DIVIGEL 0.5 mg TRANSDERMAL GEL in SACHETS

Introduction

Package Leaflet: Information for the User

Divigel 0.5mg Transdermal Gel in EFG Sachet

Estradiol

Read this package leaflet carefully before you start using this medicine because it contains important information for you.

• Keep this package leaflet, you may need to read it again.
• If you have any further questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.
• If you experience any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this package leaflet. See section 4.

Contents of the Package Leaflet

1. What is Divigel and what is it used for
2. What you need to know before you start using Divigel
3. How to use Divigel
4. Possible side effects
5. Storing Divigel
6. Package Contents and Further Information

1. What is Divigel and what is it used for

Divigel is a Hormone Replacement Therapy (HRT). It contains the female hormone estrogen. Divigel is indicated in women who have started menopause.

Estradiol is used for:

Relief of symptoms that occur after menopause

During menopause, the amount of estrogen produced by the woman's body decreases. This can cause symptoms such as heat in the face, neck, and chest ("hot flashes"). Divigel relieves these postmenopausal symptoms. You will only be prescribed Divigel if your symptoms truly interfere with your daily life.

Prevention of osteoporosis

After menopause, some women develop bone fragility (osteoporosis). You should discuss all available options with your doctor.

If you have a higher risk of fractures due to osteoporosis and other medications are not suitable for you, you can use Divigel to prevent osteoporosis after menopause.

Estrogen treatment is usually combined with a luteal hormone (progestogen), which is used cyclically.

2. What you need to know before starting to use Divigel

Medical history and regular check-ups

The use of HRT involves risks that need to be considered when deciding to start or continue treatment.

Experience in treating women with premature menopause (due to ovarian failure or surgery) is limited. If you have premature menopause, the risks of using HRT may be different. Please consult your doctor.

Before starting (or resuming) HRT, your doctor will ask about your personal and family medical history. Your doctor may decide to perform a physical examination. This may include a breast examination and/or an internal examination, if necessary. Once you have started treatment with Divigel, you should visit your doctor for regular check-ups (at least once a year). During these check-ups, discuss the benefits and risks of continuing with Divigel with your doctor.

Have regular breast checks, as recommended by your doctor.

Do not use Divigel

if any of the following apply to you. If you are unsure about any of the points described here, consult your doctorbefore using Divigel.

Do not use Divigel

• if you have or have had breast cancer, or if there is a suspicion that you may have it
• if you have an estrogen-dependent cancer, such as cancer of the lining of the uterus (endometrium), or if there is a suspicion that you may have it
• if you have abnormal vaginal bleeding
• if you have an excessive thickening of the lining of the uterus(endometrial hyperplasia) for which you are not receiving treatment
• 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(such as 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 a heart attack, stroke, or angina
• if you have or have had a liver diseaseand your liver function tests have not returned to normal
• if you have a rare blood disease called porphyriathat is inherited from parents to children (hereditary)
• if you are allergicto estradiol hemihydrateor to any of the other components of this medicine (listed in section 6).

If any of the situations mentioned appear for the first time while you are using Divigel, stop using it immediately and consult your doctor immediately.

Warnings and precautions

Before starting treatment, inform your doctor if you have ever had any of the following problems, as they may recur or worsen during treatment with Divigel. In this case, you should visit your doctor more frequently for check-ups.

• fibroids in the uterus
• growth of the uterine lining outside the uterus (endometriosis) or a history of excessive growth of the uterine lining (endometrial hyperplasia)
• increased risk of blood clots (see "Blood clots in a vein (thrombosis)")
• increased risk of developing an estrogen-sensitive cancer (such as having a mother, sister, or grandmother who has had breast cancer)
• high blood pressure
• liver disorders, such as a benign tumor in the liver
• diabetes
• gallstones
• migraines or severe headaches
• a disease of the immune system that affects many parts of the body (systemic lupus erythematosus, SLE)
• epilepsy
• asthma
• a disease that affects the eardrum and ear (otosclerosis)
• very high levels of fat in the blood (triglycerides)
• fluid retention due to heart or kidney problems
• hereditary or acquired angioedema (painful and localized swelling of the skin and mucous membranes)

Children

Divigel can be accidentally transferred from the skin to others. Do not allow others, especially children, to come into contact with the exposed skin area, and cover it, if necessary, once the gel has dried. If a child comes into contact with the skin area where estradiol has been applied, wash the child's skin with water and soap as soon as possible. The transfer of estradiol can cause young children to show unexpected signs of puberty (e.g., breast buds). In most cases, the symptoms will disappear when the child stops being exposed to the estradiol gel.

Contact your health center if you notice any signs or symptoms (breast development or other sexual changes) in a child who may have been accidentally exposed to the estradiol gel.

Stop using Divigel and consult your doctor immediately

If you notice any of the following situations while using HRT:

• any of the situations mentioned in the "Do not use Divigel" section
• yellowing of the skin or whites of the eyes (jaundice), which can be symptoms of liver disease
• swelling of the face, tongue, and/or throat, and/or difficulty swallowing or urticaria, along with difficulty breathing, which are indicative of angioedema
• a significant increase in blood pressure (symptoms may include headache, fatigue, dizziness)
• migraines that occur for the first time

• painful and swollen legs
• sudden chest pain
• difficulty breathing

For more information, see "Stop using Divigel and consult your doctor immediately".

Note:Divigel is not a contraceptive. If it has been less than 12 months since your last menstrual period or you are under 50 years old, you may still need contraceptive measures to prevent pregnancy. Ask your doctor for advice.

HRT and cancer

Excessive thickening of the uterine lining (endometrial hyperplasia) and uterine lining cancer (endometrial cancer)

Treatment with estrogen alone in HRT will increase the risk of excessive thickening of the uterine lining (endometrial hyperplasia) and uterine lining cancer (endometrial cancer).

Using a progestogen in addition to estrogen for at least 12 days in each 28-day cycle will protect you from this additional risk. Therefore, your doctor will prescribe a separate progestogen if you still have a uterus. If you have had a hysterectomy (removal of the uterus), consult your doctor to see if you can safely use this medicine without a progestogen.

In women between 50 and 65 years old who still have a uterus and are not using HRT, endometrial cancer will be diagnosed in 5 out of 1,000 women on average.

For women between 50 and 65 years old who still have a uterus and are using HRT, endometrial cancer will be diagnosed in between 10 and 60 women out of 1,000 (i.e., between 5 and 55 additional cases), depending on the dose and duration of treatment used.

Unexpected bleeding

If your doctor has prescribed oral progestogen in addition to Divigel, you will have a monthly bleed (also called withdrawal bleeding). However, if you experience unexpected bleeding or spotting between monthly bleeds that:

• continues after the first 6 months
• starts after you have been taking Divigel for more than 6 months
• continues after you stop taking Divigel

consult your doctor as soon as possible.

Breast cancer

Available data show that the use of hormone replacement therapy (HRT) with combined estrogen-progestogen or estrogen-only therapy increases the risk of breast cancer. The additional risk depends on the duration of HRT use. The additional risk becomes apparent after 3 years of use. After stopping HRT, the additional risk will decrease over time, but the risk may persist for 10 years or more if HRT has been used for more than 5 years.

Comparison

In women between 50 and 54 years old who are not using HRT, breast cancer will be diagnosed in 13 to 17 out of 1,000 women on average over a 5-year period.

In women who start estrogen-only HRT at 50 years old for 5 years, there will be between 16 and 17 cases per 1,000 users (i.e., between 0 and 3 additional cases).

In women who start combined estrogen-progestogen HRT at 50 years old for 5 years, there will be between 21 cases per 1,000 users (i.e., between 4 and 8 cases).

In women between 50 and 59 years old who are not taking HRT, an average of 27 cases of breast cancer will be diagnosed per 1,000 women over a 10-year period.

In women who start estrogen-only HRT at 50 years old for more than 10 years, there will be 34 cases per 1,000 users (i.e., 7 additional cases).

In women who start combined estrogen-progestogen HRT at 50 years old for 10 years, there will be 48 cases per 1,000 users (i.e., 21 additional cases).

Regular breast checks. Consult your doctor if you notice any changes such as:

• formation of dimples in the skin
• changes in the nipple
• any lump that you can see or feel

In addition, it is recommended to join a periodic mammography screening program. For mammography screening, it is important to inform the nurse or healthcare professional taking the X-rays that you are using HRT, as this medication may increase the density of your breasts and may affect the result of the mammogram. When breast density increases, it may not be possible to detect lumps in the mammogram.

Ovarian cancer

Ovarian cancer occurs less frequently than breast cancer. The use of HRT with estrogen-only or combined estrogen-progestogen therapy has been associated with a slightly increased risk of ovarian cancer.

The risk of ovarian cancer varies with age. For example, in women between 50 and 54 years old who are not using HRT, there are approximately 2 cases of ovarian cancer per 2,000 women over a 5-year period. In women using HRT for 5 years, there are approximately 3 cases per 2,000 patients (i.e., approximately 1 additional case).

Effect of HRT on the heart and circulation

Blood clots in a vein (thrombosis)

The risk of having blood clots in the veinsis approximately 1.3 to 3 times higher in HRT users than in non-users, especially during the first year of use.

Blood clots can be serious and, if one travels to the lungs, can cause chest pain, difficulty breathing, loss of consciousness (fainting), and even death.

It is more likely to have a blood clot in the veins as you get older and if any of the following circumstances occur:

• you are unable to walk for a long time due to major surgery, injury, or illness (see section 3, If you need to have surgery)
• you have significant obesity (body mass index > 30 kg/m2)
• you have a blood clotting disorder that requires long-term treatment with a medicine used to prevent blood clots
• if any of your close relatives have ever had a blood clot in the leg, lung, or other organ
• if you have systemic lupus erythematosus (SLE)
• if you have cancer

For more information on the symptoms of blood clots, see "Stop using Divigel and consult your doctor immediately".

Comparison

On average, over a 5-year period, among women in their 50s who are not taking HRT, 4 to 7 out of 1,000 women would be expected to have a blood clot in the veins.

Among women in their 50s who take combined estrogen-progestogen HRT for more than 5 years, there will be 9 to 12 cases per 1,000 users (i.e., 5 additional cases).

For women in their 50s who have had a hysterectomy and use estrogen-only HRT for more than 5 years, there will be 5 to 8 cases per 1,000 users (i.e., 1 additional case).

Heart disease (myocardial infarction)

There is no evidence that HRT prevents myocardial infarction.

Women over 60 years old who use combined estrogen-progestogen HRT have a slightly higher risk of developing heart disease compared to those not taking HRT.

Women who have had a hysterectomy and use estrogen-only HRT do not have an increased risk of developing heart disease.

Stroke

The risk of having a stroke is 1.5 times higher in HRT users than in non-users. The number of additional stroke cases due to HRT use will increase with age.

Comparison

Among women in their 50s who are not using HRT, on average, 8 out of 1,000 women would be expected to have a stroke over a 5-year period. Among women in their 50s who use HRT, there will be 11 cases per 1,000 users over a 5-year period (i.e., 3 additional cases).

Other warnings

• HRT will not prevent memory loss. There is some evidence that memory loss is greater in women who start using HRT after the age of 65. Ask your doctor for advice.
• Women with a tendency to skin discoloration (chloasma) should minimize sun exposure or ultraviolet radiation while using Divigel.

Possible transfer of estradiol

In case of close contact with the skin, the estradiol gel can be transferred to others (e.g., children, partner, animals) if the application area is not covered with clothing. Therefore, the following precautions should be taken:

• Wash your hands with water and soap after application
• Cover the application area with clothing as soon as the gel has dried
• Rinse the skin at the application site before having contact with others.

If the gel is accidentally transferred to others, wash the exposed area with water and soap. Contact a doctor or veterinarian if symptoms or adverse reactions occur.

Other medicines and Divigel

Some medicines may interfere with the effect of Divigel. This may cause irregular bleeding. This applies to the following medicines:

• Medicines for epilepsy (such as phenobarbital, phenytoin, and carbamazepine).
• Medicines for tuberculosis (such as rifampicin, rifabutin).
• Medicines for HIV infection (such as nevirapine, efavirenz, ritonavir, and nelfinavir).
• Preparations based on medicinal plants containing St. John's Wort (Hypericum perforatum).

HRT may affect the effect of other medicines:

• The epilepsy medicine (lamotrigine), as it may increase the frequency of seizures
• Medicines for hepatitis C virus (HCV) (such as the combined regimen of ombitasvir/paritaprevir/ritonavir with or without dasabuvir, as well as a regimen with glecaprevir/pibrentasvir) may cause increases in liver function test results (increase in liver enzyme ALT) in women using HRT that contains ethinylestradiol. Divigel contains estradiol instead of ethinylestradiol. It is not known whether an increase in liver enzyme ALT can occur when using Divigel with this HCV regimen.

Tell your doctor or pharmacist if you are taking, have recently taken, or may need to take any other medicine, including those without a prescription, herbal medicines, or other natural products. Your doctor will advise you.

Remember to mention that you are using Divigel during your next medical visits.

Laboratory tests

If you need to have a blood test, inform your doctor or the laboratory staff that you are using Divigel, as this medicine may affect the results of some tests.

Pregnancy and breastfeeding

Divigel is only indicated in postmenopausal women. If you become pregnant, stop using Divigel and contact your doctor.

If you are breastfeeding, do not use this medicine.

Driving and using machines

The effect of Divigel on the ability to drive or use machines has not been evaluated.

Divigel contains propylene glycol and ethanol

This medicine contains 62.5 to 187.5 mg of propylene glycol in each 0.5 g to 1.5 mg dose.

This medicine contains 275 to 824 mg of alcohol (ethanol) in each 0.5 g to 1.5 mg dose. It may cause a burning sensation on damaged skin.

3. How to use Divigel

Follow your doctor's or pharmacist's administration instructions for this medication exactly. If in doubt, consult your doctor or pharmacist again.

When to start using Divigel

You can start using Divigel on any day if:

• You have never used HRT
• You are switching from an HRT where you do not have menstruation

Wait until your menstruation ends if:

• You are switching from an HRT where you do have menstruation

If you have not had a hysterectomy, your doctor will likely also prescribe another medication containing the progestogen hormone.It is usually a tablet that you take for 12 to 14 days in monthly cycles. After each progestogen cycle, you will have a withdrawal bleed, like a menstruation.

How much to use

Divigel comes in sachets of 0.5 mg of estradiol in 0.5 g of gel or in sachets of 1 mg of estradiol in 1 g of gel.

• Each Divigel 0.5 mg gel transdermal pack contains only 0.5 g sachets.
• Each Divigel 1 mg gel transdermal pack contains only 1 g sachets

Use the amount of Divigel transdermal gel that your doctor has prescribed. Your doctor will try to prescribe the lowest dose to treat your symptoms for the shortest necessary time. Consult your doctor if you think this dose is too strong or not strong enough for you.

• The recommended dose is between 0.5 mg and 1.5 mg of estradiol per day
• Use the following quantities of 0.5 g or 1 g sachets according to the dose and pack that your doctor has prescribed:

For a daily dose of 0.5 mg:Use one 0.5 g sachet.

For a daily dose of 1 mg: You have two options. Use one 1 g sachet or use two 0.5 g sachets.

For a daily dose of 1.5 mg: There are two options: use three 0.5 g sachets or use one 0.5 g sachet along with one 1 g sachet.

If you are also taking progestogen tablets, take them as your doctor has indicated. You will usually have a withdrawal bleed after each progestogen cycle.

Important

If you use Divigel every day, note the day of the week and the date you started treatment on the flap under the lid of the medicine pack. This way, if you can't remember if you used your daily dose, you can check.

How to apply the gel

Divigel should be gently spread over clean, dry skin. It should not be ingested.

Where to apply the gel

• Do not apply the gel to your breasts, face, irritated skin, or vagina
• Apply the gel to the lower abdomen or thighs.
• Apply the gel to a different side of the body each day.

Follow these instructions:

1. Apply the gel once a dayto the skin of the lower abdomen or thighs
2. Spread the gel over an area the size of 1 or 2 times your hand
3. Let the gel dry for a few minutes
4. Wash your hands after applying the gel. Avoid getting the gel in your eyes. The gel can irritate your eyes.
5. Do not wash the area where the gel was applied for at least one hour
6. Do not let others touch the skin area where the gel was applied until it has dried; cover it with clothing if necessary.

If you need to undergo surgery (an operation)

If you are going to undergo surgery, inform the surgeon that you are using Divigel. It may be necessary for you to stop using Divigel for about 4 to 6 weeks before the operation to reduce the risk of blood clot formation (see section 2, "Blood clots in a vein"). Ask your doctor when you can start using Divigel again.

If you use more Divigel than you should

If you use more gel than you should, contact your doctor or pharmacist.

You may feel bloated, anxious, or irritable, or you may feel breast tenderness. In some women, nausea, vomiting, and withdrawal bleeding may also occur.

Overdose with transdermal gel is unlikely. The treatment is symptomatic. The gel should be washed off. The symptoms disappear when treatment is stopped or when the dose is reduced.

In case of overdose or accidental ingestion, consult your doctor or pharmacist or call the Toxicology Information Service. Phone 915 620 420, indicating the medication and the amount used.

In case of Divigel ingestion

In case of Divigel ingestion, there is no need to worry. However, consult your doctor.

If you forget to take Divigel

• If you forget a dose, skip it and continue with your usual treatment the next day
• Do not take a double dose to make up for forgotten doses.
• If you forget a dose, you may experience intermenstrual bleeding. This is called withdrawal bleeding.

If you interrupt treatment with Divigel

Use this medication as your doctor has prescribed. Continue using Divigel even if you feel better. If you interrupt treatment too soon or too abruptly, symptoms may recur.

If you have any other questions about using this medication, ask your doctor or pharmacist

4. Possible side effects

Like all medications, this medication can cause side effects, although not everyone will experience them.

Stop using Divigel and contact your doctor or the nearest emergency service immediatelyif you experience any of the following symptoms:

• Painful swelling of your leg
• Chest pain
• Difficulty breathing

The following diseases have been reported more frequently in women using HRT than in women not using HRT:

• breast cancer
• abnormal growth or cancer of the lining of the uterus (hyperplasia or endometrial cancer)
• ovarian cancer
• blood clots in the veins of the legs or lungs (venous thromboembolism)
• heart disease
• stroke (apoplexy)
• possible memory loss if HRT is started after age 65

For more information on these side effects, see section 2.

The potential side effects caused by Divigel are usually mild and rarely lead to treatment interruption. They occur more frequently at the beginning of treatment.

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

• breast tenderness, pain, or tension
• headache, dizziness
• swelling, weight gain, or weight loss
• unexpected bleeding, spotting, or discharge from the vagina
• vulvar and vaginal symptoms
• nausea, vomiting, stomach cramps, flatulence
• skin irritation, itching, or pain at the application site, increased sweating
• depression, nervousness, drowsiness
• hot flashes

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

• migraine (headaches), sensory disorders
• mood changes, emotional changes, and changes in libido (sexual desire), anxiety, insomnia, apathy, concentration changes
• benign tumor in the breast or endometrium
• increased appetite
• palpitations
• constipation
• acne, hair loss, dry skin
• joint disorder, muscle cramps
• fatigue
• hypersensitivity reactions
• vision changes
• urticaria or hives (elevated and itchy skin rash)
• erythema nodosum (red and painful nodules on the skin)

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

• blood clots in a vein
• high blood pressure
• changes in liver and bile duct function
• rash
• intolerance to contact lenses
• painful menstruation
• symptoms similar to premenstrual syndrome (PMS)

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

• benign uterine fibroids
• worsening of inherited or acquired angioedema
• increased blood cholesterol levels
• unfounded feeling of well-being (euphoria), agitation
• tremors
• dry eyes
• cerebral circulation disorder, superficial inflammation of a vein, red spots on the skin
• shortness of breath, runny nose
• abdominal discomfort such as abdominal pain and diarrhea
• liver disease causing yellowing of the skin
• rashes, nodules on the skin, nail symptoms, excessive hair growth
• urinary incontinence, inflammation of the bladder, urine discoloration
• uterine symptoms
• abnormal laboratory test results, weakness, fever, cold-like symptoms, feeling of discomfort.

The following side effects have been reported in other HRTs:

• gallbladder disease
• possible dementia in people over 65 years old
• various skin disorders:
• • skin discoloration, especially on the face or neck, known as "pregnancy mask" (chloasma)
  • red rash in a target shape or sores (erythema multiforme)

If you are concerned about the risks of treatment, consult your doctor: they will provide detailed information about the study if necessary. Your doctor will assess the benefits and risks of this treatment at least once a year.

Reporting side effects

If you experience any side effects, consult your doctor or pharmacist, even if they are possible side effects not listed in this leaflet. You can also report them directly through the Spanish Medicines and Healthcare Products Agency's pharmacovigilance system: https://www.notificaram.es. By reporting side effects, you can help provide more information on the safety of this medication.

5. Storage of Divigel

Keep this medication out of sight and reach of children.

This medication does not require special storage conditions.

Do not use this medication after the expiration date shown on the packaging. The expiration date is the last day of the month indicated.

Medications should not be disposed of through wastewater or household waste. Deposit the packaging and any unused medication in the pharmacy's SIGRE point. If in doubt, ask your pharmacist how to dispose of the packaging and any unused medication. This will help protect the environment.

6. Package contents and additional information

Divigel composition

• The active ingredient is estradiol hemihydrate equivalent to 0.5 mg of estradiol in each 0.5 g sachet.
• The other ingredients are carbomer 974P, tromethamine, propylene glycol, 96% ethanol, and purified water.

Product appearance and packaging contents

Soft, opalescent transdermal gel presented in a sachet.

28 sachets of 0.5 g

91 sachets of 0.5 g

Not all pack sizes may be marketed.

Marketing authorization holder and manufacturer

Marketing authorization holder

Orion Corporation

Orionintie 1

FI 02200 Espoo

Finland

Manufacturer

Orion Corporation Orion Pharma

Tengströminkatu 8

FI-20360 Turku

Finland

You can request more information about this medication from the local representative of the marketing authorization holder:

Orion Pharma, S.L.

Phone: +34 915 998 601

Date of last revision of this leaflet:June 2024

Detailed information about this medication is available on the website of the Spanish Agency for Medicines and Healthcare Products (AEMPS) http://www.aemps.gob.es