4.1. Therapeutic indications

Men:

Treatment of hormone dependent locally advanced or metastatic prostate cancer.

Women:

Preoperative reduction of myoma size to reduce the symptoms of bleeding and pain in women with symptomatic uterine myomas.

Symptomatic endometriosis confirmed by laparoscopy when suppression of the ovarian hormonogenesis is indicated to the extent that surgical therapy is not primarily indicated.

Children:

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

4.2. Posology and method of administration

The product should only be used under the supervision of an appropriate specialist having requisite facilities for regular monitoring of response.

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.

It is important that the injection of the sustained release form be performed strictly in accordance with the instructions given in section 6.6.

Following reconstitution, the suspension has to be injected immediately.

Dosage and method of administration

The dosage of one syringe, equivalent to 3.75 mg triptorelin, is injected every 28 days either subcutaneously (e.g. into the skin of the abdomen, the buttock or thigh) or deep intramuscularly. The injection site should be changed each time.

Men:

Once every four weeks an injection with one syringe, equivalent to 3.75 mg triptorelin. In order to continually suppress testosterone levels, it is important to comply with a 4-weekly administration.

Women:

- Uterine myomas and endometriosis:

Once every four weeks an injection with one syringe, equivalent to 3.75 mg triptorelin. The treatment must be initiated in the first 5 days of the cycle.

Children:

Dosing at the beginning of treatment should be based on body weight, one injection of triptorelin should be injected on days 0, 14, and 28. Thereafter one injection every 4 weeks. Should the effect be insufficient, the injections may be given every 3 weeks. Dosing should be based on body weight according to the table.

Body weight

Dosing

‹ 20 kg

1.875 mg (half dose)

20 – 30 kg

2.5 mg (2/3 dose)

› 30 kg

3.75 mg (full dose)

Note for specific patient groups:

- There is no need to adjust the dose for the elderly.

- According to current data, dose reduction or prolongation of the dosage interval in patients with impaired renal function is not necessary.

Duration of administration

- Prostate carcinoma:

Treatment with GONAPEPTYL Depot is usually a long-term therapy.

- Uterine myomas and endometriosis:

The duration of treatment depends on the initial degree of severity of endometriosis and on the evolution of its clinical manifestations (functional and anatomical) and on the evolution of the volume of the uterine myomas, determined by ultrasonography during treatment. Normally, the maximum attainable result is achieved after 3 to 4 injections.

In view of the possible effect on bone density, therapy should not exceed a duration of 6 months (see 4.4).

- Central precocious puberty (CPP):

Treatment should be stopped if a bone maturation of older than 12 years in girls and older than 13 years in boys has been achieved.

4.3. Contraindications

General:

Known hypersensitivity to triptorelin, poly-(d,l lactide coglycolide), dextran, or to any of the excipients.

Hypersensitivity to gonadotrophin-releasing hormone (GnRH) or any other GnRH analogue.

In women:

- Pregnancy

- Lactation period

4.4. Special warnings and precautions for use

General:

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).

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 incident depression (which may be severe) in patients undergoing treatment with GnRH agonists, such as triptorelin. Patients should be informed accordingly and treated as appropriate if symptoms occur.

Mood changes have been reported. Patients with known depression should be monitored closely during therapy.

Men:

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 (tumour flare) 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.

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 GONAPEPTYL,

In addition, from epidemiological data, it has been observed that patients may experience metabolic changes (e.g. glucose intolerance, fatty liver), 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.

Administration of triptorelin in therapeutic doses result 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.

Women:

Gonapeptyl Depot should only be prescribed after careful diagnosis (e.g. laparoscopy).

It should be confirmed that the patient is not pregnant before prescription of triptorelin.

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

Loss of bone mineral density

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. For this reason, therapy without add back treatment should not exceed a duration of 6 months. After withdrawal of treatment, the bone loss is generally reversible within 6 - 9 months.

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.

Uterine myomas and endometriosis:

A supervening metrorrhagia in the course of treatment is abnormal (apart from the first month) and should lead to verification of plasma oestrogen level. Should this level be less than 50 pg/ml, possible associated organic lesions should be sought. After withdrawal of treatment, ovarian function resumes, e.g. menstrual bleeding will resume after 7-12 weeks after the final injection.

Non-hormonal contraception should be used during the initial month of treatment as ovulation may be triggered by the initial release of gonadotropins. It should also be used from 4 weeks after the last injection until resumption of menstruation or until another contraceptive method has been established.

During treatment of uterine myomas the size of uterus and myoma should be determined regularly, e.g. by means of ultrasonography. Disproportionally fast reduction of uterus size in comparison with the reduction of myoma tissue has in isolated cases led to bleeding and sepsis.

There have been a few reports of bleeding in patients with submucous fibroids following GnRH analogue therapy. Typically the bleeding has occurred 6 - 10 weeks after the initiation of therapy.

Children:

The chronological age at the beginning of therapy should be under 9 years in girls and under 10 years in boys.

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 finalising the therapy, development of puberty characteristics will occur. Information with regards to future fertility is still limited. In most girls' menses will start on average one year after ending the therapy, which in most cases is regular.

Bone mineral density 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 weakens the epiphyseal 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.

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

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

Allergic and anaphylactic reactions have been reported in adults and children. These include both local site reactions and systemic symptoms. The pathogenesis could not be elucidated. A higher reporting rate was seen in children.

Idiopathic intracranial hypertension

Idiopathic intracranial hypertension (pseudotumor cerebri) has been reported in paediatric patients receiving triptorelin. 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 triptorelin should be considered.

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

When triptorelin is co-administered with drugs affecting pituitary secretion of gonadotropins caution should be given and it is recommended that the patient's hormonal status should be supervised.

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

No formal drug-drug interaction studies have been performed. The possibility of interactions with commonly used medicinal products, including histamine liberating products, cannot be excluded.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential / Contraception in males and females

Women of childbearing potential should use effective non-hormonal contraception during therapy until menses resume

Pregnancy

Prior to treatment, potentially fertile women should be examined carefully to exclude pregnancy.

Very limited data on the use of triptorelin during pregnancy do not indicate an increased risk of congenital malformations. However, long-term follow-up studies on development are far too limited. Studies in animals have shown reproductive toxicity (see section 5.3). Based on the pharmacological effects disadvantageous influence on the pregnancy and the offspring cannot be excluded and GONAPEPTYL Depot should not be used during pregnancy.

Breastfeeding

It is not known whether triptorelin is excreted in human milk. Because of the potential for adverse reactions from triptorelin in nursing infants, breastfeeding should be discontinued prior to and throughout administration.

Fertility

Due to the pharmacodynamic effect, GnRH analogues, like triptorelin, are used in infertility treatment. In animal studies, triptorelin treatment had effects on female and male reproductive systems, which were mostly reversible (see section 5.3)

4.7. Effects on ability to drive and use machines

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 should the patient experience dizziness, somnolence and visual disturbances being possible undesirable effects of treatment, or resulting from the underlying disease.

4.8. Undesirable effects

Adverse experiences reported among patients treated with triptorelin during clinical trials and from post-marketing surveillance are shown below. As a consequence of decreased testosterone or oestrogen levels, most patients are expected to experience adverse reactions, with hot flushes being the most frequently reported (30% in men and 75-100% in women). Additionally, impotence and decreased libido should be expected in 30-40% of male patients, while bleeding/spotting, sweating, vaginal dryness and/or dyspareunia, decrease in libido, headache and mood changes are expected in more than 10% of women.

Due to the fact that the testosterone levels normally increase during the first week of treatment, worsening of symptoms and complaints may occur (e.g. urinary obstruction, skeletal pain due to metastases, compression of the spinal cord, muscular fatigue and lymphatic oedema of the legs). In some cases urinary tract obstruction decreases the kidney function. Neurological compression with asthenia and paraesthesia in the legs has been observed.

General tolerance in men (refer to Special Warnings and Precautions for use)

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: Initial increase in testosterone levels, followed by almost complete suppression of testosterone. These effects included hot flushes (50%), erectile dysfunction and decreased libido.

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.

MedDRA System Organ Class

Very common (≥1/10)

Common (≥1/100 to <1/10)

Uncommon (≥1/1000 to <1/100)

Not known

Men

Infections and infestations

Nasopharyngitis

Immune system disorders

Hypersensitivity

Anaphylactic reaction

Metabolism and nutrition disorders

Decreased appetite

Increased appetite, gout, diabetes mellitus

Psychiatric disorders

Libido decreased

Mood changes, depressed mood, depression, sleep disorder

Insomnia, confusional state, decreased activity, euphoric mood, anxiety, loss of libido

Nervous system disorder

Headache

Dizziness, paraesthesia, memory impairment, dysgeusia, somnolence, dysstasia

Eye disorders

Abnormal sensation in eye, visual impairment, vision blurred

Ear and labyrinth disorders

Tinnitus, vertigo

Vascular disorders

Hot flushes

Embolism, hypertension

Hypotension

Respiratory, thoracic and mediastinal disorders

Asthma aggravated

Dyspnoea, orthopnoea, epistaxis

Gastrointestinal disorders

Nausea

Abdominal pain upper, dry mouth

Abdominal pain, constipation, diarrhoea, vomiting, abdominal distension, flatulence, gastralgia

Skin and subcutaneous tissue disorders

Hyperhidrosis

Hypotrichosis, alopecia

Acne, pruritus, rash, blister, angioedema, urticaria, purpura

Musculoskeletal and connective tissue disorders

Bone pain

Myalgia, arthralgia

Back pain, musculoskeletal pain, pain in extremity, muscle spasms, muscular weakness, joint stiffness, joint swelling, musculoskeletal stiffness, osteoarthritis

Renal and urinary disorders

Dysuria

Reproductive system and breast disorders

Erectile dysfunction

Gynaecomastia

Testicular atrophy

Breast pain, testicular pain, ejaculation failure

General disorders and administration site conditions

Fatigue, injection site reaction, injection site pain, irritability

Asthenia, injection site erythema, injection site inflammation, oedema, pain, chills, chest pain, influenza like illness, pyrexia, malaise

Investigations

Blood lactate dehydrogenase increased, gamma-glutamyltransferase increased, aspartate aminotransferase increased, alanine aminotransferase increased, weight increased, weight decreased

Blood creatinine increased, blood pressure increased, blood urea increased, blood alkaline phosphatase increased, body temperature increased

QT prolongation (see section 4.4 and 4.5)

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 Special warnings and special precautions for use).

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.

General tolerance in women (refer to Special Warnings and Precautions for use)

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 changes, 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.

MedDRA System Organ Class

Very common (≥1/10)

Common (≥1/100 to <1/10)

Uncommon (≥1/1000 to <1/100)

Not known

Women

Immune system disorders

Hypersensitivity

Anaphylactic reaction

Psychiatric disorders

Libido decreased, mood changes, sleep disorder

Depressed mood, depression

Confusional state, anxiety

Nervous system disorder

Headache

Paraesthesia

Dizziness

Eye disorders

Visual impairment

Vision blurred

Ear and labyrinth disorders

Vertigo

Vascular disorders

Hot flushes

Respiratory, thoracic and mediastinal disorders

Dyspnoea

Gastrointestinal disorders

Abdominal pain

Nausea

Abdominal discomfort, diarrhoea, vomiting

Skin and subcutaneous tissue disorders

Hyperhidrosis

Pruritus, rash, angioedema, urticaria

Musculoskeletal and connective tissue disorders

Bone pain

Myalgia, arthralgia

Back pain

Bone disorder(*), muscle spasms, muscular weakness

Reproductive system and breast disorders

Vaginal haemorrhage, vulvovaginal dryness, dyspareunia, dysmenorrhoea, ovarian hyperstimulation syndrome ovarian hypertrophy, pelvic pain

Breast pain, menorrhagia, metrorrhagia, amenorrhoea,

General disorders and administration site conditions

Asthenia

Fatigue, injection site reaction, injection site pain, irritability

Injection site erythema, injection site inflammation, pyrexia, malaise

Investigations

Blood lactate dehydrogenase increased, gamma-glutamyltransferase increased, aspartate aminotransferase increased, alanine aminotransferase increased, blood cholesterol increased

Blood pressure increased, weight increased, weight decreased

(*)Slight trabecular bone loss may occur. This is generally reversible within 6-9 months after treatment discontinuation (see section 4.4).

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.

Ovarian hypertrophy, pelvic and/or abdominal pain may be observed.

General tolerance in children (refer to Special Warnings and Precautions for use)

MedDRA System Organ Class

Very common (≥1/10)

Common (≥1/100 to <1/10)

Uncommon (≥1/1000 to <1/100)

Not known

Children

Immune system disorders

Anaphylactic reaction

Hypersensitivity reaction

Psychiatric disorders

Mood changes, depression

Affect lability, nervousness

Nervous system disorder

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

Eye disorders

Vision blurred, Visual impairment

Vascular disorders

Hot flushes

Respiratory, thoracic and mediastinal disorders

Epistaxis

Gastrointestinal disorders

Nausea, vomiting

Abdominal discomfort, abdominal pain

Skin and subcutaneous tissue disorders

Rash, angioneurotic edema, urticaria, alopecia, erythema

Musculoskeletal and connective tissue disorders

Epiphysiolysis*, myalgia

Reproductive system and breast disorders

Vaginal haemorrhage, vaginal discharge

Genital haemorrhage

General disorders and administration site conditions

Injection site erythema, injection site inflammation, malaise, pain, injection site pain

Investigations

Blood pressure increased, weight increased

(*)A few cases of slipped capital femoral epiphysis have been reported during use with triptorelin.

Cases of pre-existing pituitary adenomas enlargement were reported during treatment with LH-RH agonists, however it has not yet been observed with triptorelin therapy.

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.

4.9. Overdose

There is insufficient experience of overdosing with triptorelin to draw conclusions on possible adverse effects. Considering the package form and the pharmaceutical form, overdosing is not expected.

If overdose occurs, symptomatic management is indicated.