4.1. Therapeutic indications

Treatment of central precocious puberty (girls under 9 years of age, boys under 10 years of age with a body weight of less than 20 kg) (see section 5.1).

4.2. Posology and method of administration

Posology

The treatment of children with leuprorelin acetate should be under the overall supervision of the paediatric endocrinologist.

The dosing scheme needs to be adapted individually.

The recommended starting dose is dependent on the body weight.

Children with a body weight < 20 kg

In these rare cases, the following dosage should be administered according to the clinical activity of the central precocious puberty:

1 ml (1.88 mg leuprorelin acetate) is administered once a month as a single subcutaneous injection.

Children with a body weight ≥ 20 kg

Use a higher strength preparation (e.g. 3.75 mg powder and solvent for prolonged-release suspension for injection in pre-filled syringe administered once a month).

The child's weight gain should be monitored.

Depending on the activity of the central precocious puberty, it may be necessary to increase the dosage in the presence of inadequate suppression (clinical evidence e.g. spotting or inadequate gonadotropin suppression in the GnRH test). The minimal effective monthly dose to be administered should then be determined by means of the GnRH test.

Sterile abscesses at the injection site often occurred when leuprorelin acetate was administered intramuscularly at higher than the recommended dosages. Therefore, in such cases, the medicinal product should be administered subcutaneously (see section 4.4).

The duration of treatment depends on the clinical parameters at the start of treatment or during the course of treatment (final height prognosis, growth velocity, bone age and/or bone age acceleration) and is decided by the treating paediatrician together with the legal guardian and, if appropriate, the treated child. The bone age should be monitored during treatment at 6-12 month intervals.

In girls with bone maturation of older than 12 years and boys with bone maturation of older than 13 years discontinuation of treatment should be considered taking into account the clinical parameters.

In girls, pregnancy should be excluded before the start of treatment. The occurrence of pregnancy during treatment cannot be generally excluded. In such cases, medical advice should be sought.

Note:

The administration interval should be 30 ± 2 days in order to prevent the recurrence of precocious puberty symptoms.

Method of administration

Read this Instructions For Use before injecting.

This product should be prepared, reconstituted and administered only by healthcare professionals who are familiar with these procedures.

Warnings

Wash hands before opening the syringe package.

Hold syringe upright (with needle side up) throughout entire preparation to prevent leakage.

Use immediately after mixing as the suspension settles out very quickly following reconstitution.

Check the expiration date printed on the syringe label, and check the powder and diluent in the syringe barrel. The powder should be white and dry, and the diluent should be clear. Inspect the syringe for any damage.

• Do not use the syringe if the expiration date has passed.

• Do not use the syringe if the powder appears clumped or caked.

• Do not use the syringe if powder or diluent appear discoloured.

• Do not use the syringe if any part of it is damaged.

Step 1. Attach plunger and tighten needle

• Remove the plunger from the package.

• Screw the plunger rod into the bottom of the syringe until the end stopper begins to rotate.

• Do not twist or pull the plunger rod back once it has been attached.

• Without removing the needle cap, twist the needle to the right (clockwise) to ensure it is secured tightly.

• Do not remove needle cap until you are ready to inject.

Step 2. Release diluent

• Holding the syringe upright, release the diluents by slowly pushing the plunger until the middle stopper reaches the blue line in the middle of the syringe. You should see the diluent flowing into the interior chamber above the blue line.

• Do not push the plunger too quickly or push past the blue line as these actions may cause leaking.

• Do not withdraw plunger again.

Step 3. Mix suspension

• Gently tap the syringe against the palm of your hand to mix the powder and diluent until it forms a uniform suspension. When properly mixed, the suspension should appear milky with no visible lumps.

• Note: If particles stick to the stopper during mixing, dislodge them by gently tapping the syringe with your finger.

• Avoid hard tapping or shaking to prevent the generation of bubbles.

• Use immediately after mixing as the suspension settles out very quickly following reconstitution.

Step 4. Remove needle cap and prime syringe

• Remove the needle cap by pulling it straight upwards.

• Do not twist the needle cap.

• Prime the syringe by pushing the plunger upward until all air has been expelled from the syringe.

Step 5. Inject

• The syringe is now ready for injection. Use immediately as the suspension settles out very quickly following reconstitution.

• At the time of injection, check the direction of the safety device (with round mark pointing towards you) and inject the entire contents of the syringe subcutaneously or intramuscularly as you would for a normal injection.

Step 6. Activate safety device

• When injection is complete, withdraw the needle from the patient. Immediately activate the safety device by pressing upward from just below the arrow until a “CLICK” is heard or felt and the needle is fully covered.

Step 7. Dispose of syringe

• Dispose of the used device in the appropriate sharps container in accordance with your local standard procedure.

Detailed and up-to-date information for this product is available by scanning the QR Code, shown on the Health Professionals' User Leaflet, with a smartphone. The same information is also available on the following URL: https://www.medicines.org.uk/emc/xxxxxxxxxxx

4.3. Contraindications

Hypersensitivity to the active substance, any of the excipients listed in section 6.1 or to other synthetic gonadotrophin releasing hormone (GnRH) analogues or GnRH derivatives.

In girls:

Pregnancy and breastfeeding.

Undiagnosed vaginal bleeding.

4.4. Special warnings and precautions for use

PROSTAP PD DCS suspension must be prepared at the time of use and, after reconstitution, used immediately (see section 4.2).

Depression

There is an increased risk of incident depression (which may be severe) in patients undergoing treatment with GnRH agonists, such as leuprorelin acetate. Patients should be informed accordingly and treated as appropriate if symptoms occur.

Seizure

Postmarketing reports of seizures have been observed in patients treated with leuprorelin acetate. These events have been reported in those with or without a history of epilepsy, seizure disorders or risk disorders for seizures.

Idiopathic intracranial hypertension

Idiopathic intracranial hypertension (pseudotumor cerebri) has been reported in patients receiving leuprorelin. Patients should be warned for signs and symptoms of idiopathic intracranial hypertension, including severe or recurrent headache, vision disturbances and tinnitus. If idiopathic intracranial hypertension occurs, discontinuation of leuprorelin should be considered.

Severe cutaneous adverse reactions

Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS), and Toxic epidermal necrolysis (TEN) which can be life-threatening or fatal, have been reported in association with leuprorelin treatment. At the time of prescription patients should be advised of the signs and symptoms and monitored closely for severe skin reactions. If signs and symptoms suggestive of these reactions appear, leuprorelin should be withdrawn immediately and an alternative treatment considered (as appropriate).

Metabolic changes associated with GnRH agonist may also include fatty liver disease.

Before starting the therapy, a precise diagnosis of idiopathic and/or neurogenic central precocious puberty is nscessary and, in girls, pregnancy must be excluded (see section 4.3).

The therapy is a long-term treatment, adjusted individually. PROSTAP PD DCS should be administered as precisely as possible in regular monthly periods. An exceptional delay of the injection date for a few days (30 ± 2 days) does not influence the results of the therapy.

In the event of a sterile abscess at the injection site (mostly reported after i.m. injection of higher than the recommended dosage) the absorption of leuprorelin acetate from the depot can be decreased. In this case the hormonal parameters (testosterone, estradiol) should be monitored at 2-week intervals (see section 4.2).

The treatment of children with progressive brain tumours should follow a careful individual appraisal of the risks and benefits.

The occurrence of vaginal bleeding, spotting and discharge after the first injection may occur as a sign of hormone withdrawal in girls. Vaginal bleeding beyond the first/second month of treatment needs to be investigated.

Bone mineral density (BMD) may decrease during GnRHa therapy for central precocious puberty. However, after cessation of treatment subsequent bone mass accrual is preserved and peak bone mass in late adolescence does not seem to be affected by treatment.

Slipped femoral epiphysis can be seen after withdrawal of GnRHa treatment. The suggested theory is that the low concentrations of estrogen during treatment with GnRH agonists weakens the epiphysial plate. The increase in growth velocity after stopping the treatment subsequently results in a reduction of the shearing force needed for displacement of the epiphysis.

PROSTAP PD DCS contains sodium. This medicine contains less than 1 mmol sodium (23 mg) per injection, that is to say it is essentially 'sodium free'.

4.5. Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

4.6. Fertility, pregnancy and lactation

Pregnancy

Safe use of leuprorelin acetate in pregnancy has not been established clinically.

Studies in animals have shown reproductive toxicity (see section 5.3). Before starting treatment with PROSTAP PD DCS, pregnancy must be excluded. There have been reports of foetal malformation when PROSTAP PD DCS has been given during pregnancy.

PROSTAP PD DCS must not be used in girls who are pregnant (see section 4.3).

When used monthly at the recommended dose, PROSTAP PD DCS usually inhibits ovulation and stops menstruation. Contraception is not ensured, however, by taking PROSTAP PD DCS 1.88 mg and therefore patients should use non-hormonal methods of contraception during treatment and after cessation of treatment until the return of menses.

Patients should be advised that if they miss successive doses of PROSTAP PD DCS, breakthrough bleeding or ovulation may occur with the potential for conception. Patients should be advised to see their physician if they believe they may be pregnant. If a patient becomes pregnant during treatment, the drug must be discontinued. The patient must be apprised of this evidence and the potential for an unknown risk to the foetus.

Breastfeeding

PROSTAP PD DCS must not be used in girls who are breastfeeding (see section 4.3).

4.7. Effects on ability to drive and use machines

Leuprorelin acetate can influence the ability to drive and use machines due to visual disturbances and dizziness.

4.8. Undesirable effects

Adverse reactions seen with leuprorelin acetate are due mainly to the specific pharmacological action, namely increases and decreases in certain hormone levels.

The following table lists adverse reactions with leuprorelin based on experience from clinical trials as well as from post-marketing experience. Adverse reactions are grouped by MedDRA System Organ Classes and frequency classification. Frequencies are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).

In the initial phase of therapy, a short-term increase as flare-up of the sex hormone level occurs, followed by a decrease to values within the pre-pubertal range. Due to this pharmacological effect, adverse events may occur particularly at the beginning of treatment.

Tabulated list of adverse reactions in children

SOC

Very common

Common

Uncommon

Rare

Very rare

Not known

Immune system disorders

Hypersensitivity (rash, pruritus, urticaria, wheezing, fever, chills and anaphylactic reactions)

Metabolic disorders

Hepatic steatosis

Psychiatric disorders

Depression (see Section 4.4), emotional lability

Nervous system disorders

Headache

Pituitary apoplexy has been reported following initial administration in patients with pituitary adenoma, pituitary haemorrhage

Seizure, idiopathic intracranial hypertension (pseudotumor cerebri) (see section 4.4)

Gastrointestinal disorders

Abdominal pain / abdominal cramps, nausea/vomiting

Skin and subcutaneous tissue disorders

Acne

Stevens-Johnson syndrome/Toxic Epidermal Necrolysis (SJS/TEN) (see section 4.4), Toxic Skin Eruption, Erythema Multiforme

Musculoskeletal and connective tissue disorders

Myalgia

Respiratory, thoracic and mediastinal disorders

Interstitial lung disease

Reproductive system and breast disorders

Vaginal haemorrhage, spotting**, vaginal discharge

General disorders and administration site conditions

Injection site reactions (e.g. induration, erythema, pain, abscess, swelling, nodules and necrosis)

** In general, the occurrence of vaginal spotting with continued treatment (subsequent to possible withdrawal bleeding in the first month of treatment), should be assessed as a sign of potential underdosage. Pituitary suppression should then be determined by gonadotropin releasing hormone (GnRH) stimulation test.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

No case of overdose has been reported.

In animal studies, doses of up to 500 times the recommended human dose resulted in dyspnoea, decreased activity and local irritation at the injection site. In cases of overdose, the patients should be monitored closely and management should be symptomatic and supportive.