Divina

Package leaflet: Information for the user

Please read this leaflet carefully before using the medicine, as it contains important information for the patient.

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

Table of contents of the leaflet

1. What Divina is and what it is used for
2. Important information before taking Divina
3. How to take Divina
4. Possible side effects
5. How to store Divina
6. Contents of the pack and other information

1. What Divina is and what it is used for

Divina is a cyclic, biphasic medication intended for use in hormone replacement therapy (HRT). This medicine contains two types of female hormones: estradiol valerate (an estrogen) and medroxyprogesterone acetate (a progestagen).

Divina is used:

To relieve postmenopausal symptoms
During menopause, the amount of estrogen produced by a woman's body decreases. This may result in symptoms such as sudden feelings of heat in the face, neck, and chest (hot flushes). Divina helps to relieve these postmenopausal symptoms. Divina is prescribed only when symptoms significantly impair the patient's daily life.

For the prevention of osteoporosis
After menopause, some women develop brittle bones (osteoporosis). All available treatment options should be discussed with the treating physician. If a patient is at increased risk of fractures due to osteoporosis and other medications are not suitable, Divina may be used to prevent osteoporosis.

Experience with treatment in patients over 65 years of age is limited.

2. Important Information Before Using Divina

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

When Not to Use Divina:
If any of the following apply to you, or if you have any doubts about any of the following points, you should consult your doctor before using Divina.

Do not use Divina:

• if you are allergic to the active substances or any of the other ingredients of this medicine (listed in section 6),
• if you have or have had breast cancer or if breast cancer is suspected,
• if you have a malignant estrogen-sensitive tumour, such as cancer of the lining of the womb (endometrium), or if such a tumour is suspected,
• if you have vaginal bleeding of unknown cause,
• if you have untreated excessive thickening of the lining of the womb (endometrial hyperplasia),
• if you have or have had venous thrombosis (venous thromboembolic disease) in the legs (deep vein thrombosis) or 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 arterial thromboembolic disorders, such as myocardial infarction, stroke, or angina pectoris,
• if you have or have had liver disease and liver function tests have not returned to normal,
• if you have a rare inherited blood disorder called porphyria.

If any of the above conditions occur for the first time while taking Divina, stop taking the medicine immediately and contact your doctor without delay.

Warnings and Precautions
Before starting Divina, discuss this with your doctor or pharmacist.
Before starting treatment, inform your doctor if you currently have or have had any of the following conditions, as they may recur or worsen during treatment with Divina. In the following cases, the frequency of check-up visits should be increased:

• uterine fibroids (myomas),
• endometriosis (growth of the endometrial tissue outside the uterus) or previous cases of excessive endometrial growth (endometrial hyperplasia),
• increased risk of venous thromboembolic disorders (see "Blood clots in the veins (thrombosis)"),
• increased risk of estrogen-sensitive cancer (e.g., if your mother, sister, or grandmother had breast cancer),
• high blood pressure,
• liver function disorders, such as benign liver tumour,
• diabetes with or without vascular complications,
• gallstones,
• severe headaches or migraine-type headaches,
• an autoimmune disease affecting multiple organs (systemic lupus erythematosus, SLE),
• epilepsy,
• asthma,
• a condition affecting the eardrum and hearing (otosclerosis),
• very high levels of fats (triglycerides) in your body,
• fluid retention due to heart or kidney problems,
• hereditary or acquired angioedema (a condition characterised by swelling, usually of the face, limbs, and joints).

Stop taking Divina and contact your doctor immediately
if you notice any of the following symptoms while using HRT:

• any of the diseases listed under "When not to use Divina",
• yellowing of the skin or whites of the eyes (jaundice); these may be signs of liver disease,
• swelling of the face, tongue and (or) throat and (or) difficulty swallowing or hives, together with breathing difficulties, which may indicate angioedema,
• a significant increase in blood pressure (possible symptoms include headache, fatigue, dizziness),
• new-onset migraine-type headaches,
• if you become pregnant,
• if you notice signs of blood clot formation, such as:
• painful swelling and redness in the legs,
• sudden chest pain,
• difficulty breathing. More information is available under "Blood clots in the veins (thrombosis)".

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

HRT and Malignant Tumours

Excessive thickening of the endometrium (endometrial hyperplasia) and cancer of the endometrium
Using oestrogen-only HRT increases the risk of excessive thickening of the endometrium (endometrial hyperplasia) and cancer of the endometrium.
Using oestrogens in combination with a progestagen for at least 12 days per cycle, or continuous combined therapy, significantly reduces this additional risk.
In women with an intact uterus who do not use HRT, an average of 5 out of 1,000 women aged 50 to 65 will be diagnosed with endometrial cancer.
In women with an intact uterus who use oestrogen-only HRT, 10 to 60 out of 1,000 women will be diagnosed with endometrial cancer (i.e., 5 to 55 additional cases), depending on the dose and duration of treatment.

Irregular Bleeding
Irregular bleeding or spotting may occur during the first 3–6 months of using Divina. If irregular bleeding:

• lasts longer than the first 6 months,
• occurs after you have been taking Divina for more than 6 months,
• continues after stopping Divina, you should see your doctor immediately.

Breast Cancer
Evidence confirms that taking hormone replacement therapy (HRT) in the form of oestrogen-progestagen combination or oestrogen-only increases the risk of breast cancer. The additional risk depends on how long you use HRT. This additional risk becomes apparent after 3 years of HRT use. After stopping HRT, the additional risk gradually decreases, but may persist for 10 years or longer if HRT was used for more than 5 years.

Comparison
In women aged 50 to 54 who do not use HRT, breast cancer will be diagnosed in an average of 13 to 17 out of 1,000 women over 5 years.
In women aged 50 who start a 5-year oestrogen-only HRT, the number of cases will be 16–17 per 1,000 women (i.e., 0 to 3 additional cases).
In women aged 50 who start a 5-year oestrogen-progestagen HRT, the number of cases will be 21 per 1,000 women (i.e., 4 to 8 additional cases).
In women aged 50 to 59 who do not use HRT, breast cancer will be diagnosed in an average of 27 out of 1,000 women over 10 years.
In women aged 50 who start a 10-year oestrogen-only HRT, the number of cases will be 34 per 1,000 women (i.e., 7 additional cases).
In women aged 50 who start a 10-year oestrogen-progestagen HRT, the number of cases will be 48 per 1,000 women (i.e., 21 additional cases).

Regularly examine your breasts. Contact your doctor if you notice any changes such as:

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

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

Ovarian Cancer
Ovarian cancer is rare—much rarer than breast cancer. Using HRT with oestrogen-only or oestrogen-progestagen combinations is associated with a slightly increased risk of ovarian cancer.
The risk of ovarian cancer depends on age. For example, in women aged 50–54 who do not use HRT, ovarian cancer will be diagnosed in about 2 out of 2,000 women over 5 years. In women who have used HRT for 5 years, it will occur in about 3 out of 2,000 women (i.e., about 1 additional case).

Effects of HRT on the Heart and Circulation

Blood Clots in the Veins (Thrombosis)
The risk of developing venous thromboembolic disease is approximately 1.3 to 3 times higher in women using HRT than in women who do not, especially during the first year of therapy.
Blood clots can have serious consequences and, if a clot travels to the lungs, may cause chest pain, shortness of breath, fainting, or even death.
The likelihood of developing blood clots in the veins increases with age and depending on the presence of the following factors. Inform your doctor if any of the following situations apply:

• you are unable to walk for a prolonged period due to major surgery, injury, or illness (see also section 3 "If you need surgery"),
• you are obese (BMI >30 kg/m²),
• you have a blood clotting disorder requiring long-term anticoagulant treatment,
• if any close relatives have had a blood clot in the leg, lung, or another organ,
• you have had extensive surgery,
• you have systemic lupus erythematosus,
• you have cancer,
• you are pregnant or in the postpartum period.

Symptoms of a blood clot are listed under "Stop taking Divina and contact your doctor immediately".

Comparison
In women aged 50 to 59 who do not use HRT, a venous thrombosis will likely occur in an average of 4 to 7 out of 1,000 women over 5 years.
Among women aged 50 to 59 who have used combined oestrogen-progestagen HRT for more than 5 years, a venous thrombosis will occur in 9 to 12 out of 1,000 women (i.e., 5 additional cases).

Heart Disease (Myocardial Infarction)
There is no scientific evidence that HRT prevents heart attacks.
Women over 60 years of age who use combined oestrogen-progestagen HRT have a slightly higher risk of heart disease than women who do not use HRT.

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

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

Other Medical Conditions

• HRT does not prevent cognitive decline. Evidence suggests an increased risk of dementia in women who start HRT after age 65. Consult your doctor.
• Oestrogens may cause fluid retention, particularly in patients with heart or kidney dysfunction.
• HRT may affect the results of certain endocrine tests and liver function tests. Inform your doctor that you are taking Divina before undergoing such tests.
• You should inform your doctor if you know you have high triglyceride levels in your blood. In very rare cases, a significant increase in blood triglyceride levels during oestrogen therapy may lead to pancreatitis.
• Divina does not prevent pregnancy. Therefore, it should not be used as a contraceptive.

Divina and Other Medicines
Some medicines may interfere with the action of Divina, which may lead to irregular bleeding. These include:

• medicines used to treat epilepsy (e.g., phenobarbital, phenytoin, carbamazepine),
• medicines used to treat tuberculosis (e.g., rifampicin, rifabutin),
• medicines used to treat HIV infection and hepatitis C virus (HCV)
• (protease inhibitors and non-nucleoside reverse transcriptase inhibitors (e.g., nevirapine, efavirenz, ritonavir, nelfinavir)),
• herbal preparations containing St John's wort ( Hypericum perforatum ).

Hormone replacement therapy with oestrogen may affect how other medicines work. This applies to:

• the antiepileptic medicine lamotrigine, as this may increase the risk of seizures.
• medicines used to treat hepatitis C (HCV) (such as the combination regimen of ombitasvir/paritaprevir/ritonavir with or without dasabuvir, or the combination regimen of glecaprevir/pibrentasvir), as they may cause increased blood test values indicating liver function [increased activity of the liver enzyme alanine aminotransferase (AlAT)] in women using combined hormonal contraceptives containing ethinylestradiol. It is not known whether concomitant use of Divina with these HCV treatment regimens may increase AlAT enzyme activity.

Tell your doctor or pharmacist about all medicines you are currently taking, have recently taken, or might take in the future, including those available without a prescription, herbal medicines, or other natural products. Your doctor will advise you accordingly.

Laboratory Tests
If blood tests are required, inform the laboratory staff that you are taking Divina, as it may affect the results of certain tests.

Pregnancy and Breastfeeding
Divina is intended for use only in postmenopausal women. If you become pregnant, stop taking Divina and contact your doctor.
Divina is contraindicated during breastfeeding.

Driving and Operating Machinery
No effects on the ability to drive or operate machinery have been observed.

Divina contains lactose.
If you have previously been diagnosed with intolerance to certain sugars, you should consult your doctor before taking this medicine.
One white tablet contains 86.6 mg of lactose; one blue tablet contains 72.0 mg of lactose.

3. How to use the medicine Divina

This medicine should always be taken exactly as directed by your doctor. If in doubt, consult your doctor.
Your doctor will aim to prescribe the lowest effective dose needed to treat symptoms, for the shortest possible duration. If you feel that the dose is too high or too low, inform your doctor.

Divina should be taken according to the instructions on the calendar pack, one tablet daily in 21-day cycles without interruption, followed by a 7-day break from tablets. During the tablet-free interval, most women will experience a withdrawal bleed similar to menstruation. It is recommended to take the tablet in the evening.

1. Each blister has the label "First day" with the days of the week marked. Mark the day of the week on the blister (e.g. by making a hole) when treatment is started. This allows easy checking whether tablets have been taken according to schedule.
2. Postmenopausal women may start treatment immediately. Women who still have menstrual cycles should start treatment on the fifth day of the menstrual cycle (the fifth day from the start of menstruation).
3. Women who have not previously used HRT, or those switching from another continuous combined HRT product, may start treatment on any convenient day.
4. Women switching from cyclic or continuous sequential HRT should start Divina the day after completing the previous 28-day treatment cycle.
5. Tablets should be taken in the order shown on the packaging – first the white tablets, then the blue tablets. After this, there is a 7-day break. During this time, most women will experience a withdrawal bleed.
6. The next cycle of tablet-taking should begin on the same day of the week as the first cycle started. Some women may not have a bleed during the 7-day treatment break, or bleeding may occur only in some cycles.

In case of bleeding
During the first few months of treatment, breakthrough bleeding and spotting may occur. Contact your doctor if prolonged or irregular bleeding occurs. It may be helpful to record the dates of bleeding, as your doctor may ask about this during visits.
If you feel that the effect of Divina is too strong or insufficient, do not change the dose or stop taking the medicine without first consulting your doctor.

If surgery is required
Inform your surgeon that you are taking Divina. It may be necessary to stop taking Divina 4 to 6 weeks before surgery to reduce the risk of blood clots (see section 2 "Blood clots in veins"). Consult your doctor about when you may resume taking Divina.

Taking more Divina than prescribed
No serious symptoms of overdose have been observed after large oral doses of HRT medicines. Estrogen overdose may cause nausea, headache, and vaginal bleeding. If you take more Divina than prescribed, contact your doctor or pharmacist immediately.

Missing a dose of Divina
If one tablet is missed, take it the next morning and take the tablet for that day in the evening as usual. If you completely forget to take a tablet, continue with the next tablet in the pack. A small breakthrough bleed during the cycle may occur.
If planning a longer trip, ensure you have an adequate supply of tablets.
Do not take a double dose to make up for a missed dose.

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

4. Possible adverse effects

Like all medicines, this medicine can cause adverse effects, although not everyone will experience them.
The Divina medicine may cause adverse effects, particularly during the first months of treatment. These are
usually mild and subside during continued treatment.
The most common adverse effects during treatment with Divina are headache and breast tenderness
(in 10% of patients).

The following diseases are reported more frequently in women using hormone replacement therapy (HRT) than in those who do not use it:

• breast cancer,
• abnormal endometrial growth or cancer of the lining of the womb (endometrial hyperplasia or endometrial cancer),
• ovarian cancer,
• blood clots in the veins of the legs or lungs (venous thromboembolic disorders),
• heart diseases,
• stroke,
• risk of dementia if HRT is initiated after the age of 65.

More information about the above adverse effects is provided in section 2.

Common (may affect up to 1 in 10 people)

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

Uncommon (may affect up to 1 in 100 people)

• mood changes, decreased libido, anxiety, insomnia, apathy, emotional lability, difficulty concentrating, euphoria, restlessness,
• migraine, numbness, convulsions,
• visual disturbances, dry eyes,
• hypertension, superficial thrombophlebitis, purpura,
• shortness of breath, catarrh,
• benign breast or endometrial tumour,
• increased appetite, high blood cholesterol levels,
• palpitations,
• constipation, dyspepsia, diarrhoea, anorectal disorders,
• acne, alopecia, dry skin, nail disorders, skin nodules, hirsutism, erythema nodosum, urticaria,
• joint disorders, muscle cramps,
• increased frequency of urination and/or increased urge to urinate, urinary incontinence, cystitis, discoloured urine, haematuria,
• breast tenderness or swelling, endometrial hyperplasia, uterine disorders,
• fatigue, abnormal laboratory test results, asthenia, fever, flu, malaise,
• hypersensitivity.

Rare (may affect up to 1 in 1000 people)

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

Not known (frequency cannot be estimated from available data)

• uterine fibroids (leiomyomas),
• exacerbation of hereditary or acquired angioedema,
• cerebrovascular disorders (episodes of cerebral ischaemia),
• abdominal pain, bloating,
• liver disorders causing yellowing of the skin (cholestatic jaundice),
• eruption.

The following adverse effects have been observed with other HRTs:

• myocardial infarction,
• gallbladder disorders,
• various skin and subcutaneous tissue disorders:
• skin pigmentation, particularly on the face or neck, known as "melasma" (chloasma),
• painful skin nodules (erythema nodosum),
• rash with erythematous ring-shaped lesions or ulceration (erythema multiforme).

Reporting of adverse effects
If any adverse effects occur, including any adverse effects not listed in this leaflet, inform your doctor or pharmacist.
Adverse effects can be reported directly to the Department of Monitoring Adverse Drug Reactions, Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
Al. Jerozolimskie 181C, 02-222 Warsaw
Tel.: + 48 22 49 21 301
Fax: + 48 22 49 21 309
Website: https://smz.ezdrowie.gov.pl
Adverse effects can also be reported to the marketing authorisation holder.
Reporting adverse effects helps to provide more information on the safety of the medicine.

5. How to store the medicine Divina

The medicine should be stored in a place inaccessible and out of sight 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 stated month.
Do not store above 25°C.
Medicines must not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer in use. This will help protect the environment.

6. Contents of the pack and other information

What Divina contains
Each white tablet contains:

• The active substance: 2 mg estradiol valerate.
• The other ingredients: monohydrate lactose, maize starch, gelatin, talc, magnesium stearate.

Each blue tablet contains:

• The active substances: 2 mg estradiol valerate and 10 mg medroxyprogesterone acetate.
• The other ingredients: monohydrate lactose, maize starch, indigotine (E 132), gelatin, povidone, talc, magnesium stearate.

What Divina looks like and contents of the pack
Pack size
The blister contains 21 tablets (11 white + 10 blue).
1 or 3 blisters in a cardboard box.

Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder
CS 50070
Lys Lez Lannoy 59452
France
For further information regarding this medicinal product, please contact the local representative of the Marketing Authorisation Holder:
Orion Pharma Poland Sp. z o.o.
[email protected]