DIVIGEL 1 mg TRANSDERMAL GEL in SACHETS

• 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 hives, 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 cancer of the uterine lining (endometrial cancer)

Treatment with estrogen alone in HRT will increase the risk of excessive thickening of the uterine lining (endometrial hyperplasia) and cancer of the uterine lining (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, consult your doctor to see if you can safely use this medication 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 regular 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 apply:

• 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 are significantly overweight (body mass index > 30 kg/m2)
• you have a blood clotting disorder that requires long-term treatment with a medication used to prevent blood clots
• if any of your close relatives have ever had a blood clot in the leg, lung, or another 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 increased risk of heart disease compared to those who do not use 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, an average of 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 coming into 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 medications and Divigel

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

• Medications for epilepsy (such as phenobarbital, phenytoin, and carbamazepine).
• Medications for tuberculosis (such as rifampicin, rifabutin).
• Medications 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 medications:

• The epilepsy medication (lamotrigine), as it may increase the frequency of seizures
• Medications 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 containing 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 medication, including medications without a prescription, herbal remedies, 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 laboratory staff that you are using Divigel, as this medication 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 medication.

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

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

3. How to use Divigel

Follow the administration instructions for this medication exactly as indicated by your doctor or pharmacist. 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 changing from an HRT where you do not have menstruation

Wait until your menstruation ends if:

• You are changing 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 is available 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 transdermal gel pack contains only 0.5 g sachets.
• Each Divigel 1 mg transdermal gel pack contains only 1 g sachets

Use the amount of Divigel transdermal gel that your doctor has prescribed for you. Your doctor will try to prescribe the lowest dose to treat your symptoms for the shortest time necessary. 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 you:

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

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

For a daily dose of 1.5mg: 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 do not remember if you have 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 has been applied for at least one hour.
6. Do not let others touch the skin area where the gel has been applied until the gel 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. Telephone 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, leave it and continue with your usual treatment the next day
• Do not take a double dose to make up for forgotten doses.
• In case of forgetting a dose, intermenstrual bleeding may occur. 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 the use of 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
• hives or rash (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 the available data)

• benign uterine tumors
• worsening of inherited or acquired angioedema
• increased blood cholesterol levels
• unfounded feeling of well-being (euphoria), agitation
• tremor
• dry eyes
• disorder of cerebral circulation, 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, symptoms on the nails, excessive hair growth
• urinary incontinence, inflammation of the bladder, discoloration of the urine
• uterine symptoms
• abnormal laboratory test results, weakness, fever, symptoms similar to a cold, 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 type of side effect, consult your doctor or pharmacist, even if it is a possible side effect that does not appear in this leaflet. You can also report them directly through the Spanish Medicines and Healthcare Products Agency's online platform: 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 collection 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

Composition of Divigel

• 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, ethanol 96%, and purified water.

Appearance of the product and package 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.

Telephone: +34 915 998 601

Date of the last revision of thisleaflet: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