing estrogens by small children do not indicate the occurrence of severe overdose symptoms.
Generally, estrogens are well-tolerated even in large doses. Acute toxicity studies have not shown a risk of severe side effects in the event of unintentional ingestion of multiple times the daily therapeutic dose. In some women, nausea, vomiting, and withdrawal bleeding may occur. The effects of overdose are usually breast tenderness, abdominal swelling, anxiety, irritability, and emotional instability. These symptoms disappear after stopping treatment or reducing the dose.
Overdose due to transdermal administration is unlikely. There is no specific antidote; symptomatic treatment should be initiated. The gel should be washed off.

Missing a dose of Divigel 0.1%

If the patient forgets to apply one dose, the missed dose should be applied as soon as possible, if the delay is no more than 12 hours. If the delay is more than 12 hours, the dose should be skipped and treatment should continue according to the previous schedule.
Missing a dose may increase the likelihood of irregular bleeding and spotting from the genital tract.
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The patient should obtain a sufficient amount of medicine for a longer trip.
A double dose should not be used to make up for a missed dose.

If the gel is accidentally ingested

If someone accidentally ingests the gel, there is no reason for great concern. However, the doctor should be contacted.

Stopping the use of Divigel 0.1%

If the patient stops treatment with Divigel 0.1%, the symptoms of estrogen deficiency will return after some time.
In case of any further doubts about the use of this medicine, the doctor or pharmacist should be consulted.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
The most common side 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 those who do not use it:

• breast cancer,
• abnormal growth or malignant tumor of the endometrium (endometrial hyperplasia or endometrial cancer),
• ovarian cancer,
• thrombosis in the veins of the lower limbs or lungs (thromboembolic disorders),
• heart disease,
• stroke,
• risk of dementia, if HRT is started at an age over 65. More information about the above side effects can be found in section 2.

During the first months of treatment, intermenstrual bleeding, spotting, and breast tenderness may occur. These symptoms are usually temporary and disappear when treatment is continued.
The following side effects may occur during the use of Divigel 0.1%:
Frequent(less than 1 in 10 people):

• weight gain,
• weight loss,
• headaches, dizziness,
• nausea, vomiting, stomach cramps, gas in the intestines,
• discharge, vulvovaginal diseases, menstrual cycle disorders,
• skin irritation, itching at the application site, pain, increased sweating,
• breast tenderness or pain,
• bleeding or spotting, irregular menstrual periods,
• depression, nervousness, lethargy (apathy, lack of reaction to most stimuli),
• edema,
• hot flashes.

Uncommon(less than 1 in 100 people):
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• mood changes, changes in libido, anxiety, insomnia, apathy, emotional instability, concentration disorders, euphoria, agitation,
• migraine, numbness, seizures,
• vision disorders, dry eyes,
• hypertension, superficial thrombophlebitis, purpura,
• shortness of breath, runny nose,
• benign breast tumor or endometrial tumor,
• increased appetite, high cholesterol levels in the blood,
• palpitations,
• constipation, indigestion, diarrhea, anal disease,
• acne, hair loss, dry skin, nail diseases, skin tumors, excessive hair growth, erythema multiforme, hives,
• joint pain, muscle cramps,
• increased urination and (or) increased need to urinate, urinary incontinence, cystitis, urine discoloration, hematuria,
• breast tenderness or swelling, endometrial hyperplasia, uterine disease,
• fatigue, abnormal laboratory test results, weakness, fever, flu, malaise,
• hypersensitivity.

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

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

Side effects reported after the product was placed on the market:
Unknown(cannot be estimated from available data):

• uterine fibroids,
• exacerbation of inherited or acquired angioedema,
• cerebral circulation disorders (episodes of cerebral ischemia),
• abdominal pain, bloating,
• liver disease causing jaundice (cholestatic jaundice),
• contact dermatitis, rash.

Other side effects observed during the use of HRT include:
breast cancer, endometrial cancer, coronary heart disease, gallbladder disease, stroke, skin and subcutaneous tissue disorders: chloasma, erythema multiforme, dementia.
The following side effects have been observed in other HRTs:

• gallbladder disease,
• various skin disorders:
• skin discoloration, especially on the face or neck, known as "pregnancy spots" (chloasma),
• painful skin nodules (Erythema nodosum),
• rash with red, ring-shaped changes or ulcers (Erythema multiforme).

Reporting side effects

If any side effects occur, including any side effects not listed in this leaflet, the doctor, pharmacist, or nurse should be informed. Side effects can be reported directly to the Department of Drug Adverse Reaction Monitoring of the 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
By reporting side effects, more information can be collected on the safety of the medicine.

5. How to store Divigel 0.1%

The medicine should be stored out of sight and reach of children.
Do not store above 25°C.
Do not use this medicine after the expiry date stated on the packaging. The expiry date refers to the last day of the month stated.
Medicines should not be disposed of via wastewater or household waste. The pharmacist should be asked how to dispose of medicines that are no longer needed. This will help protect the environment.

6. Contents of the packaging and other information

What Divigel 0.1% contains

One sachet of Divigel 0.1% 1.0 g contains:

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

What Divigel 0.1% looks like and contents of the packaging

1.0 g of gel in a sachet contains a single dose.
The packaging contains 28 or 91 sachets of Aluminum/PE/polyester in a cardboard box.
For more detailed information, the marketing authorization holder or parallel importer should be contacted.

Marketing authorization holder in France, the 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 by:

Delfarma Sp. z o.o.
ul. Św. Teresy od Dzieciątka Jezus 111
91-222 Łódź
Marketing authorization number in France, the country of export: 34009 342 399 4 6
342 399-4
342 400-2
34009 342 400 2 7

Parallel import authorization number: 253/18

Date of leaflet approval: 31.05.2023

[Information about the trademark]
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