Enantone

Package leaflet: Information for the patient

ENANTONE 3.75 mg/ml powder and solvent for prolonged-release injectable suspension for
intramuscular or subcutaneous use
Leuprorelin acetate
Please read this leaflet carefully before this medicine is administered to you, as it
contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor, pharmacist or nurse.
• This medicine has been prescribed for you/your child only. Do not pass it on to others, even if their symptoms are the same as yours, as it may be harmful.
• If you experience any adverse reaction, including those not listed in this leaflet, contact your doctor, pharmacist or nurse. See section 4.

Contents of this leaflet:

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

Many of the information items in this leaflet apply to both men and women and children.

• When information applies only to men, it is preceded by the heading Information for men
• When information applies only to women, it is preceded by the heading Information for women
• When information applies only to children, it is preceded by the heading Information for children

1. What ENANTONE is and what it is used for

ENANTONE is a medicine containing leuprorelin acetate, belonging to the group of gonadotropin-releasing hormone (GnRH) analogues.

Use of ENANTONE in men:
ENANTONE is used to treat prostate cancer (a gland that produces seminal fluid) and its spread to other organs (metastases).

Use of ENANTONE in women:
ENANTONE is used to:

• treat a condition called endometriosis, in which cells normally found only in the lining of the uterus are present in other parts of the body (usually in nearby organs);
• treat breast cancer in women approaching menopause when hormone treatment is indicated;
• treat benign growths in the uterus called uterine fibroids;
• thin the lining of the uterus before undergoing surgery.

Use of ENANTONE in children:
ENANTONE is a synthetic hormone that can be used to reduce circulating levels of testosterone and estrogen in the body. ENANTONE is used to treat central precocious puberty, which is caused by the release of certain hormones from the pituitary gland, in girls under 9 years of age and boys under 10 years of age.

Contact your doctor if you/your child do not feel better or feel worse.

2. What you should know before ENANTONE is administered

Your doctor must make an accurate diagnosis of central precocious puberty.
ENANTONE will not be administered to you/your child

• If you are allergic to leuprorelin or to any of the other ingredients of this medicine (listed in section 6) or to synthetic gonadotropin-releasing hormone (GnRH) or GnRH derivatives.
• If you are pregnant (see section “Pregnancy and breastfeeding”).
• If you are breastfeeding (see section “Pregnancy and breastfeeding”).
• If you have ongoing vaginal bleeding of unknown cause.

Warnings and precautions
Talk to your doctor, pharmacist, or nurse before ENANTONE is administered.
Initially, after the first administration of the medicine, you/your child may experience a temporary worsening of general condition. However, these symptoms disappear with continued treatment.
Contact your doctor if you/your child has any of the following conditions:

• Any heart or blood vessel disorder, including problems with heart rhythm (arrhythmias), or if you are being treated with medicines for these conditions. The risk of heart rhythm problems may increase with the use of ENANTONE.

Inform your doctor, who will closely monitor you/your child:

• If you have hepatic steatosis.
• If you have diabetes.
• If you have a heart disease.

If you (or your child) suffer from severe or recurrent headaches, have vision problems, or experience ringing or buzzing in the ears, contact your doctor immediately.
Severe skin reactions, including Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), have been reported in association with leuprorelin treatment. Discontinue treatment with leuprorelin and contact your doctor immediately if you develop any of the symptoms related to these serious skin reactions described in section 4.

• Information for men Inform your doctor:
  • If you have difficulty urinating or notice blood in your urine.
  • If you have back pain.
  • If you feel weakness in your legs.

Your doctor may consider performing blood tests and examinations to assess bone and prostate health.
The use of medicines such as ENANTONE (GnRH agonists), which block testosterone production, may cause thinning of the bones (reduced bone mass – see section 4 “Possible side effects”).

• Information for women Inform your doctor:
  • If you have back pain.
  • If you are of childbearing age (see section “Pregnancy and breastfeeding”).
  • If you experience heavy bleeding between menstrual periods and have endometriosis or uterine fibroids.

The use of medicines such as ENANTONE (GnRH agonists) may cause thinning of the bones (reduced bone mineral density). Therefore, treatment duration should be limited to 6 months (see section 3 “How to administer ENANTONE”). If treatment needs to be repeated, your doctor will perform bone mass checks.
Children and adolescents

• Information for children Inform your doctor:
  • If the child’s weight approaches 20 kg. Your doctor may decide to perform blood tests to monitor hormone levels.
  • If the child shows signs of depression. Cases of depression, including severe depression, have been reported in patients taking ENANTONE (see section 4 “Possible side effects”).
  • If, after the first injection, the girl experiences vaginal bleeding. Your doctor may prescribe appropriate treatment if such bleeding continues beyond the first month of treatment.
  • If the child has a brain tumor. In children: In case of sterile abscess at the injection site (mostly reported after intramuscular injection), your doctor will monitor hormone levels, as reduced absorption of leuprorelin from the injection site may occur.

If the child has a progressing brain tumor, your doctor will decide whether leuprorelin treatment is appropriate.
Girls with central precocious puberty
Vaginal bleeding (spotting) and discharge may occur after the first injection, as a sign of suppression of hormone release. Vaginal bleeding beyond the first/second month of treatment should be investigated.
Before starting treatment, tests must be performed to rule out existing pregnancy.
Bone density may decrease during treatment of central precocious puberty with ENANTONE. However, after treatment discontinuation, subsequent bone mass growth is preserved, and treatment does not appear to affect the peak of bone mass increase in late adolescence.
Sterile abscesses at the injection site have frequently occurred when ENANTONE is administered at doses higher than recommended or when administered into a muscle. Therefore, your doctor must administer the medicine subcutaneously, for example, in the abdomen, buttock, or thigh.
Discontinuation of treatment may lead to slippage of the femoral growth cartilage. A possible cause could be weakness of the growth cartilage due to lower concentrations of female sex hormones during treatment.
Other medicines and ENANTONE
Inform your doctor or pharmacist if you/your child are taking, have recently taken, or might take any other medicines.
ENANTONE may interfere with certain medicines used to treat heart rhythm problems (e.g., quinidine, procainamide, amiodarone, and sotalol) or may increase the risk of heart rhythm problems when used together with certain other drugs (e.g., methadone (used to relieve pain and in drug detoxification programs), moxifloxacin (an antibiotic), antipsychotics (used for severe mental illnesses)).
Pregnancy and breastfeeding
Do not use ENANTONE during pregnancy or breastfeeding (see section 2 “ENANTONE will not be administered to you/your child”).
Before treatment, if you are potentially fertile, your doctor will request careful testing to exclude existing pregnancy (see section 2 “ENANTONE will not be administered to you/your child”). During treatment and until menstrual cycles resume, use non-hormonal contraceptive methods (e.g., condom and diaphragm).
Driving and using machines
ENANTONE may affect the ability to drive vehicles (including bicycles) and to use machinery.
ENANTONE contains sodium
This medicine contains less than 1 mmol (23 mg) of sodium per dose, i.e., it is essentially “sodium-free”.
For those engaged in sports activities: Using this medicine without therapeutic need constitutes doping and may lead to a positive anti-doping test.

3. How to administer ENANTONE

ENANTONE must be administered only by your doctor or by a nurse. They will also take care of preparing the medicinal product.
Information for men
The recommended dose is 3.75 mg (entire contents of the pre-filled syringe) of active substance administered once a month, for a duration determined by the physician.
Information for women
The recommended dose is 3.75 mg (entire contents of the pre-filled syringe) of active substance administered once a month, for a duration determined by the physician.
The duration of treatment may vary depending on the indication:

• in endometriosis: 6 months;
• in uterine fibroids: 6 months;
• to thin the uterine lining prior to surgery: 1–3 months.

Information for children
Treatment of children should be carried out under the general supervision of a pediatric endocrinologist.
Dosage must be individually adjusted.
The recommended initial dose depends on body weight:
a) children with body weight of 20 kg or more
Unless otherwise prescribed, 1 ml of ENANTONE (3.75 mg of leuprorelin acetate) once a month subcutaneously, for example in the abdomen, buttock, or thigh, as a single injection.
b) children with body weight below 20 kg
Taking into account the clinical activity of central precocious puberty, the following applies in these rare cases:
Unless otherwise prescribed, 0.5 ml of ENANTONE (1.88 mg of leuprorelin acetate) once a month subcutaneously, for example in the abdomen, buttock, or thigh, as a single injection. The remaining suspension must be discarded. The doctor will monitor the child's weight gain.
Depending on the activity of central precocious puberty, the doctor may increase the dosage in case of insufficient suppression (e.g., vaginal bleeding). The doctor will determine the minimum effective dose with the help of a blood test.
The duration of treatment depends on the clinical symptoms at the beginning or during the course of treatment and will be decided by the doctor together with the legal guardian and, if appropriate, the child being treated. The doctor will assess the child's bone age at regular intervals.
In girls with bone maturation corresponding to an age over 12 years and in boys with bone maturation corresponding to an age over 13 years, the doctor will consider discontinuing treatment, depending on the clinical effects observed in the child.
In girls, pregnancy must be ruled out before starting treatment. Occurrence of pregnancy during treatment cannot generally be excluded. In such cases, please consult your doctor.
This therapy is a long-term, individually tailored treatment. Please coordinate with your doctor to ensure that ENANTONE is administered as precisely as possible and at regular intervals.
An occasional delay in the injection date by a few days (30 ± 2 days) does not affect the outcome of therapy.
If more ENANTONE has been administered than prescribed
If you/your child have been given more ENANTONE than prescribed, contact your doctor or go to hospital immediately.
The doctor will manage symptoms with specific therapies.
If a dose of ENANTONE is missed
Do not administer a double dose to make up for the missed dose.
If you stop treatment with ENANTONE
If you have any doubts about using this medicine, consult your doctor or pharmacist.

4. Possible adverse effects

Like all medicines, this medicine can cause adverse effects, although not everyone experiences them.
The adverse effects are listed below by frequency in different patient populations:

• Information for all patients Common (may affect up to 1 in 10 people)

• depression,

• mood changes (long-term use). Uncommon (may affect up to 1 in 100 people)

• mood changes (short-term use). Very rare (may affect up to 1 in 10,000 people)

• pituitary infarction,

• bleeding of the pituitary gland (a gland located at the base of the brain) in patients with a benign tumour (adenoma) of the pituitary. Not known (frequency cannot be estimated from available data)

• fatty liver (hepatic steatosis),

• uncontrolled body movements (convulsive seizures),

• idiopathic intracranial hypertension (increased intracranial pressure around the brain, characterized by headache, double vision and other visual disturbances, and ringing or buzzing in one or both ears).

• flat, reddish, circular spots or target-like skin lesions on the trunk, often with central blisters, skin peeling, and ulcers in the mouth, throat, nose, genitals, and eyes. These serious skin reactions may be preceded by fever or flu-like symptoms (Stevens-Johnson syndrome/toxic epidermal necrolysis),

• skin redness and itchy rash (toxic rash),

• a skin reaction causing red spots or patches on the skin, which may appear target-shaped with a dark red center surrounded by lighter red rings (erythema multiforme),

• blisters on the skin which may vary in size and contain fluid (bullous dermatitis).

• Information for all adult patients Very common (may affect more than 1 in 10 people)

• hot flushes. Common (may affect up to 1 in 10 people)

• joint pain (arthralgia),

• swelling of the ankles (oedema). Uncommon (may affect up to 1 in 100 people)

• muscle pain (myalgia). Not known (frequency cannot be estimated from available data)

• reduction in red blood cells, white blood cells, and platelets (anaemia, leucopenia, thrombocytopenia),

• allergic reactions including skin rash, itching, hives, wheezing, fever, and chills,

• metabolic syndrome (including increased blood pressure, changes in blood fat and sugar levels),

• lung inflammation, lung disease,

• bone fragility (osteoporosis).

• Information for women Very common (may affect more than 1 in 10 people)

• headache (occasionally severe). Common (may affect up to 1 in 10 people)

• dizziness,

• numbness and tingling (paraesthesia),

• breast pain,

• reaction at injection site (e.g. hardening, redness, pain, abscess, swelling, nodules, and death of a portion of the skin (necrosis)). Uncommon (may affect up to 1 in 100 people)

• abnormal liver function tests (usually transient). Not known (frequency cannot be estimated from available data)

• liver dysfunction (hepatic dysfunction, including jaundice).

• Additional adverse effects in patients with breast cancer or with different frequency compared to patients with endometriosis or fibroids Very common (may affect more than 1 in 10 people)

• weight gain,

• decreased appetite,

• nausea,

• excessive sweating,

• bone pain,

• muscle weakness,

• vaginal bleeding,

• decreased sexual desire,

• vulvovaginal dryness,

• fatigue. Common (may affect up to 1 in 10 people)

• insomnia,

• visual disturbances,

• palpitations,

• vomiting,

• diarrhoea,

• hair loss,

• inflammation and infections of the vulva and vagina (vulvovaginitis). Rare (may affect up to 1 in 1,000 people)

• change in breast size.

• Additional adverse effects in patients with endometriosis/uterine fibroids or with different frequency compared to patients with breast cancer Very common (may affect more than 1 in 10 people)

• Insomnia. Common (may affect up to 1 in 10 people)

• weight gain/weight changes,

• nausea,

• excessive sweating,

• muscle weakness,

• loss of breast firmness (mammary atrophy),

• vulvovaginal dryness. Uncommon (may affect up to 1 in 100 people)

• decreased appetite,

• visual disturbances,

• palpitations,

• vomiting,

• diarrhoea,

• hair loss,

• fatigue. Very rare (may affect up to 1 in 10,000 people)

• change in breast size. Not known (frequency cannot be estimated from available data)

• inflammation and infections of the vulva and vagina (vulvovaginitis),

• vaginal haemorrhage,

• decreased sexual desire.

• Information for men At the beginning of therapy, a short-term increase in sex hormone levels occurs (a "flare-up" phenomenon). Adverse effects that may occur particularly at the start of treatment include urinary symptoms such as narrowing of the urinary tract; in patients with spinal cord compression, bone pain, weakness in the lower limbs, and paraesthesia may also occur (as neurological symptoms).
  Very common (may affect more than 1 in 10 people)

• weight gain,

• drowsiness,

• excessive sweating,

• muscle weakness,

• inability to achieve or maintain erection (erectile dysfunction),

• testicular atrophy,

• decreased sexual desire,

• reaction at injection site (e.g. hardening, redness, pain, abscess, swelling, nodules, and death of a portion of the skin (necrosis)),

• fatigue. Common (may affect up to 1 in 10 people)

• decreased appetite,

• insomnia,

• headache (occasionally severe),

• nausea,

• constipation,

• liver dysfunction (hepatic dysfunction including jaundice),

• abnormal liver function tests, usually transient,

• breast enlargement in men (gynaecomastia). Uncommon (may affect up to 1 in 100 people)

• dizziness,

• vomiting,

• diarrhoea. Rare (may affect up to 1 in 1,000 people)

• hair loss. Not known (frequency cannot be estimated from available data)

• visual disturbances,

• palpitations,

• changes in ECG trace (QT prolongation).

• Additional adverse effects in children and adolescents At the beginning of treatment, a short-term increase in sex hormone levels occurs, followed by a decrease to prepubertal levels. Due to this pharmacological effect, adverse reactions may occur particularly at the start of treatment. Common (may affect up to 1 in 10 people)

• mood changes,

• headache,

• abdominal pain,

• abdominal cramps,

• nausea,

• vomiting,

• acne,

• vaginal bleeding*,

• vaginal discharge,

• reaction at injection site (e.g. hardening, redness, pain, abscess, swelling, nodules, and death of a portion of the skin (necrosis)). Very rare (may affect up to 1 in 10,000 people)

• allergic reactions including skin rash, itching, hives, wheezing, fever, and chills.

Not known (frequency cannot be estimated from available data)

• muscle pain (myalgia).

*In general, if vaginal bleeding occurs also after continued treatment (after possible withdrawal bleeding in the first month of treatment), this may be a sign of potential underdosing. Inform your doctor if vaginal bleeding occurs.
Reporting of adverse effects
If you/your child experience any adverse effects, including those not listed in this leaflet, talk to your doctor, pharmacist, or nurse. You can also report adverse effects directly via the national reporting system at
https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse. By reporting adverse effects, you can help provide more information on the safety of this medicine.

5. How to store ENANTONE

This medicine does not require any special storage temperature.
Do not refrigerate or freeze.
Store in the original packaging to protect the medicine from light.
Use immediately after mixing, as the suspension settles very rapidly after reconstitution.
Keep this medicine out of the sight and reach of children.
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 dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What ENANTONE contains

• The active substance is leuprorelin.
• The other components of the powder are DL-lactic acid and glycolic acid copolymer, mannitol, gelatin.
• The other components of the solvent are: mannitol, sodium carmellose (see section “ENANTONE contains sodium”), polysorbate 80, glacial acetic acid for pH adjustment, water for injections.

Description of the appearance of ENANTONE and package contents
ENANTONE is presented as a white powder and a clear, colourless solvent.
ENANTONE is available in a pack containing 1 dual-chamber pre-filled syringe, with the lyophilized powder (3.75 mg leuprorelin acetate) in the front chamber and the solvent (1 ml) in the rear chamber, 1 needle with safety device, and 1 plunger.

Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder
TAKEDA ITALIA S.p.A. - Viale Manzoni 30 - Rome
under licence from Takeda Pharmaceutical Company Ltd - Osaka - Japan
Manufacturer
Delpharm Novara S.r.l. – Via Crosa 86 - Cerano (NO)

The following information is intended exclusively for healthcare professionals:

ENANTONE is available in a dual-chamber pre-filled syringe for intramuscular or subcutaneous injection.
Important information

• Do not use if the medicine is expired.
• This medicine does not require any specific storage temperature. Do not refrigerate or freeze.
• Store the dual-chamber syringe in its original packaging to protect the medicine from light.
• Keep the syringe in an upright position (with the needle pointing upwards) throughout all preparation steps to prevent product loss. If product leakage occurs, the dose must not be administered.
• Use immediately after mixing, as the suspension settles very rapidly after reconstitution.
• The medicine may be injected by intramuscular or subcutaneous route.

Dual-chamber pre-filled syringe

Fig. 1
Preparation

1. Before beginning syringe preparation, wash hands thoroughly and wear protective gloves. Keep the syringe in an upright position throughout all preparation steps.

Reconstitution

2. Open the package and remove the syringe.
3. Check the expiration date printed on the syringe and inspect the powder and solvent in the syringe chambers. The powder should be white and dry; the solvent should be clear.
4. Examine the syringe for any signs of damage.
   • Do not use the syringe after the expiration date;
   • Do not use the syringe if the powder is lumpy or compacted;
   • Do not use the syringe if the powder or solvent has an abnormal color;
   • Do not use the syringe if any of its components are damaged.
5. The needle is covered by a standard cap. Do not touch the safety device around the needle at this stage (Fig. 2).

Fig. 2

6. Gently tap the syringe to dislodge any clumps and detach any powder adhering to the syringe walls.
7. Remove the plunger from the packaging.
8. Screw the plunger onto the base of the syringe until the end stopper begins to turn.
   • Do not rotate or pull back the plunger once it has been secured.
9. Without removing the needle cap, check that the needle is securely attached by rotating it (clockwise). Do not overtighten.
   • Do not remove the needle cap until ready for injection.
10. Keeping the syringe upright, slowly push the plunger until the intermediate stopper reaches the blue line in the center of the syringe (Fig. 3). The solvent will be seen flowing into the front chamber past the blue line.

• Do not remove the needle cap before the solvent is released;
• Do not push the plunger too quickly or beyond the blue line, as this may cause leakage of the suspension from the needle;
• Do not pull the plunger back again.

Fig. 3

11. Gently tap the syringe in the palm of your hand while keeping it upright, to mix the powder and solvent until a uniform suspension is formed. The suspension will appear milky, without visible lumps (Fig. 4).

• If particles adhere to the stopper during mixing, gently tap the syringe with your finger;
• Avoid tapping or shaking vigorously to prevent bubble formation.

Fig. 4

12. Remove the needle cap by pulling it straight upward.

• Do not rotate the needle cap.

13. Push the plunger upward until all air has been expelled from the syringe.
14. The syringe is now ready for injection. Use immediately, as the suspension settles very rapidly after reconstitution. Administration by intramuscular or subcutaneous route
15. Select the injection site. Intramuscular injection sites include the shoulder (deltoid), upper buttock (ventrogluteal), and thigh (Figure 5). Subcutaneous injection sites include the periumbilical area, thighs, upper arms, and buttocks (Figure 6).
16. Clean the skin at the injection site with an alcohol swab and allow to air dry.
    • Do not inject where the skin is red, swollen, scarred, or damaged;
    • Do not use the same injection site for more than one consecutive injection.

Figure 5: Intramuscular injection sites Figure 6: Subcutaneous injection sites

3. Intramuscular injection
   • Gently stretch the skin at the injection site and insert the needle at a 90º angle to the skin. Before inserting the needle, check the orientation of the safety device. The arrow on the safety device must point toward the patient, with the black dot facing upward (Figure 7).
   • After needle insertion, aspirate by pulling back the plunger for 5–10 seconds. Care must be taken to avoid inadvertent injection into a blood vessel. If blood appears in the syringe barrel, stop the injection and immediately discard the needle.
4. Subcutaneous injection
   • Pinch a 2.5 cm section of skin between the fingers and insert the needle at a 30º–90º angle. Before inserting the needle, check the orientation of the safety device. The arrow on the safety device must point toward the patient, with the black dot facing upward (Figure 7).

Fig. 7

5. Slowly push the plunger fully to inject the entire contents of the syringe. Withdraw the needle at the same angle used for insertion, then apply gentle pressure with a clean gauze pad.
   • Do not rub the injection site.

• Do not recap the needle after injection. 6. After completing the injection, withdraw the needle from the patient. Immediately activate the safety device by pushing the wing upward with one finger until a CLICK is heard, indicating that the device is fully extended and the needle is covered (Fig. 8).

Fig. 8

http://takeda.info/3wQCXRj

Patient information leaflet

ENANTONE 11.25 mg/ml powder and solvent for prolonged-release injectable suspension

for intramuscular or subcutaneous use
Leuprorelin acetate
Please read this leaflet carefully before this medicine is administered, as it contains important information for you.

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

Contents of this leaflet:

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

Many of the informations contained in this leaflet apply to both men, women, and children.

• When information applies only to men, it is preceded by the heading Information for men
• When information applies only to women, it is preceded by the heading Information for women
• When information applies only to children, it is preceded by the heading Information for children

1. What ENANTONE is and what it is used for

ENANTONE is a medicine containing leuprorelin acetate, belonging to the group of gonadotropin-releasing hormone (GnRH) analogues.
Use of ENANTONE in men:
ENANTONE is used to treat prostate cancer (the gland that produces seminal fluid) and its spread to other organs (metastases).
Use of ENANTONE in women:
ENANTONE is used to:

• treat a condition called endometriosis, which occurs when cells normally found only in the lining of the uterus are present in other parts of the body (usually in nearby organs near the uterus);
• treat breast cancer in women approaching menopause when hormone treatment is indicated;
• treat benign growths in the uterus called uterine fibroids.

Use of ENANTONE in children:
ENANTONE is a synthetic hormone that can be used to reduce circulating levels of testosterone and estrogen in the body. ENANTONE is used to treat central precocious puberty, which is caused by the release of certain hormones from the pituitary gland, in girls under 9 years of age and boys under 10 years of age.
Consult your doctor if you/your child do not feel better or feel worse.

2. What you should know before ENANTONE is administered

Your doctor must make a precise diagnosis of central precocious puberty.
ENANTONE will not be administered to you/your child

• If you are allergic to leuprorelin or to any of the other ingredients of this medicine (listed in section 6) or to synthetic gonadotropin-releasing hormone (GnRH) or GnRH derivatives.
• If you are pregnant (see section “Pregnancy and breastfeeding”).
• If you are breastfeeding (see section “Pregn游戏副本

3. How to administer ENANTONE

ENANTONE must be administered only by your doctor or a nurse. They will also take care of preparing the medicine.
Information for men
The recommended dose is 11.25 mg (entire contents of the pre-filled syringe) of active substance to be administered every 3 months, for a period of time determined by the doctor.
Information for women
The recommended dose is 11.25 mg (entire contents of the pre-filled syringe) of active substance to be administered every 3 months, for a period of time determined by the doctor.
The duration of treatment may vary depending on the indication:

• in endometriosis: 6 months;
• in uterine fibroids: 6 months;
• to thin the lining of the uterus prior to surgery: 1–3 months.

Information for children
Treatment of children should be carried out under the general supervision of a paediatric endocrinologist.
Dosage must be individually adjusted.
The recommended initial dose depends on body weight:
a) children with body weight of 20 kg or more
Unless otherwise prescribed, 1 ml of ENANTONE (11.25 mg of leuprorelin acetate) once every 3 months subcutaneously, for example in the abdomen, buttock or thigh, as a single injection.
b) children with body weight below 20 kg
Taking into account the clinical activity of central precocious puberty, in these rare cases the following applies:
Unless otherwise prescribed, 0.5 ml of ENANTONE (5.63 mg of leuprorelin acetate) once every 3 months subcutaneously, for example in the abdomen, buttock or thigh, as a single injection. The remaining suspension must be discarded. The doctor will monitor the child's weight gain.
Depending on the activity of central precocious puberty, the doctor may increase the dosage in case of insufficient suppression (e.g. vaginal bleeding). The doctor will determine the minimum effective dose with the help of a blood test.
The duration of treatment depends on the clinical symptoms at the beginning or during the course of treatment and will be decided by the doctor together with the legal guardian and, if appropriate, the child. The doctor will determine the child's bone age at regular intervals.
In girls with bone maturation corresponding to an age above 12 years and in boys with bone maturation corresponding to an age above 13 years, the doctor will consider discontinuing treatment, depending on the clinical effects in the child.
In girls, pregnancy must be excluded before starting treatment. The occurrence of pregnancy during treatment cannot generally be ruled out. In such cases, please consult your doctor.
The therapy is a long-term treatment individually regulated. Please coordinate with your doctor to ensure that ENANTONE is administered as precisely as possible and at regular intervals.
An occasional delay in the injection date of a few days (90 ± 2 days) does not affect the outcome of therapy.
If more ENANTONE has been administered than intended
If you/your child have been given more ENANTONE than you should have, contact your doctor or go to hospital immediately.
The doctor will monitor symptoms and provide specific treatments.
If a dose of ENANTONE is missed
A double dose must not be administered to make up for a missed dose.
If you stop treatment with ENANTONE
If you have any doubts about the use of this medicine, consult your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
The side effects are listed below by frequency in different patient populations:

• Information for all patients Common (may affect up to 1 in 10 people)
• depression,
• mood changes (long-term use). Uncommon (may affect up to 1 in 100 people)
• mood changes (short-term use). Very rare (may affect up to 1 in 10,000 people)
• pituitary infarction,
• bleeding in the pituitary gland (a gland located at the base of the head) in patients with a benign tumour (adenoma) of the pituitary gland. Not known (frequency cannot be estimated from the available data)
• fatty liver (hepatic steatosis),
• uncontrolled body movements (seizures), idiopathic intracranial hypertension (increased intracranial pressure around the brain, characterised by headache, double vision and other visual disturbances, and ringing or buzzing in one or both ears).
• flat, reddish circular spots or target-like skin lesions on the trunk, often with central blisters, skin peeling, mouth, throat, nose, genital, and eye ulcers. These serious skin reactions may be preceded by fever or flu-like symptoms (Stevens-Johnson syndrome/toxic epidermal necrolysis),
• skin redness and itchy rash (toxic rash),
• a skin reaction causing red spots or patches on the skin, which may appear as targets with a dark red center surrounded by lighter red rings (erythema multiforme),
• fluid-filled blisters on the skin that may vary in size (bullous dermatitis).
• Information for all adult patients Very common (may affect more than 1 in 10 people)
• hot flushes. Common (may affect up to 1 in 10 people)
• joint pain (arthralgia),
• swelling of the ankles (oedema). Uncommon (may affect up to 1 in 100 people)
• muscle pain (myalgia). Not known (frequency cannot be estimated from the available data)
• reduction in red blood cells, white blood cells, and platelets (anaemia, leucopenia, thrombocytopenia),
• allergic reactions including skin rash, itching, hives, wheezing, fever, and chills,
• metabolic syndrome (including increased blood pressure, altered levels of fats and sugars in the blood),
• lung inflammation, lung disease,
• bone fragility (osteoporosis).
• Information for women Very common (may affect more than 1 in 10 people)
• headache (occasionally severe). Common (may affect up to 1 in 10 people)
• dizziness,
• numbness and tingling (paraesthesia),
• breast pain,
• reaction at the injection site (e.g. hardening, redness, pain, abscess, swelling, nodules, and death of a portion of the skin (necrosis)). Uncommon (may affect up to 1 in 100 people)
• abnormal liver function test results (usually transient). Not known (frequency cannot be estimated from the available data)
• liver dysfunction (including jaundice).
• Additional side effects in patients with breast cancer or occurring at a different frequency compared to patients with endometriosis or fibroids Very common (may affect more than 1 in 10 people)
• weight gain,
• decreased appetite,
• nausea,
• excessive sweating,
• bone pain,
• muscle weakness,
• vaginal bleeding,
• decreased sexual desire,
• vulvovaginal dryness,
• fatigue. Common (may affect up to 1 in 10 people)
• insomnia,
• visual disturbances,
• palpitations,
• vomiting,
• diarrhoea,
• hair loss,
• inflammation and infections of the vulva and vagina (vulvovaginitis). Rare (may affect up to 1 in 1,000 people)
• change in breast size.
• Additional side effects in patients with endometriosis/uterine fibroids or occurring at a different frequency compared to patients with breast cancer Very common (may affect more than 1 in 10 people)
• Insomnia. Common (may affect up to 1 in 10 people)
• weight gain/weight changes,
• nausea,
• excessive sweating,
• muscle weakness,
• loss of breast firmness (mammary atrophy),
• vulvovaginal dryness. Uncommon (may affect up to 1 in 100 people)
• decreased appetite,
• visual disturbances,
• palpitations,
• vomiting,
• diarrhoea,
• hair loss,
• fatigue. Rare (may affect up to 1 in 1,000 people)
• change in breast size. Not known (frequency cannot be estimated from the available data)
• inflammation and infections of the vulva and vagina (vulvovaginitis),
• vaginal haemorrhage,
• decreased sexual desire.
• Information for men At the beginning of therapy, a short-term increase in sex hormone levels occurs (a "flare-up" phenomenon). Side effects that may occur particularly at the start of treatment include urinary symptoms such as narrowing of the urinary tract; in patients with spinal cord compression, bone pain, weakness in the lower limbs, and paraesthesia may also occur (as neurological symptoms).

Very common (may affect more than 1 in 10 people)

• weight gain,
• drowsiness,
• excessive sweating,
• muscle weakness,
• inability to achieve or maintain an erection (erectile dysfunction),
• testicular atrophy,
• decreased sexual desire,
• reaction at the injection site (e.g. hardening, redness, pain, abscess, swelling, nodules, and death of a portion of the skin (necrosis)),
• fatigue. Common (may affect up to 1 in 10 people)
• decreased appetite,
• insomnia,
• headache (occasionally severe),
• nausea,
• constipation,
• liver dysfunction (including jaundice),
• abnormal liver function test results, usually transient,
• breast enlargement in men (gynaecomastia). Uncommon (may affect up to 1 in 100 people)
• dizziness,
• vomiting,
• diarrhoea. Rare (may affect up to 1 in 1,000 people)
• hair loss. Not known (frequency cannot be estimated from the available data)
• visual disturbances,
• palpitations,
• changes in ECG trace (QT prolongation).
• Additional side effects in children and adolescents At the beginning of treatment, a short-term increase in sex hormone levels occurs, followed by a decrease to prepubertal levels. Due to this pharmacological effect, side effects may occur particularly at the beginning of treatment.

Common (may affect up to 1 in 10 people)

• mood changes,
• headache,
• abdominal pain,
• abdominal cramps,
• nausea,
• vomiting,
• acne,
• vaginal bleeding*,
• vaginal discharge,
• reaction at the injection site (e.g. hardening, redness, pain, abscess, swelling, nodules, and death of a portion of the skin (necrosis)). Very rare (may affect up to 1 in 10,000 people)
• allergic reactions including skin rash, itching, hives, wheezing, fever, and chills. Not known (frequency cannot be estimated from the available data)
• muscle pain (myalgia).

*In general, if vaginal bleeding occurs also after continued treatment (after possible withdrawal bleeding during the first month of treatment), this may be a sign of potential underdosing. Inform your doctor if vaginal bleeding occurs.
Reporting of side effects
If you or the child experience any side effects, including those not listed in this leaflet, talk to your doctor, pharmacist, or nurse. You can also report side effects directly via the national reporting system at the website
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 ENANTONE

This medicine does not require any special storage temperature.
Do not refrigerate or freeze.
Store in the original packaging to protect the medicine from light.
Use immediately after mixing, as the suspension settles very rapidly after reconstitution.
Keep this medicine out of the sight and reach of children.
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 dispose of any medicine via wastewater or household waste. Ask your pharmacist how to
dispose of medicines you no longer use. This will help protect the environment.

6. Contents of the pack and other information

What ENANTONE contains

• The active substance is leuprorelin.
• The other components of the powder are polylactic acid, mannitol.
• The other components of the solvent are: mannitol, sodium carboxymethylcellulose (see section “ENANTONE contains sodium”), polysorbate 80, glacial acetic acid for pH adjustment, water for injections.

Description of the appearance of ENANTONE and contents of the pack
ENANTONE is presented as a white powder and a clear, colourless solvent.
ENANTONE is available in a pack containing 1 dual-chamber pre-filled syringe, with the lyophilised powder (11.25 mg leuprorelin acetate) in the front chamber and the solvent (1 ml) in the rear chamber, 1 needle with safety device, 1 plunger.

Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder
TAKEDA ITALIA S.p.A. - Viale Manzoni 30 - Rome
under licence from Takeda Pharmaceutical Company Ltd - Osaka - Japan

Manufacturer
Delpharm Novara S.r.l. – Via Crosa 86 - Cerano (NO)

The following information is intended exclusively for healthcare professionals:

ENANTONE is available in a dual-chamber pre-filled syringe for intramuscular or subcutaneous injection.
Important information

• Do not use if the medicinal product has expired.
• This medicinal product does not require any specific storage temperature. Do not refrigerate or freeze.
• Store the dual-chamber syringe in its original packaging to protect the medicinal product from light.
• Keep the syringe in an upright position (with the needle pointing upwards) throughout all preparation steps to prevent product loss. If product leakage occurs, the dose must not be administered.
• Use immediately after mixing, as the suspension settles very rapidly after reconstitution.
• The medicinal product may be injected by intramuscular or subcutaneous route.

Dual-chamber pre-filled syringe

Fig. 1
Preparation

15. Before beginning syringe preparation, wash hands thoroughly and put on protective gloves. Keep the syringe in an upright position during all preparation steps.

Reconstitution

16. Open the packaging and remove the syringe.
17. Check the expiration date printed on the syringe and inspect the powder and solvent within the syringe chambers. The powder should be white and dry; the solvent should be clear.
18. Inspect the syringe for any signs of damage.

• Do not use the syringe after the expiration date;
• Do not use the syringe if the powder is clumped or compacted;
• Do not use the syringe if the powder or solvent has an abnormal color;
• Do not use the syringe if any of its components are damaged.

19. The needle is covered by a standard cap. Do not touch the safety device around the needle at this stage (Fig. 2).

Fig. 2

20. Gently tap the syringe to dislodge any clumps and detach any powder adhering to the syringe walls.
21. Remove the plunger from its packaging.
22. Screw the plunger onto the base of the syringe until the terminal stopper begins to rotate.

• Do not rotate or pull back the plunger once it has been secured.

23. Without removing the needle cap, check that the needle is securely attached by rotating it (clockwise). Do not overtighten.

• Do not remove the needle cap until ready for injection.

24. Keeping the syringe upright, slowly push the plunger until the intermediate stopper reaches the blue line in the center of the syringe (Fig. 3). You will see the solvent flow into the front chamber past the blue line.

• Do not remove the needle cap before the solvent is released;
• Do not push the plunger too quickly or beyond the blue line, as this may cause leakage of the suspension from the needle;
• Do not pull the plunger back again.

Fig. 3

25. Gently tap the syringe in the palm of your hand while keeping it upright to mix the powder and solvent until a uniform suspension is formed. The suspension will appear milky, without visible clumps (Fig. 4).

• If particles adhere to the stopper during mixing, gently tap the syringe with your finger;
• Avoid tapping or shaking vigorously to prevent bubble formation;

Fig. 4

26. Remove the needle cap by pulling it straight upward.

• Do not rotate the needle cap.

27. Push the plunger upward until all air is expelled from the syringe.
28. The syringe is now ready for injection. Use immediately, as the suspension settles very rapidly after reconstitution. Administration by intramuscular or subcutaneous route
29. Select the injection site. Intramuscular injection sites include the shoulder (deltoid), upper buttock (ventrogluteal), and thigh (Figure 5). Subcutaneous injection sites include the periumbilical area, thighs, upper arms, and buttocks (Figure 6).
30. Clean the skin at the injection site with an alcohol swab and allow it to air dry.
    • Do not inject where the skin is red, swollen, scarred, or damaged;
    • Do not use the same injection site for more than one consecutive injection.

Figure 5: Intramuscular injection sites Figure 6: Subcutaneous injection sites

6. Intramuscular injection
   • Gently stretch the skin at the injection site and insert the needle at a 90º angle to the skin. Before inserting the needle, check the orientation of the safety device. The arrow on the safety device must point toward the patient, with the black dot facing upward (Figure 7).
   • After inserting the needle, aspirate by pulling back the plunger for 5–10 seconds. Care must be taken to avoid accidental intravascular injection. If blood is visible in the needle barrel, stop the injection immediately and dispose of the syringe.
7. Subcutaneous injection
   • Pinch a 2.5 cm section of skin between fingers and insert the needle at a 30º–90º angle. Before inserting the needle, check the orientation of the safety device. The arrow on the safety device must point toward the patient, with the black dot facing upward (Figure 7).

Fig. 7

6. Slowly push the plunger fully to inject the entire contents of the syringe. Withdraw the needle at the same angle used for insertion, then apply gentle pressure with a clean gauze.
   • Do not rub the injection site.
   • Do not recap the needle after injection.
7. After completing the injection, remove the needle from the patient. Immediately activate the safety device by pushing the wing upward with one finger until a CLICK is heard, indicating that the device is fully extended and the needle is covered (Fig. 8).

Fig. 8

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