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4.4 Special warnings and precautions for use

Text in red added:

…

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

4.8 Undesirable effects

Text in red added

…

Nervous system disorders:

Common:  headache (occasionally severe)

Rare: dizziness

Very rare: pituitary apoplexy has been reported after administration of both short-and long acting GnRH agonists

Not known: paralysis, seizure

…

Nervous system disorders:          

Common: headache

Not known: seizure

10. Date of revision of the text

Updated text in red:

23 February 2016

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4.1. Therapeutic indications

Added:

In children:

Treatment of central precocious puberty (girls under 9 years of age, boys under 10 years of age).

4.2. Posology and method of administration

Added:

Posology

Paediatric population:

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

1 ml (11.25 mg leuprorelin acetate) suspension of 130.0 mg sustained-release microcapsules in 1 ml vehicle solution are administered every 3 months as a single subcutaneous injection.

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:

0.5 ml (5.625 mg leuprorelin acetate) suspension of 130.0 mg sustained-release microcapsules in 1 ml vehicle solution are administered every 3 months as a single subcutaneous injection.

The remainder of the suspension should be discarded. 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 LHRH test). The minimal effective 3-monthly dose to be administered should then be determined by means of the LHRH 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 4.4).

It is recommended to use the lowest volumes possible for injections in children in order to decrease the inconvenience which is associated with the intramuscular/subcutaneous injection.

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 90 ± 2 days in order to prevent the recurrence of precocious puberty symptoms.

Removed:

Children: Safety and effectiveness in children have not been established.

4.3. Contraindications

Added:

In girls with central precocious puberty:

- Pregnancy and lactation

- Undiagnosed vaginal bleeding.

4.4.  Special warnings and precautions for use

Added:

In girls with central precocious puberty: 

Before starting the therapy, a precise diagnosis of idiopathic and/or neurogenic central precocious puberty is necessary.

The therapy is a long-term treatment, adjusted individually. PROSTAP 3 should be administered as precisely as possible in regular 3-monthly periods. An exceptional delay of the injection date for a few days (90 ± 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, oestradiol) should be monitored at 2-week intervals (see 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 GnRH 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 GnRH 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.

4.8. Undesirable Effects

Added:

In Children:  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.

Immune system disorders:

Very rare: general allergic reactions (fever, rash, e.g. itching, anaphylactic reactions)

Psychiatric disorders:

Common: emotional lability

Nervous system disorders:

Common: headache

As with other medicinal products of this class, very rare cases of pituitary apoplexy have been reported following initial administration in patients with pituitary adenoma.

Gastrointestinal disorders:

Common: abdominal pain / abdominal cramps, nausea/vomiting

Skin and subcutaneous tissue disorders:

Common: acne

Reproductive system and breast disorders:

Common: vaginal bleeding, spotting, discharge

Note:

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. The pituitary suppression should then be determined by an LHRH test.

General disorders and administration site conditions:

Common: injection site reactions.

5.1. Pharmacodynamic properties

Added:

In children:

Reversible suppression of pituitary gonadotropin release occurs, with a subsequent decrease in oestradiol (E2) or testosterone levels to values in the pre-pubertal range. 

Initial gonadal stimulation (flare-up) may cause vaginal bleeding in girls who are already post-menarchal at start of treatment. Withdrawal bleeding may occur at the start of treatment. The bleeding normally stops as treatment continues.

The following therapeutic effects can be demonstrated:

-           Suppression of basal and stimulated gonadotropin levels to pre-pubertal levels.

-           Suppression of prematurely increased sexual hormone levels to pre-pubertal levels and arrest of premature menstruation;

-           Arrest/involution of somatic pubertal development (Tanner stages);

-           Improvement/normalisation of the ratio of chronological age to bone age;

-           Prevention of progressive bone age acceleration;

-           Decrease of growth velocity and its normalization;

-           Increase in final height.

Treatment result is the suppression of the pathologically, prematurely activated hypothalamic-pituitary-gonadal axis according to pre-pubertal age.

In a long-term clinical trial in children treated with leuprorelin at doses up to 15mg monthly for > 4 years resumption of pubertal progression were observed after cessation of treatment. Follow up of 20 female subjects to adulthood showed normal menstrual cycles in 80% and 12 pregnancies in 7 of the 20 subjects including multiple pregnancies for 4 subjects.

5.2.  Pharmacokinetic properties

Added:

In children:

Figure 1 presents the leuprorelin serum levels in children during the first 6 months of treatment following s.c. administration of leuprorelin acetate 3-month depot (two injections). 

From the first injection, the leuprorelin serum levels increase reaching maximal serum levels at month 4 (294.79 pg/ml ± 105.42) and slightly decrease until month 6 (229.02 pg/ml ± 103.33).

Figure 1: Leuprorelin serum levels during the first six months of treatment with the leuprorelin acetate 3-month depot formulation (two s.c. injections) (n=42-43)

10. DATE OF REVISION OF THE TEXT

Changed to:

29^th September 2015

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4.4 Special warnings and precautions for use

Addition of text:

Androgen deprivation therapy may prolong the QT interval.

In patients with a history of or risk factors for QT prolongation and in patients receiving concomitant medicinal products that might prolong the QT interval (see section 4.5) physicians should assess the benefit risk ratio including the potential for Torsade de pointes prior to initiating PROSTAP 3.

4.5       Interaction with other medicinal products and other forms of interaction

Addition of text:

Since androgen deprivation treatment may prolong the QT interval, the concomitant use of PROSTAP 3 with medicinal products known to prolong the QT interval or medicinal products able to induce Torsade de pointes such as class IA (e.g. quinidine, disopyramide) or class III (e.g. amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmic medicinal products, methadone, moxifloxacin, antipsychotics, etc. should be carefully evaluated (see section 4.4).

4.8       Undesirable effects

Addition of text:

under “Men”:

Frequency unknown:, QT prolongation (see sections 4.4 and 4.5)

10        DATE OF REVISION OF THE TEXT

31/10/2014