Divigel 0,1%

Leaflet accompanying the packaging: patient information

Divigel 0.1%, 0.5 mg/0.5 g, gel
Divigel 0.1%, 1.0 mg/1.0 g, gel
Estradiol

You should carefully read the contents of the leaflet before using the medicine, as it contains important information for the patient.

• You should keep this leaflet, so that you can read it again if you need to.
• If you have any doubts, you should consult a doctor or pharmacist.
• This medicine has been prescribed specifically for you. Do not pass it on to others. The medicine may harm another person, even if their symptoms are the same as yours.
• If you experience any side effects, including those not listed in this leaflet, you should tell your doctor or pharmacist. 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 result in 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. You should consult a 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

The use of HRT is associated with a risk that should be considered when deciding to start or continue therapy.
Cases of therapy in women with premature menopause (caused by ovarian failure or surgical procedures) are rare. In the case of women with premature menopause, the risk of using HRT may be different. You should consult a doctor.
Before starting (or reusing) HRT, the doctor will conduct a medical interview with the patient and her family. The doctor may perform a physical examination, including a breast examination and (or) internal organs, if necessary.
After starting the use of Divigel 0.1%, you should regularly visit your doctor for check-ups (at least once a year). During these visits, you should discuss with your doctor the benefits and risks of continuing to use Divigel 0.1%.
According to the doctor's recommendations, you should undergo regular breast examinations.

When not to use Divigel 0.1%

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

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

If any of the above factors occur for the first time while using Divigel 0.1%, you should stop using it immediately and contact your doctor.

Warnings and precautions

Before starting the use of Divigel 0.1%, you should discuss it with your doctor or pharmacist.
You should inform your doctor if you currently have or have had any of the following conditions, as they may recur or worsen during treatment with Divigel 0.1%. In such cases, you should be monitored more frequently:

• uterine fibroids (benign tumors),
• endometriosis (growth of endometrial tissue outside the uterus) or previous cases of excessive growth of endometrial tissue (endometrial hyperplasia),
• increased risk of thromboembolic disorders or a history of them (see "Blood clots in the veins (thrombosis)"),
• increased risk of estrogen-sensitive tumors (e.g. if the patient's mother, sister, or grandmother had breast cancer),
• high blood pressure,
• liver function disorders, such as a benign liver tumor,
• diabetes with vascular complications 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).

You should stop using Divigel 0.1% and contact your doctor immediately

If you experience 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 whites of the 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 a blood clot, 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 your last menstrual period or if you are under 50 years old, you may need additional contraceptive measures to prevent pregnancy. You should consult a doctor.

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 against this increased risk. The doctor will prescribe progestogen separately if the patient has a preserved uterus. If the uterus has been removed (hysterectomy), you should discuss with your doctor 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.

Vaginal bleeding of unknown cause

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

• lasts longer than the first 6 months,
• occurs when the patient has been using Divigel 0.1% for more than 6 months,
• persists after stopping Divigel 0.1%, you should contact your doctor 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 more 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 is diagnosed in approximately 13-17 out of 1,000 women over a 5-year period.
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 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 is diagnosed in approximately 27 out of 1,000 women over a 10-year period.
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 estrogen-progestogen HRT, the number of cases will be 48 out of 1,000 patients (i.e. 21 additional cases).

You should have your breasts examined regularly. You should contact your doctor if you notice any changes such as:

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

In addition, it is recommended to participate in offered breast cancer screening programs.
It is important to inform the medical staff performing the mammography about the use of HRT, 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 is diagnosed over a 5-year period in 2 out of 2,000 women. In women who have used HRT for 5 years, it occurs in approximately 3 out of 2,000 patients (i.e. 1 additional case).

Effect of HRT on the heart and circulation

Blood clots 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 blood clot enters the lungs, it can cause chest pain, shortness of breath, fainting, or even death.
The likelihood of blood clots in the veins increases with age and depends on the presence of the following factors. You should inform your doctor if any of the following situations occur:

• you are unable to walk for a long time due to extensive surgery, injury, or illness (see also section 3 "If surgery is necessary"),
• you are obese (Body Mass Index, BMI >30 kg/m),
• you have blood clotting disorders and require long-term treatment with anticoagulant medication,
• any of your close relatives have had a blood clot in a limb, lung, or other organ,
• you are pregnant and (or) postpartum,
• you have systemic lupus erythematosus (SLE),
• you have cancer.

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

Coronary artery disease (heart attack)

There is no scientific evidence to confirm that HRT can prevent heart attacks.
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 people 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, an ischemic stroke is likely to occur in 8 out of 1,000 women over a 5-year period. In women between the ages of 50 and 59 who use HRT, an ischemic stroke occurs in 11 out of 1,000 women over a 5-year period (i.e. 3 additional cases).

Other conditions

• HRT does not improve cognitive function (memory loss, perception disorders, attention). There is evidence of an increased risk of dementia in women who start HRT at an age over 65. You should consult a doctor.
• 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

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

You should tell your doctor or pharmacist about all medicines you are currently taking, plan to take, or are taking without a prescription, as well as about herbal products or other natural products.

Laboratory tests

If a blood test is necessary, you should inform the laboratory staff 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 during breastfeeding.
Divigel 0.1% is intended for use only in postmenopausal women. If you become pregnant, you should stop using Divigel 0.1% and contact your doctor.

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 from 62.5 mg to 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 (ethanol)

The medicine contains from 271 mg to 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 your doctor. If you are unsure, you should consult your doctor.
Divigel 0.1% is a gel for application to the skin. Divigel 0.1% can be used for continuous or cyclic 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 you think the effect of the medicine is too weak or too strong, you should inform your 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.
Method of administration
The dose of Divigel 0.1% is applied once a day to the skin of the lower abdomen 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. You should avoid contact between the gel and the eyes.

• After applying the gel, you should wash your hands with soap and water.
• Cover the application site with clothing immediately after the applied gel has dried,
• Take a shower before engaging in any activity that may involve skin-to-skin contact with another person.
• If another person (e.g. a child or spouse) or an animal accidentally touches the application site, you should wash the skin in the affected area 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. If any side effects occur, you should contact your doctor or veterinarian.
In women who do not use HRT or in women who are switching from another medicine to combined HRT used continuously, treatment with Divigel 0.1% can be started on any day. In women who are switching from sequential HRT, treatment should be started the day after the end of the previous 28-day treatment cycle.
If you think the effect of Divigel 0.1% is too strong or too weak, you should consult your doctor.

If surgery is necessary

Before surgery, you should inform the surgeon 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 blood clots (see section 2 "Blood clots in the veins (thrombosis)"). You should consult your doctor about when you can start using Divigel 0.1% again.

If you use more Divigel 0.1% than you should

Overdose of estrogens can 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 a multiple of the daily therapeutic dose. In some women, nausea, vomiting, and withdrawal bleeding may occur. The consequences of overdose are usually breast tenderness, abdominal bloating, anxiety, irritability. These symptoms disappear after stopping the treatment or reducing the dose.
Overdose after transdermal administration is unlikely. There is no specific antidote; symptomatic treatment should be initiated. The gel should be washed off.

If you forget to use Divigel 0.1%

If you forget 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 dose is delayed by more than 12 hours, it should be omitted, and treatment should be continued according to the previous schedule. Missing a dose may increase the likelihood of irregular bleeding and spotting from the genital tract.
You should have a sufficient amount of medicine for a longer trip.
You should not use a double dose to make up for a missed dose.

If you accidentally swallow the gel

If someone accidentally swallows the gel, there is no reason for great concern. However, you should contact your doctor.

If you stop using Divigel 0.1%

If you stop using Divigel 0.1%, the symptoms of estrogen deficiency will return after some time.
If you have any further doubts about the use of this medicine, you should consult your doctor or pharmacist.

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 cancer of the endometrium (endometrial hyperplasia or endometrial cancer),
• ovarian cancer,
• blood clots in the veins of the legs or lungs (venous thromboembolism),
• 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 few months of treatment, irregular 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,
• discharge, vulvovaginal disorders, menstrual cycle disorders,
• skin irritation, itching at the application site, pain, increased sweating,
• breast tenderness or pain,
• bleeding or spotting, irregular periods,
• depression, nervousness, lethargy (apathy, lack of reaction to most stimuli),
• edema,
• hot flashes.

Uncommon(less than 1 in 100 people):

• mood changes, sexual desire disorders, 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 disorders,
• acne, hair loss, dry skin, nail disorders, skin nodules, excessive hair growth, erythema multiforme, hives,
• joint disorders, 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-like symptoms, malaise,
• hypersensitivity.

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

• venous thromboembolism (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 the available data):

• uterine fibroids,
• exacerbation of inherited or acquired angioedema,
• cerebrovascular disorders (episodes of cerebral ischemia),
• abdominal pain, bloating,
• liver diseases causing yellowing of the skin (cholestatic jaundice),
• contact dermatitis, rash.

Other side effects observed during the use of HRT include:
breast cancer, endometrial cancer, coronary artery disease, gallbladder disease, stroke, skin and subcutaneous tissue disorders: chloasma, erythema multiforme, dementia.
The following side effects have been observed in the case of 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),
• a rash with ring-shaped or ulcerative lesions ( Erythema multiforme).

Reporting side effects
If you experience any side effects, including those not listed in this leaflet, you should tell your doctor or pharmacist. Side effects can be reported directly to the Department of Drug Safety Monitoring of the Office for Registration of Medicinal Products, Medical Devices, and Biocidal Products,
Jerozolimskie Avenue 181C, 02-222 Warsaw, phone: +48 22 49 21 301, fax: +48 22 49 21 309,
website: https://smz.ezdrowie.gov.pl
Side effects can also be reported to the marketing authorization holder.
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Divigel 0.1%

The medicine should be stored out of sight and reach of children.
Do not use this medicine after the expiry date stated on the packaging after "Expiry date (EXP)". The expiry date refers to the last day of the month indicated.
Store at a temperature below 25°C.
Medicines should not be disposed of via wastewater or household waste. You should ask your pharmacist 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% 0.5 g contains:

• The active substance of the medicine is estradiol in the form of estradiol hemihydrate 0.5 mg.
• The other ingredients are: carbomer 974P, tromethamine, propylene glycol, ethanol 96%, purified water.

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: carbomer 974P, tromethamine, propylene glycol, ethanol 96%, purified water.

What Divigel 0.1% looks like and contents of the packaging

0.5 g or 1.0 g of gel in a sachet contains a single dose.
The packaging contains 28 or 91 sachets made of polyester/Al/polyethylene in a cardboard box.

Marketing authorization holder and manufacturer

Marketing authorization holder:

Orion Corporation
Orionintie 1
FI-02200 Espoo
Finland

Manufacturer:

Orion Corporation,
Tengströminkatu 8
FI-20360 Turku
Finland
To obtain more detailed information about this medicine, you should contact the local representative of the marketing authorization holder:
Orion Pharma Poland Sp. z o. o.
[email protected]

Date of last revision of the leaflet: