Tablets 
estradiol valerate / medroxyprogesterone

Read all of this leaflet carefully before you start taking this medicine. It contains information that is important to you.

– Save this information, you may need to read it again.

– If you have any further questions, ask your doctor, pharmacist, or nurse.

– This medicine has been prescribed for you only. Do not give it to others. It can harm them, even if they show signs of illness similar to yours.

– If you get any side effects, talk to your doctor, pharmacist, or nurse. This also applies to any side effects not mentioned in this information. See section 4.

In this leaflet you will find information about: 
1. What Divina Plus is and what it is used for 
2. What you need to know before taking Divina Plus 
3. How to take Divina Plus 
4. Possible side effects 
5. How to store Divina Plus 
6. Contents of the packaging and other information 

1. What Divina Plus is and what it is used for

Divina Plus is a preparation used for hormonal substitution therapy ( HormoneReplacement Therapy, HRT ). It contains two female sex hormones; estrogen and a progestogen. Divina Plus is used for women whose menstruation has stopped ( menopause ), at least 6 months after their last natural menstruation.

Divina Plus is used to:

Relieve symptoms during and after menopause

When menstruation ends ( menopause ), the woman’s estrogen drops. It can cause problems such as sweating and hot flashes. Divina Plus relieves these symptoms after menopause. Divina Plus should only be used if the problems cause problems in daily life.

Prevent osteoporosis

After menopause, some women suffer from osteoporosis. Discuss all possible options with your doctor. If you have an increased risk of fractures (bone fractures) and other medicines that are not suitable for you, you can use Divina Plus to prevent osteoporosis after menopause .

2. What you need to know before taking Divina Plus

Medical background and regular check-ups

The use of HRT involves risks that must be taken into account when deciding to start treatment or continue an ongoing treatment.

Experience is limited for the treatment of women whose menstruation has stopped prematurely (when the ovaries have stopped working or the uterus has been removed). If you belong to that group, the risks of HRT may be different. Talk to your doctor.

Before starting treatment (or resuming treatment), your doctor will ask about your own, and your family’s, medical background. Your doctor may do a general medical and gynecological examination, which also includes an examination of your breasts. Once you have started treatment, you should go for regular medical check-ups, at least once a year. During these check-ups, you should discuss with your doctor the benefits and risks of continued treatment.

Perform regular breast examinations according to your doctor’s recommendations.

Do not take Divina Plus:

Do not take Divina Plus if any of the following apply to you. If you are not sure, talk to your doctor before taking Divina Plus:

– If you have or have had breast cancer or there is a suspicion that you may have it

– If you have or have had estrogen-dependent cancer, such as cancer of the uterine lining (endometrium), or if there is a suspicion of such cancer.

– If you have unexpected genital bleeding that has not been investigated by a doctor.

– If you have endometrial hyperplasia (severe thickening of the uterine lining) and are not being treated for it.

– If you have or have had a blood clot in a vein (venous thromboembolism ), in your legs (deep vein thrombosis ), or your lungs ( pulmonary embolism ).

– If you have a coagulation disorder, a condition with an increased risk of blood clots (lack of protein C, protein S, or antithrombin).

– If you have or have had a disease caused by blood clots in the arteries are as heart attack stroke (stroke), or angina.

– If you have or have had any liver disease and still have abnormal liver values.

– If you have porphyria, a rare inherited blood disorder.

– If you are allergic to estradiol valerate or medroxyprogesterone acetate or any of the other ingredients of this medicine (listed in section 6).

If any of the above affects you the first time you use Divina Plus, stop taking Divina Plus and contact your doctor immediately.

Warnings and cautions

Talk to your doctor, pharmacist, or nurse before using Divina Plus.

Talk to your doctor if you have or have had any of the following problems before starting treatment. They may recur or worsen during treatment with Divina Plus. Should this occur, have more frequent check-ups with a doctor.

  • If you have any disease affecting the lining of the uterus, as well as muscle knots ( fibroids ), endometriosis, or have had endometrial hyperplasia (severe thickening of the uterine lining).
  • If you have an increased risk of getting a blood clot (see below “Blood clots in a vein ( thrombosis )”)
  • If a close relative has had breast cancer or other estrogen-dependent cancer.
  • High blood pressure
  • Liver disease eg liver adenoma (benign tumor )
  • Diabetes
  • Gallstone disease
  • If you get a migraine or severe headache
  • If you have systemic lupus erythematosus ( SLE ) – an autoimmune disease that affects many organs in the body
  • Epilepsy
  • Asthma
  • Otosclerosis (ossification of the middle ear leading to a hearing loss)
  • Hypertriglyceridemia (elevated blood lipids)
  • Fluid deficiency due to heart or kidney disease
  • Angioedema (hereditary and acquired).

You should contact a doctor immediately and discontinue treatment if any of the following occur:

  • Some of what is mentioned in the section ‘Do not take Divina Plus’
  • If skin or whites of the eyes turn yellow (jaundice); it may be a symptom of liver disease
  • If your blood pressure rises sharply (symptoms may include headache, fatigue, or dizziness)
  • If you are experiencing migraine-like headaches for the first time
  • If you become pregnant
  • If you get symptoms of a blood clot, such as
    • painful swelling and redness of the legs
    • sudden chest pain
    • breathing difficulties

For further information, see below “Blood clots in a vein ( thrombosis )”

Note: Divina Plus is not a contraceptive. If it is less than 12 months since your last period, or if you are under 50, you may still need to use contraception to avoid pregnancy. Consult your doctor.

HRT and cancer

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

The use of HRT with estrogen alone increases the risk of severe thickening of the uterine lining and cancer of the uterine lining.

The progestogen in Divina Plus protects you against this extra risk.

Unexpected bleeding

You will have bleeding once a month (so-called dropout bleeding) when you take Divina Plus. But if you get unexpected bleeding or splashing in addition to your monthly bleeding, and these:

– lasts longer than 6 months

– starts after taking Divina Plus for 6 months

– continues after you stop taking Divina Plus

you should see a doctor as soon as possible.

Breast cancer

Data show that hormone replacement therapy ( HRT ) with combined estrogen-progestogen or with estrogen alone, increases the risk of breast cancer. The risk depends on the treatment time. The extra risk depends on how long you use HRT. The increased risk is seen within 3 years. When treatment is stopped, the increased risk decreases over time, but it can persist for 10 years or more if you have used HRT for more than 5 years.

Comparison

For women aged 50–54 who do not take HRT, an average of 13–17 out of 1,000 will be diagnosed with breast cancer over a 5-year period.

In women who are 50 years old and start taking HRT with estrogen alone for 5 years, 16-17 cases per 1,000 users (ie 0-3 extra cases) will occur.

For women over the age of 50 who start taking estrogen – the progestin HRT for 5 years, 21 out of 1,000 users will be diagnosed (ie 4-8 extra cases).

Among women aged 50-59 who do not take HRT, an average of 27 out of 1,000 will be diagnosed with breast cancer over a 10-year period.

In women who are 50 years old and start taking HRT with estrogen alone for 10 years, 34 cases per 1,000 users (ie 7 extra cases) will occur.

In women who are 50 years old and start taking HRT with estrogen-progestogen for 10 years, 48 ​​cases per 1,000 users (ie 21 extra cases) will occur.

Check your breasts regularly. Contact a doctor if you notice changes such as:

indentations or pits

changes in the nipple

nodules you can see or feel

It is also recommended that you participate in a mammography examination when you are called to do so. At the mammogram, you must tell the nurse/healthcare professional who performs the examination that you are using HRT, as this medicine may increase the density of the breasts. An increased density in the breasts can make it more difficult to detect lumps on the mammography images.

Ovarian cancer ( ovarian cancer )

Ovarian cancer is rare – much more rare than breast cancer. Use of HRT with estrogen alone or combined estrogen-progestogen has been associated with a slightly increased risk of ovarian cancer.

The risk of ovarian cancer varies with age. The diagnosis of ovarian cancer will, for example, be made on about 2 women out of 2,000 aged 50 to 54 who do not take HRT for a 5-year period. For women who have taken HRT for 5 years, there will be about 3 cases per 2,000 users (ie about 1 extra case).

How HRT affects the heart and blood circulation

Blood clots in a vein ( thrombosis )

The risk of blood clots in the veins is 1.3–3 times higher for women who take HRT than for those who do not, especially during the first year of treatment.

Blood clots can be serious. If a blood clot ends up in the lungs, it can cause chest pain, shortness of breath, collapse or even lead to death.

You are more likely to get a blood clot in a vein if any of the following apply to you. Tell your doctor if any of the following apply to you:

– You have not been able to walk or stand for a long time due to a major operation, injury or illness (see also section 3, “If you need surgery”)

– You are severely overweight ( BMI over 30 kg / m 2 )

– You have a coagulation disorder that requires long-term treatment with drugs that prevent blood clots

– If a close relative has had a blood clot in the bone, lung, or another organ

– You have SLE (systemic lupus erythematosus)

– You have cancer.

The symptoms of a blood clot are described in the section “You should contact a doctor immediately and stop the treatment”.

Comparison

For women in their 50s who do not take HRT, an average of 4-7 out of 1,000 people are expected to have a blood clot in a vein over a 5-year period.

For women in their 50s who have taken HRT with estrogen-progestogen for more than 5 years, 9-12 out of 1,000 users are expected to get a blood clot in a vein (ie 5 extra cases)

Heart disease (heart attack)

There is no evidence that HRT prevents heart attacks.

For women over the age of 60 who take HRT with estrogen-progestin, the risk of developing heart disease is slightly higher than those who do not take HRT.

Stroke (apoplexy)

The risk of stroke is about 1.5 times higher for those who take HRT compared to those who do not. The risk of stroke is age-dependent, therefore the number of cases of stroke increases due to the use of HRT with increasing age.

Comparison

For women in their 50s who do not take HRT, an average of 8 out of 1,000 people is expected to have a stroke over a 5-year period.

For women in their 50s who have taken HRT for more than 5 years, 11 out of 1,000 users are expected to have a stroke (ie 3 extra cases)

Other conditions

  • Estrogen therapy can cause fluid to build up in the body ( edema ), especially in women who suffer from impaired heart or kidney function.
  • Estrogen treatment can cause an increase in blood lipid levels ( triglycerides ), which in women with elevated levels of blood lipids can lead to a risk of inflammation of the pancreas ( pancreatitis ).
  • Using HRT does not prevent memory loss. The risk of memory loss may be slightly higher in women who start using HRT after the age of 65. Consult your doctor.
  • The results of certain laboratory tests (eg tests that measure thyroid function and liver function) may be affected by Divina Plus treatment.
  • If you have or have had chloasma (yellowish-brown pigmentation of the skin, especially in the face), do not expose yourself to sunlight or ultraviolet light when taking Divina Plus.

Other medicines and Divina Plus

Some medicines may affect the effect of Divina Plus, which may lead to irregular bleeding. The following applies:

  • Medicines for epilepsy (eg phenobarbital, phenytoin, and carbamazepine)
  • Medicines for tuberculosis (eg rifampicin, rifabutin)
  • Drugs for HIV – infection, and hepatitis C virus (called protease inhibitors and non-nucleoside reverse transcriptase inhibitors such as nevirapine, efavirenz, ritonavir, and nelfinavir)
  • An herbal medicine containing St. John’s wort ( Hypericum perforatum ).

Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.

Results from blood test analyze

If you need to take a blood sample, tell your doctor, or the person taking the blood sample, that you are taking Divina Plus as it may affect the results of some tests.

Pregnancy and breastfeeding

Divina Plus is intended for women whose menstruation has stopped. If you become pregnant, stop taking Divina Plus and consult a doctor.

Driving and using machines

Divina Plus is not expected to affect the ability to drive or use machines.

Divina Plus contains lactose

This medicine contains 82 mg (white tablet) and 68 mg (blue tablet) of lactose(monohydrate). If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.

How to take Divina Plus

Always take this medicine exactly as your doctor or pharmacist has told you. Ask your doctor or pharmacist if you are unsure.

Dosage

Dosing of Divina Plus takes place according to a calendar map with one tablet daily for 28-day cycles, without pauses between the calendar maps.

The treatment mimics the menstrual cycle: 9 tablets containing estrogen (white tablet) are accompanied by 12 tablets (blue tablet) with both estrogen and progestogen and finally there is a period of 7 tablets with estrogen (white tablet) when menstrual-like bleeding usually occurs. Women switching from another sequencing drug should start treatment the day after the end of the previous 28-day cycle.

It is advisable to take the tablet at about the same time each day.

Your doctor will strive to give you the lowest dose, which will give you relief of symptoms, and that you should use Divina Plus for the shortest possible time. Talk to your doctor if you do not get any relief from the symptoms, or feel that the dose is too high.

Bleeding pattern

During the first months of treatment, there may be a breakthrough or minor bleeding. If bleeding persists, consult your doctor for a re-evaluation of the treatment. Continuous or prolonged bleeding during a hormone treatment may in rare cases indicate endometrial hyperplasia or that the dosage is not right for you. If breakthrough or minor bleeding occurs only later in the treatment or if it persists after the end of treatment, contact your doctor.

If you need surgery

If you are going to have surgery, tell your surgeon that you are taking Divina Plus. You may need to stop taking Divina Plus for 4 to 6 weeks before surgery to avoid the risk of blood clots (see section 2, “Blood clots in a vein ( thrombosis )”). Ask your doctor when it is appropriate to start taking Divina Plus again.

If you take more Divina Plus then you should

If you have ingested too much medicine or if e.g. If a child has inadvertently ingested the medicine, contact a doctor, hospital, or the Poison Information Center for risk assessment and advice.

If you forget to take Divina Plus

If you forget to take a tablet at the usual time, try to take it within 12 hours. Otherwise, skip the tablet and take the next tablet at the next regular time. Do not take a double dose to make up for a forgotten dose.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

The following diseases are more common in women who take HRT than those who do not:

• Breast cancer

• Severe thickening of the uterine lining ( endometrial hyperplasia ) or cancer of the uterine lining (endometrial cancer)

• Ovarian cancer ( ovarian cancer )

• Blood clot in veins in bones or lungs (venous thromboembolism )

• Heart disease

• Stroke (apoplexy)

• Probable memory loss, if treatment with HRT is started after the age of 65

See section 2 for more information on these side effects.

The side effects of Divina Plus are most common during the first months of treatment. They are usually mild and subside with continued treatment.

The following side effects have been associated with HRT treatment:

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

  • weight gain or loss, swelling caused by fluid retention
  • depression, nervousness, lethargy
  • headache, dizziness
  • hot flashes, sweating
  • nausea, vomiting, abdominal cramps, flatulence
  • tension and pain in the breasts, discharge, bleeding or breakthrough bleeding, diseases of the external genitalia/vagina, menstrual disorders.

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

  • benign breast cancer, benign cancer of the uterus
  • allergic reaction ( hypersensitivity reaction )
  • increased appetite, high levels of cholesterol in the blood
  • anxiety, insomnia, apathy, mood swings, difficulty concentrating,
  • changes in sexual drive and mood, euphoria, agitation
  • migraine, the feeling of tingling, and crawling and numbness of the skin, tremors
  • visual disturbances, dry eyes
  • abnormally fast or irregular heartbeat
  • high blood pressure  superficial inflammation of the veins, redness or red spots on the skin
  • shortness of breath, runny or stuffy nose
  • constipation, indigestion/heartburn diarrhea, diseases of the rectum
  • acne, hair loss, dry skin, nail changes, skin nodules, severe hair growth ( hirsutism), painful red skin nodules (erythema nodosum), hives (itchy raised skin rashes)
  • joint diseases, muscle cramps
  • increased frequency of urination/urination, loss of bladder control, urinary tract infection, discoloration of the urine, blood in the urine
  • breast enlargement, breast tenderness, the thickened lining of the uterus, diseases of the uterus
  • fatigue, abnormal laboratory test results, weakness, fever, flu-like symptoms, general malaise

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

  • hypersensitivity to contact lenses
  • changes in liver function and bile flow
  • rash
  • blood clots in the veins of the leg or the lungs
  • painful menstruation ( dysmenorrhea ), PMS-like syndrome

Has been reported (occurs in an unknown number of users):

  • increase in the size of tissue nodules in the uterus (uterine fibroids)
  • exacerbation of symptoms of angioedema (hereditary and acquired as a severe allergic reaction with swelling of the tongue, pharynx, and eyes)
  • decreased blood flow to the brain or a part of the brain
  • abdominal pain, bloating, yellowing of the skin or eyes
  • eczema

The following side effects have been reported with other HRTs:

  • gallbladder disease
  • inflammation of the pancreas
  • myocardial infarction
  • various skin diseases:
    • dark skin spots, especially on the face and neck, so-called “pregnancy spots” (chloasma)
    • annular redness or sore rash (erythema multiforme).

Reporting of side effects ar

If you get any side effects, talk to your doctor, pharmacist, or nurse. This also applies to any side effects not mentioned in this information. You can also report side effects directly (see details below). By reporting side effects, you can help increase drug safety information.

The Medical Products Agency

Box 26

751 03 Uppsala

5. How to store Divina Plus

Keep this medicine out of the sight and reach of children.

Do not store above 25 ° C.

Do not use this medicine after the expiry date which is stated on the carton or blister. The expiration date is the last day of the specified month.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

6. Contents of the packaging and other information

Content declaration

White Divina Plus tablet:

The active substance is Estradiol valerate 2 mg.

The other ingredients are lactose monohydrate 86.6 mg, corn starch, gelatin, talc, magnesium stearate.

Blue Divina Plus tablet:

The active substances are Estradiol valerate 2 mg, medroxyprogesterone acetate 10 mg (MPA).

The other ingredients are lactose monohydrate 72 mg, corn starch, gelatin, talc, magnesium stearate, indigo carmine (dye E 132), povidone.

What the medicine looks like and the contents of the pack

White tablet: white or almost white, round, cupped, marked D, Ø 7 mm.

Blue tablet: light blue, round, flat, beveled edge, Ø 7 mm.

Packaging: Blister cards with 3×28 tablets.

Marketing Authorization Holder and Manufacturer

Marketing Authorisation Holder:

Orion Corporation

Orionintie 1

FI-02200 Espoo

Finland

Manufacturer:

Orion Corporation Orion Pharma

Orionintie 1

FI-02200 Espoo

Finland

Orion Corporation Orion Pharma

Connector current 8

FI-20360 Turku

Finland

Delpharm Little Sas – Lys Lez Lannoy

Roubaix-Est Activity Park

22 rue de Toufflers

CS 50070

Lys Lez Lannoy 59452

France

For further information on this medicine, please contact your local representative:

Orion Pharma AB, Danderyd

medinfo@orionpharma.com

Muhammad Nadeem

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