Prostate cancer
Treatment of locally advanced or metastatic prostate cancer.
Treatment of high-risk localised or locally advanced prostate cancer in combination with radiotherapy.
See section 5.1.
A favourable effect of the treatment is all the more pronounced and more frequent if the patient has not
previously received any other hormone treatment.
 Genital and extragenital endometriosis (stage I to IV)
Treatment should not be administered for more than 6 months (see section 4.8). It is not recommended
to undertake a second course of treatment by triptorelin or by another GnRH analogue.
 Central precocious puberty (before 8 years in girls and 10 years in boys).

Posology
 Prostate cancer :
One intramuscular injection of DIPHERELINE P.R. 11.25 mg repeated every 3 months.
Duration of the treatment:
In high-risk localised or ‘locally advanced hormone-dependent prostate cancer as concomitant to and
following radiation therapy’ clinical data have shown that radiotherapy followed by long-term androgen
deprivation therapy is preferable to radiotherapy followed by short-term androgen deprivation therapy.
See section 5.1.
The treatment duration of androgen deprivation therapy recommended by medical guidances for
patients with high-risk localised or locally advanced prostate cancer receiving radiotherapy is 2-3 years.
For patients with metastatic prostate cancer castration-resistant, chirurgically uncastrated, treated by a
GnRH agonist as triptorelin, and eligible to a treatment by abiraterone acetate, an inhibitor of androgen
CIS : 6 000 000 0 M000/1000/003 2
biosynthesis or enzalutamide, an inhibitor of signalling pathway of androgen receptors, the treatment by
a GnRH agonist must be followed.
 Endometriosis :
One intramuscular injection of DIPHERELINE P.R. 11.25 mg repeated every 3 months.
The treatment must be initiated in the first five days of the menstrual cycle.
Treatment duration: this depends on the initial severity of the endometriosis and the changes observed
in the clinical features (functional and anatomical) during treatment. In principle, endometriosis should
be treated for at least 3 months and for at most 6 months. It is not recommended to start a second
treatment course with triptorelin or another GnRH analogue.
NB: The prolonged released form must be injected in strict compliance with the instructions given in the
package leaflet. Any incomplete injections resulting in the loss of suspension volumes greater than the
volume generally remaining in the injection syringe must be reported.
 Central precocious puberty :
The treatment of children with triptorelin should be under the overall supervision of the paediatric
endocrinologist or of a paediatrician or endocrinologist with expertise in the treatment of central
precocious puberty.
Children over 20 kg in body weight: one intramuscular injection of DIPHERELINE P.R. 11.25 mg
administered every 3 months.
Treatment should be stopped around the physiological age of puberty in boys and girls and it is
recommended that treatment is not continued in girls with bone maturation of more than 12 years. There
are limited data available in boys relating to the optimum time to stop treatment based on bone age,
however it is advised that treatment is stopped in boys with a bone maturation age of 13-14 years.
DIPHERELINE P.R. 11.25 mg must not be injected intravascularly.
For reconstitution of DIPHERELINE before use, see section 6.6.

The use of GnRH agonists may cause reduction in bone mineral density. In men, preliminary data suggest that the use of a bisphosphonate in combination with a GnRH agonist may reduce bone mineral loss. Particular caution is necessary in patients with additional risk factors for osteoporosis (e.g. chronic alcohol abuse, smokers, long-term therapy with drugs that reduce bone mineral density, e.g. anticonvulsants or corticoids, family history of osteoporosis, malnutrition).

It should be confirmed that the patient is not pregnant before prescription of DIPHERELINE P.R. 11.25 mg.

Rarely, treatment with GnRH agonists may reveal the presence of a previously unknown gonadotroph cell pituitary adenoma. These patients may present with a pituitary apoplexy characterised by sudden headache, vomiting, visual impairment and ophthalmoplegia.

There is an increased risk of depression (which may be severe) in patients undergoing treatment with GnRH agonists, such as triptorelin. Patients should be informed accordingly and treated appropriate if symptoms occur. Patients with known depression should be monitored closely during therapy. DIPHERELINE P.R. 11.25 mg contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially “sodium-free”.

Caution should be given to patients treated with anti-coagulants as haematoma may potentially appear at the intramuscular injection site.

Prostate cancer

Initially, triptorelin, like other GnRH agonists, causes a transient increase in serum testosterone levels. As a consequence, isolated cases of transient worsening of signs and symptoms of prostate cancer may occasionally develop during the first weeks of treatment. During the initial phase of treatment, consideration should be given to the additional administration of a suitable anti-androgen to counteract the initial rise in serum testosterone levels and the worsening of clinical symptoms.

A small number of patients may experience a temporary worsening of signs and symptoms of their prostate cancer and temporary increase in cancer related pain (metastatic pain), which can be managed symptomatically.

As with other GnRH agonists, isolated cases of spinal cord compression or urethral obstruction have been observed. If spinal cord compression or renal impairment develops, standard treatment of these complications should be instituted, and in extreme cases an immediate orchiectomy (surgical castration) should be considered. Careful monitoring is indicated during the first weeks of treatment, particularly in patients suffering from vertebral metastasis, at the risk of spinal cord compression, and in patients with urinary tract obstruction. For the same reason, particular care should be taken when beginning treatment in patients with premonitory signs of spinal cord compression.

After surgical castration, triptorelin does not induce any further decrease in serum testosterone levels.

Long-term androgen deprivation either by bilateral orchiectomy or administration of GnRH analogues is associated with increased risk of bone loss and may lead to osteoporosis and increased risk of bone fracture.

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 DIPHERELINE.

In addition, from epidemiological data, it has been observed that patients may experience metabolic changes (e.g. glucose intolerance), or an increased risk of cardiovascular disease during androgen deprivation therapy. However, prospective data did not confirm the link between treatment with GnRH analogues and an increase in cardiovascular mortality. Patients at high risk for metabolic or cardiovascular diseases should be carefully assessed before commencing treatment and adequately monitored during androgen deprivation therapy.

Treatment with GnRH analogues may increase risk of anemia because of androgen deprivation. This risk should be evaluated in patients treated and undertaken in a proper way. 

Administration of triptorelin in therapeutic doses results in suppression of the pituitary gonadal system. Normal function is usually restored after treatment is discontinued. Diagnostic tests of pituitary gonadal function conducted during treatment and after discontinuation of therapy with GnRH analogues may therefore be misleading.

A transitory increase in acid phosphatases may be observed at the beginning of the treatment.

It may be advantageous to check blood testosterone levels periodically with an accurate method as these should not exceed 1 ng/ml.

In women

It should be confirmed that patient is not pregnant before prescription of DIPHERELINE P.R. 11.25 mg. The use of GnRH agonists is likely to cause reduction in bone mineral density averaging 1% per month during a six month treatment period. Every 10% reduction in bone mineral density is linked with about a two to three times increased fracture risk.

In the majority of women, currently available data suggest that recovery of bone loss occurs after cessation of therapy.

No specific data is available for patients with established osteoporosis or with risk factors for osteoporosis (e.g. chronic alcohol abuses, smokers, long-term therapy with drugs that reduce bone mineral density, e.g. anticonvulsants or corticoids, family history of osteoporosis, malnutrition, e.g. anorexia nervosa). Since reduction in bone mineral density is likely to be more detrimental in these patients, treatment with triptorelin should be considered on an individual basis and only be initiated if the benefits of treatment outweigh the risk following a very careful appraisal. Consideration should be given to additional measures in order to counteract loss of bone mineral density.

The administration, of DIPHERELINE P.R. 11.25 mg results in constant hypogonadotrophic amenorrhoea.

If genital haemorrhage occurs after the first month, plasma oestradiol levels should be measured and if levels are below 50 pg/ml, possible organic lesions should be investigated.

Since menses should stop during triptorelin treatment, the patient should be instructed to notify her physician if regular menstruation persists.

A non-hormonal method of contraception should be used throughout treatment including for 1 month after the last injection (see section 4.6).

After withdrawal of treatment, ovarian function resumes and ovulation occurs approximately 5 months after the last injection.

Central precocious puberty

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

In girls initial ovarian stimulation at treatment initiation, followed by the treatment-induced oestrogen withdrawal, may lead, in the first month, to vaginal bleeding of mild or moderate intensity.

After discontinuation of treatment the development of puberty characteristics will occur.

Information with regards to future fertility is still limited. In most girls, regular menses will start on average one year after ending the therapy.

DIPHERELINE PR 11.25 mg is not indicated in transient precocious puberty as well as the normal variants of pubertal development (premature thelarche, pubarche and menarche) and isolated menstruation associated, or not, with breast development with inconsistent response to the LHRH test and presence of functioning cysts of the ovary.

Pseudo-precocious puberty (gonadal or adrenal tumour or hyperplasia) and gonadotropin-independent precocious puberty (testicular toxicosis, familial Leydig cell hyperplasia) should be precluded.

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 capital femoral epiphysis can be seen after withdrawal of GnRH treatment. The suggested theory is that the low concentrations of oestrogen during treatment with GnRH agonists weaken 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.

When triptorelin is used in combination with drugs that modify the secretion of pituitary gonadotropins, special precautions must be taken and it is recommended to close monitored with hormone assays.

Since androgen deprivation treatment may prolong the QT interval, the concomitant use of DIPHERELINE 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).

Pregnancy

Pregnancy should be excluded before DIPHERELINE is prescribed.

Triptorelin should not be used during pregnancy since concurrent use of GnRH agonists is associated with a theoretical risk of abortion or foetal abnormality. Prior to treatment, potentially fertile women should be examined carefully to exclude pregnancy. Non-hormonal methods of contraception should be employed during therapy until menses resume.

Breast-feeding

Triptorelin should not be used during breast feeding.

No studies on the effects on the ability to drive and use machines have been performed.

However, the ability to drive and use machines may be impaired by dizziness, somnolence and visual disturbances which are possible undesirable effects of treatment, or resulting from the underlying disease.

General tolerance in men (see section 4.4)

Since patients suffering from locally advanced or metastatic, hormone-dependent prostate cancer are generally old and have other diseases frequently encountered in this aged population, more than 90 % of the patients included in clinical trials reported adverse events, and often the causality is difficult to assess.

As seen with other GnRH agonist therapies or after surgical castration, the most commonly observed adverse events related to triptorelin treatment were due to its expected pharmacological effects. These effects included hot flushes and decreased libido. 

With the exception of immuno-allergic (rare) and injection site (< 5 %) reactions, all adverse events are known to be related to testosterone changes.

The following adverse reactions, considered as at least possibly related to triptorelin treatment, were reported. Most of these events are known to be related to biochemical or surgical castration.

The frequency of the adverse reactions is classified as follows: 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). No frequency can be determined for the adverse reactions reported after marketing. Consequently, they are reported with “frequency not known”.

* This frequency is based on class-effect frequencies common for all GnRH agonists

Triptorelin causes a transient increase in circulating testosterone levels within the first week after the initial injection of the sustained release formulation. With this initial increase in circulating testosterone levels, a small percentage of patients (≤ 5%) may experience a temporary worsening of signs and symptoms of their prostate cancer (tumour flare), usually manifested by an increase in urinary symptoms (< 2%) and metastatic pain (5%), which can be managed symptomatically. These symptoms are transient and usually disappear in one to two weeks. 

Isolated cases of exacerbation of disease symptoms, either urethral obstruction or spinal cord compression by metastasis have occurred. Therefore, patients with metastatic vertebral lesions and/or with upper or lower urinary tract obstruction should be closely observed during the first few weeks of therapy (see section 4.4).

The use of GnRH agonists, to treat prostate cancer may be associated with increased bone loss and may lead to osteoporosis and increases the risk of bone fracture. 

An increase in lymphocytes has been reported in patients treated with GnRH analogues. This secondary lymphocytosis is apparently related to castration induced by GnRH and suggests that gonadal hormones are involved in thymic involution.

Patients receiving long-term treatment by GnRH analogue in combination with radiation may have more side effects especially gastrointestinal, related to radiotherapy.

General tolerance in women (see section 4.4)

As a consequence of decreased oestrogen levels, the most commonly reported adverse events (expected in 10% of women or more) were headache, libido decreased, sleep disorder, mood altered, dyspareunia, dysmenorrhoea, genital haemorrhage, ovarian hyperstimulation syndrome, ovarian hypertrophy, pelvic pain, abdominal pain, vulvovaginal dryness, hyperhidrosis, hot flushes and asthenia.

The following adverse reactions, considered as at least possibly related to triptorelin treatment, were reported. Most of these are known to be related to biochemical or surgical castration.

The frequency of the adverse reactions is classified as follows: very common (≥1/10); common (≥1/100 to <1/10). No frequency can be determined for the adverse reactions reported after marketing. Consequently, they are reported with frequency “not known”.

*Long term use. This frequency is based on class-effect frequencies common for all GnRH agonists

** Short term use. This frequency is based on class-effect frequencies common for all GnRH agonits

At the beginning of treatment, the symptoms of endometriosis including pelvic pain, dysmenorrhoea may be exacerbated very commonly (≥ 10%) during the initial transient increase in plasma oestradiol levels. These symptoms are transient and usually disappear in one or two weeks.

Genital haemorrhage including menorrhagia, metrorrhagia may occur in the month following the first injection.

Long-term use of GnRH analogues may lead to bone loss which is a risk factor of osteoporosis.

General tolerance in children (see section 4.4) 

As seen with other GnRH agonist therapies, the most commonly observed adverse events related to triptorelin treatment in clinical trials were due to its expected pharmacological effects. These effects included vaginal bleeding that could be of low intensity (spotting).

The following adverse reactions, considered as at least possibly related to triptorelin treatment, were reported. 

The frequency of the adverse reactions is classified as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100). No frequency can be estimated for the adverse reactions reported after marketing. Consequently they are reported with “frequency not known”.

Vaginal bleeding may occur in the month following the first injection.

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 national reporting system: Agence nationale de sécurité du médicament et des produits de santé (ANSM) and the network of the Centres Régionaux de Pharmacovigilance – Internet site: www.ansm.sante.fr.

If overdose occurs, symptomatic management is indicated.

Pharmacotherapeutic group: gonadotrophin-releasing hormone analogue

ATC code: L02AE04

Triptorelin is a synthetic decapeptide analogue of natural GnRH (gonadotrophin-releasing hormone).

Studies conducted in both humans and animals have shown that after initial stimulation, the prolonged administration of triptorelin inhibits gonadotrope secretion with consequent suppression of testicular and ovarian function.

The administration of DIPHERELINE P.R. 11.25 mg may initially increase blood LH and FSH levels and may consequently increase initial testosterone level (flare-up) in men and oestradiol level in women. Continuing the treatment decreases LH and FSH levels leading to decreased testosterone and oestradiol levels similar to those observed after castration within about 20 days after the injection and for as long as the active substance is released.

Prostate Cancer

An opened, not controlled and multicentric phase 3 clinical trial involving 126 patients with advanced prostate cancer has been conducted during 6 months in order to assess the efficacy of subcutaneous administration of DIPHERELINE P.R. 11.25 (one administration every 3 months). After four weeks 97.6% of subjects were castrated (testosterone levels <50 ng/dL) (95% CI: [93.2; 99.5]) and castration was maintained at Month 6 in 96.6% of subjects (95%CI: [91.6; 99.1]) (coprimary endpoints). The probability for a subject to be castrated within the first month of treatment and to remain castrated at each measurement up to 6 months was 96% (95%CI [0.92, 0.99]) (see Figure 1).

Figure 1 Kaplan-Meier Plot for Probability of Testosterone < 50 ng/dL from Day 29 through Day 183 after subcutaneous administration

During the treatment by triptorelin, median PSA levels were reduced by 64.2% at Month 1 and by 96% at Month 6 (secondary endpoint). Median PSA values remained within normal range (0-4 ng/mL) from Month 2 until the end of the study.

In patients with locally advanced prostate cancer several randomized long-term clinical trials provide evidence for the benefit of androgen deprivation therapy (ADT) in combination with radiotherapy (RT) compared to RT alone (RTOG 85-31, RTOG 86-10, EORTC 22863, D’Amico et al., JAMA, 2008).

A randomized phase III study (EORTC 22961) of 970 patients with prostate cancer locally advanced (mainly T2c-T4 with some T1C to T2B patients with pathological regional nodale disease) has investigated whether radiation therapy associated with short term androgen deprivation therapy (6 months, n = 483) was non-inferior to radiotherapy associated with long term androgen deprivation therapy (3 years, n = 487). The GnRH agonist was triptorelin (62.2%) or other GnRH agonists (37.8%) and the trial was not further stratified by the type of agonist. 

Overall, total mortality at 5 years was 19.0% and 15.2% respectively in the "short term hormonal treatment" and "long term hormonal treatment" groups, with a relative risk of 1.42 (CI-sided 95, 71% = 1.79; 95.71% CI = [1.09; 1.85], p = 0.65 for noninferiority and p = 0.0082 for post-hoc test of difference between groups of treatment). The 5-year mortality specifically related to the prostate was 4.78% and  3.2% respectively in the " short term hormonal treatment "and" long term hormonal treatment" groups, with a relative risk of 1.71 (CI 95% [1.14 to 2.57], p = 0.002). Overall quality of life using QLQ-C30 did not differ significantly between the two groups (P= 0.37).

The post hoc analysis in the subgroup triptorelin also show the advantage of the long term treatment versus the short term treatment on overall mortality (relative risk 1.28; 95.71% CI = [0.89 ; 1.84], p = 0.38 and p = 0.08 respectively for noninferiority post-hoc tests and for difference between treatment groups).

 Evidence for the indication of high-risk localised prostate cancer is based on published studies of radiotherapy combined with GnRH analogues. Clinical data from five published studies were analyzed (EORTC 22863, RTOG 85-31, RTOG 92-02, RTOG 86-10, and D’Amico et al., JAMA, 2008), which all demonstrate a benefit for the combination of GnRH analogue with radiotherapy. Clear differentiation of the respective study populations for the indications locally advanced prostate cancer and high-risk localised prostate cancer was not possible in the published studies.

For patients with metastatic prostate cancer castration-resistant, clinical trials have shown the benefice of adding androgen biosynthesis inhibitors as abiraterone acetate or inhibitors of signaling pathway of androgen receptors as enzalutamide to the treatment by a GnRH analog as triptorelin.

Endometriosis

Continued administration of DIPHERELINE SR 11.25 mg induces suppression of oestrogen secretion and thus enables resting of ectopic endometrial tissue in women. 

Pediatric population – precocious puberty

The inhibition of hypophyseal gonadotrophic hyperactivity in both sexes manifests as suppression of oestradiol or testosterone secretion, as a lowering of the LH peak and as improved Height Age /Bone Age ratio.

Initial gonadic stimulation may cause slight genital haemorrhages requiring medroxyprogesterone or cyproterone acetate treatment.

Following intramuscular injection of DIPHERELINE P.R. 11.25 mg in patients (men and women), a peak plasma concentration of triptorelin is observed about 3 hours after injection. After a declining concentration phase, which continues during the first month, circulating triptorelin levels remain constant until the end of the third month following the injection.

The molecule did not demonstrate any specific toxicity in animal toxicological studies. The effects observed are related to the pharmacological properties of the substance on the endocrine system.

The resorption of the product is complete in 120 days.

D,L lactide coglycolide polymer; mannitol; sodium carmellose; polysorbate 80.

Solvent: mannitol, water for injections

Not applicable.

Do not store above 30°C.

To be injected immediately after reconstitution.

Powder in 4ml vial ml (glass type I) with a stopper (elastomer) and a cap (aluminium) + 2 ml of solvent in ampoule (glass); Box containing 1 vial and 1 ampoule with 1 syringe and 2 needles.

The powder should be suspended in the specific solvent immediately before injection by shaking the vial gently until a milky homogeneous liquid is obtained (The instructions for reconstitution hereafter and in the leaflet must be strictly followed.  ).

o For single use only. Any unused suspension should be discarded.An overfill is included to allow for this loss.

The powder is to be suspended in 2 ml of mannitol solution:

Using the reconstitution needle (20 G, without safety device), one of the injection needles, all of the solvent is drawn up into the injection syringe supplied and transferred to the vial containing the powder. The vial should be gently shaken to completely disperse the powder to obtain a homogenous, milky suspension. The suspension obtained is then drawn back into the injection syringe. The injection needle  (20G, with safety device) should be changed and the suspension should be injected immediately.

The suspension should be discarded if it is not administered immediately after reconstitution. See also section 6.3.

Used injection needles should be disposed in a designated sharp container. Any remaining product should be discarded.

Used needles, any unused suspension or other waste material should be disposed of in accordance with local requirements.