Bijuve

Patient Information Leaflet

BIJUVA 1 mg/100 mg soft capsules

estradiol/progesterone
Please read all of this leaflet carefully before taking this medicine, because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not give it to others, even if they have the same symptoms as yours, because it could be harmful.
• If you experience any side effects, including those not listed in this leaflet, talk to your doctor or pharmacist. See section 4.

Contents of this leaflet

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

1. What BIJUVA is and what it is used for

BIJUVA is a Hormone Replacement Therapy (HRT).
It contains two types of female hormones, an oestrogen and a progestogen. BIJUVA is used in postmenopausal women who have been without a natural menstrual period for at least 12 months (1 year).
Relief of symptoms occurring after menopause
During menopause, the amount of oestrogen produced by a woman's body decreases. This may cause symptoms such as flushing of the face, neck, and chest ("hot flushes"). BIJUVA can relieve these symptoms after menopause.
BIJUVA will only be prescribed if your symptoms are severe enough to interfere with your normal daily life.

2. What you should know before taking BIJUVA

Medical history and regular check-ups
HRT carries certain risks that must be considered when deciding whether to start or continue treatment.
Experience with treating premature menopause (due to ovarian dysfunction or surgical intervention) is limited. If you are experiencing early menopause, the risks associated with HRT may differ in significance. Please consult your doctor.
Before starting (or restarting) HRT, your doctor will ask about your personal and family medical history. Your doctor may decide to perform a medical examination, which may include a breast examination and/or internal pelvic exam, if necessary.
Once you have started treatment with BIJUVA, you must have regular medical check-ups (at least once a year). During these visits, you can discuss with your doctor the risks and benefits of continuing BIJUVA therapy.
Undergo regular mammographic screening as recommended by your doctor.

Do not take BIJUVA:
if any of the following conditions apply to you. If you have any doubts about any of the points listed below, consult your doctor before taking BIJUVA.

Do not take BIJUVA

• If you are allergic to estradiol hemihydrate or progesterone or to any of the other ingredients of this medicine (listed in section 6).
• If you have or have previously had breast cancer, or if breast cancer is suspected.
• If you have or are suspected of having an estrogen-sensitive tumour, such as cancer of the lining of the uterus (endometrium).
• If you experience unexplained vaginal bleeding.
• If you have excessive thickening of the lining of the uterus (endometrial hyperplasia) that has not been treated.
• If you have or have previously been treated for a blood clot (thrombus) in a vein (venous thrombosis), for example in the legs (deep vein thrombosis) or in the lungs (pulmonary embolism).
• If you have blood clotting disorders (e.g. deficiency of protein C, protein S or antithrombin).
• If you suffer or have recently suffered from an arterial disease caused by blood clots, such as heart attack, stroke, or angina.
• If you have or have had liver disease and your liver function tests are not within normal limits.
• If you suffer from a rare inherited blood disorder called “porphyria”. If any of the above conditions occurs for the first time while using BIJUVA, stop treatment immediately and consult your doctor without delay.

Warnings and precautions
Inform your doctor if you currently suffer or have previously suffered from any of the following conditions before starting treatment, as these conditions may recur or worsen during treatment with BIJUVA. In such cases, more frequent medical check-ups may be required:
uterine fibroids;
endometriosis (growth of uterine lining tissue outside the uterus); or history of abnormal growth of the uterine lining (endometrial hyperplasia);
increased risk of developing blood clots (see “Blood clots in a vein (thrombosis)”);
increased risk of developing tumours sensitive to estrogens (such as having a mother, sister, or grandmother who had breast cancer);
high blood pressure;
liver disorders, such as benign liver tumour;
diabetes;
gallstones;
migraine or severe headaches;
an autoimmune disease affecting multiple organs (systemic lupus erythematosus, SLE);
epilepsy;
asthma;
a disease affecting the eardrum and hearing (otosclerosis);
very high levels of fats in the blood (triglycerides);
fluid retention due to heart or kidney problems;
hereditary or acquired angioedema.

Stop taking BIJUVA and contact your doctor immediately if any of the following conditions occur during HRT treatment:

• any of the conditions listed under “Do not take BIJUVA”;
• yellowing of the skin or whites of the eyes (jaundice), which may be signs of liver disease;
• swelling of the face, tongue and/or throat and/or difficulty swallowing or hives, with breathing difficulties, which are signs of angioedema;
• a significant increase in blood pressure (symptoms may include headache, fatigue, dizziness);
• a first occurrence of a migraine-type headache;
• pregnancy;
• signs of a blood clot, such as:
• painful swelling and redness in the legs;
• sudden chest pain;
• difficulty breathing. For further information, see “Blood clots in a vein (thrombosis)”.
• very high levels of fats in the blood (triglycerides);
• fluid retention due to heart or kidney problems.

Note: BIJUVA 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, you may need to use additional contraceptive measures to avoid pregnancy. Please consult your doctor for advice.

HRT and cancer
Excessive thickening of the lining of the uterus (endometrial hyperplasia) and cancer of the lining of the uterus (endometrial carcinoma)
Using estrogen-only HRT increases the risk of excessive thickening of the lining of the uterus (endometrial hyperplasia) and cancer of the lining of the uterus (endometrial carcinoma).
The progestogen component in BIJUVA protects against this additional risk.

Irregular bleeding
You may experience irregular bleeding or spotting during the first 3–6 months of using BIJUVA. However, if irregular bleeding:
• persists beyond the first 6 months of treatment
• occurs after more than 6 months of treatment with BIJUVA
• continues after stopping BIJUVA treatment
consult your doctor as soon as possible.

Breast cancer
Evidence shows that taking combined estrogen-progestogen HRT or estrogen-only HRT increases the risk of breast cancer. The additional risk depends on the duration of HRT use. This increased risk becomes apparent within 3 years of use. After stopping HRT, the additional risk gradually decreases over time, but may persist for 10 years or more if HRT has been used for more than 5 years.

Comparison
Among women aged 50 to 54 years not using HRT, breast cancer will be diagnosed in approximately 13–17 out of 1,000 over a 5-year period.
Among women aged 50 who start estrogen-only HRT for 5 years, there will be 16–17 cases per 1,000 users (i.e. 0–3 additional cases).
Among women aged 50 who start combined estrogen-progestogen HRT for 5 years, there will be 13–21 cases per 1,000 women treated (i.e. 4–8 additional cases).
Among women aged 50–59 not using HRT, breast cancer will be diagnosed in an average of 27 out of 1,000 over 10 years.
Among women aged 50 who start estrogen-only HRT for 10 years, there will be 34 cases per 1,000 users (i.e. 7 additional cases).
Among women aged 50 who start combined estrogen-progestogen HRT for 10 years, there will be 48 cases per 1,000 users (i.e. 21 additional cases).

• Regularly examine your breasts. Consult your doctor if you notice any changes such as:
  • skin retraction;
  • changes in the appearance of the nipple;
  • any visible or palpable hardening.

You are also advised to participate in mammographic screening programmes when available. For mammographic screening, it is important to inform the nurse/healthcare professional performing the X-ray that you are using hormone replacement therapy (HRT), as HRT may increase breast density and thus affect the mammogram image. In cases of increased breast density, mammography may not detect all lumps.

Ovarian cancer
Ovarian cancer is much rarer than breast cancer. The use of estrogen-only or combined estrogen-progestogen therapy has been associated with a slight increase in the risk of ovarian cancer.
The risk of ovarian cancer varies with age. For example, among women aged 50–54 not using HRT, about 2 in 2,000 will be diagnosed with ovarian cancer over 5 years. Among women using HRT for 5 years, there will be about 3 cases per 2,000 women treated (i.e. about 1 additional case).

Effect of HRT on the heart and circulation
Blood clots in a vein (thrombosis)
The risk of developing blood clots in veins is approximately 1.3 to 3 times higher in women using HRT compared to non-users, especially during the first year of treatment.
Blood clots can be dangerous; if a clot travels to the lungs, it can cause chest pain, shortness of breath, fainting, or even death.
The likelihood of developing venous blood clots increases with age and with the presence of any of the following conditions. Therefore, inform your doctor if any of the following apply to you:

• you are unable to walk for prolonged periods due to major surgery, injury, or illness (see also section 3 if you are scheduled for surgery);
• you are severely overweight (BMI >30 kg/m²);
• you have blood clotting disorders requiring long-term anticoagulant therapy;
• a close relative has had blood clots in the legs, lungs, or other organs;
• you have systemic lupus erythematosus (SLE);
• you have cancer.

For information on signs of blood clots, see “Stop taking BIJUVA and contact your doctor immediately”.

Comparison
Among women over 50 not using HRT, it is estimated that 4 to 7 out of 1,000 will develop venous blood clots over 5 years.
Among women around 50 using combined estrogen-progestogen HRT for 5 years, the number rises to 9–12 per 1,000 (i.e. 5 additional cases).

Heart disease (heart attack)
There is no evidence that HRT protects against heart attacks.
Women over 60 years of age using combined estrogen-progestogen HRT have a slightly higher risk of developing heart disease compared to women not using HRT.

Stroke
The risk of stroke is approximately 1.5 times higher in women using HRT compared to non-users. The number of additional stroke cases due to HRT use increases with age.

Comparison
Among women over 50 not using HRT, it is estimated that 8 out of 1,000 will have a stroke over 5 years. Among women around 50 using HRT, the number increases to 11 per 1,000 over 5 years (i.e. 3 additional cases compared to non-users).

Other conditions
HRT does not prevent memory loss. There is some evidence of an increased risk of memory loss in women who start HRT after age 65. Please consult your doctor.

Children
BIJUVA is not indicated for use in children.

Other medicines and BIJUVA
BIJUVA may interfere with the way other medicines work. Some medicines may interfere with the effect of BIJUVA, which may cause irregular bleeding. These medicines include:

• medicines for epilepsy (such as phenobarbital, phenytoin, and carbamazepine);
• medicines for tuberculosis (such as rifampicin, rifabutin);
• medicines for HIV infections (such as nevirapine, efavirenz, ritonavir, and nelfinavir);
• herbal preparations containing St. John’s wort (Hypericum perforatum);
• bromocriptine used for pituitary gland disorders or Parkinson’s disease;
• ketoconazole, griseofulvin (used for fungal infections);
• cyclosporine (used to suppress the immune system);
• lamotrigine (used to control epileptic seizures);
• medicines for hepatitis C virus (HCV) (such as the combination regimen with ombitasvir/paritaprevir/ritonavir with or without dasabuvir, and the regimen based on glecaprevir/pibrentasvir) may cause increases in liver function blood test results (elevated liver ALT enzyme) in women using COCs containing ethinylestradiol. BIJUVA contains estradiol, not ethinylestradi0l. It is not known whether elevated liver ALT levels may occur when BIJUVA is used with this HCV treatment regimen. Your doctor will provide you with appropriate instructions. Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines, including over-the-counter, herbal, or other natural products.

Laboratory tests
If you are scheduled for a blood test, inform your doctor or laboratory staff that you are taking BIJUVA, as this medicine may affect the results of certain tests.

Pregnancy and breastfeeding
BIJUVA is intended for use exclusively in postmenopausal women. If you become pregnant, stop taking BIJUVA and contact your doctor.

BIJUVA contains the colouring agent Allura Red
BIJUVA contains 0.042 mg of Allura Red (E129).
It may cause allergic reactions.

3. How to take BIJUVA

Use this medicine exactly as your doctor or pharmacist has told you. If you are unsure, ask your doctor or pharmacist. Your doctor will prescribe the lowest effective dose needed to treat your symptoms for the shortest necessary duration. Contact your doctor if you think the dose is too strong or not strong enough for you.
Take one capsule daily in the evening with a meal.
Take this medicine every day without interruption of treatment.
If you take more BIJUVA than you should
If you have taken too many BIJUVA capsules, contact your doctor or go to hospital immediately. Take the medicine pack with you.
The following effects may occur: drowsiness, dizziness, sleepiness, or fatigue.
If you forget to take BIJUVA
If you forget to take a dose, take it as soon as possible. However, if more than 12 hours have passed, skip the missed dose.
Do not take a double dose to make up for the forgotten dose.
The likelihood of breakthrough bleeding or spotting may increase.
If you stop taking BIJUVA
Do not stop treatment with BIJUVA without first consulting your doctor. If you have any doubts about using this medicine, speak to your doctor or pharmacist.
If you are scheduled for surgery
If you are scheduled for surgery, inform your surgeon that you are taking BIJUVA. You may need to stop using BIJUVA approximately 4–6 weeks before the procedure to reduce the risk of blood clots (see section 2, Blood clots in a vein).
Ask your doctor when you can start taking BIJUVA again.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
The following conditions are observed more frequently in women using HRT than in women who do not use it:

• breast cancer;
• abnormal growth or cancer of the inner lining of the uterus (endometrial hyperplasia or cancer);
• ovarian cancer;
• blood clots in the veins of the legs or lungs (venous thromboembolism);
• heart disease;
• stroke;
• possible memory loss if HRT is started after the age of 65. For further information on these side effects, see section 2.

Contact your doctor if you experience any of the following side effects while using BIJUVA:

Very common (affects more than 1 in 10 people)

• breast tenderness

Common (affects less than 1 in 10 people)

• headache, dizziness
• mood changes
• fatigue
• back pain
• abdominal pain, indigestion
• pelvic pain
• weight gain
• acne, dry skin
• breast pain
• feeling unwell (nausea)
• vaginal discharge (white or yellowish discharge from the vagina)
• vaginal bleeding or strong uterine contractions
• hair loss
• pain in extremities (e.g., back, arms, legs, wrists, ankles)

Uncommon (affects less than 1 in 100 people)

• low iron levels in the blood
• high blood pressure
• fluid retention in the legs
• increased cholesterol levels
• increased appetite
• problems with bowel movements
• muscle pain
• breast cancer
• reduced sleep
• tumours of the uterus or fallopian tubes
• memory loss, severe headaches
• tingling sensation
• loss of smell
• difficulty falling asleep or abnormal dreams
• mood swings or feeling irritable
• vomiting
• dry mouth
• constipation
• diarrhoea
• weight loss, dizziness
• chills
• acute pancreatitis
• anxiety, feeling depressed
• increased interest in sex compared to usual
• hot flushes
• vaginal irritation or burning sensation
• vaginal infections such as candidiasis
• blood clots
• dry, itchy skin or skin discoloration
• skin rash or appearance of red lines on the skin
• dizziness
• hirsutism
• impaired vision
• abdominal discomfort, abdominal tenderness
• indigestion (dyspepsia)
• excessive hunger (hyperphagia)
• oral discomfort
• altered taste (dysgeusia)
• flatulence
• hypersensitivity
• gastroenteritis
• boils
• acute otitis media
• abnormal liver function test
• pain in extremities
• uterine adnexal cysts
• attention disorder
• paraesthesia
• altered sense of smell (parosmia)
• restlessness
• breast disorders
• fibrocystic mastopathy
• nipple pain
• benign breast tumour
• endometrial hypertrophy
• abnormal biopsy
• postmenopausal bleeding
• vulvovaginal pruritus and telangiectasia

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

• muscle weakness
• benign growths in the smooth muscle of the uterus
• cysts near the fallopian tube

Very rare (affects less than 1 in 10,000 people)

• itching, dark-coloured urine

The following side effects have been reported with other HRTs:

• gallbladder problems
• various skin changes:
  • skin discoloration, especially on the face or neck, known as “melasma” (chloasma)
  • painful red nodules (erythema nodosum)
  • skin rash with redness or target-shaped ulcers (erythema multiforme)

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist. You can also report side effects directly via the national reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store BIJUVA

Keep this medicine out of the sight and reach of children.
This medicine does not require any special storage conditions.
Keep the blister pack in the outer packaging to protect the medicine from light.
Do not use this medicine after the expiry date stated on the carton after "Exp". The expiry date refers to the last day of that month.
Do not use this medicine if you notice any visible signs of deterioration.
Do not dispose of medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. This will help protect the environment.

6. Package contents and other information

What BIJUVA contains

• The active substances are estradiol (as estradiol hemihydrate) and progesterone.
• The other components are: mono/diglycerides of medium-chain fatty acids, lauroyl macrogol glycerides 32, gelatin 200 Bloom, hydrolyzed gelatin, glycerol (E422), Allura Red (E129), titanium dioxide (E171), propylene glycol (E1520), phthalate polyvinyl alcohol, polyethylene glycol (E1521) and ammonium hydroxide (E527).

Description of the appearance of BIJUVA and pack contents
BIJUVA capsules are oval, opaque, light pink on one side and dark pink on the other,
with "1C1" printed in white ink.
Blister pack containing 28 and 84 capsules.
Not all pack sizes may be marketed.

Marketing Authorization Holder
Theramex Ireland Limited
3 Floor, Kilmore House,
Park Lane, Spencer Dock,
Dublin 1
D01 YE64
Ireland

Manufacturer
Millmount Healthcare Ltd
Block-7
City North Business Campus
Stamullen, Co. Meath
K32 YD60
Ireland

This medicinal product is authorized in the European Economic Area countries under the following names:
Belgium, France, Germany, Italy, Luxembourg, Netherlands, Poland, Spain: BIJUVA