DIPHERELINE Powder and solvent for suspension for injection Ref.[50753] Active ingredients: Triptorelin

Prostate Cancer

Initially triptorelin 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 prostate cancer (tumour flare) and a 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 should be considered. Careful monitoring is indicated during the first weeks of treatment, particularly in patients suffering from vertebral metastases, 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. Once the castration levels of testosterone have been achieved by the end of the first month, serum testosterone levels are maintained for as long as the patients receive their injection every one, three or six months. The effectiveness of treatment can be monitored by measuring serum levels of testosterone and prostate specific antigen.

QT prolongation

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 INTERACTIONS WITH OTHER MEDICINES) physicians should assess the benefit risk ratio including the potential for Torsade de pointes prior to initiating Diphereline.

Precocious puberty

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.

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 but future reproductive function and fertility appears to be unaffected by GnRH treatment. In most girls, regular menses will start on average one year after ending the therapy.

Bone mineral density may decrease during GnRH agonist therapy for central precocious puberty due to the expected effects of oestrogen suppression. 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 agonist 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.

Cardiovascular disease

An increased risk of developing myocardial infarction, sudden cardiac death and stroke has been reported in association with use of GnRH agonists in men. The risk appears low based on the reported odds ratio, and should be evaluated carefully along with cardiovascular risk factors when determining a treatment for patients with prostate cancer. Patients receiving a GnRH agonist should be monitored for symptoms and signs suggestive of development of cardiovascular disease and managed according to current clinical practice.

Osteoporosis and bone mineral density

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 an 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).

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. This may also lead to an incorrect diagnosis of bone metastases.

Depression

There is an increased risk of mood changes and 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. Patients with known depression should be monitored closely during therapy.

Hyperglycaemia and Diabetes

Hyperglycaemia and an increased risk of developing diabetes have been reported in men receiving GnRH agonists. Hyperglycaemia may represent development of diabetes mellitus or worsening of glycaemic control in patients with diabetes. Monitor blood glucose and/or glycosylated haemoglobin (HbA1c) periodically in patients receiving a GnRH agonist and manage with current practice for the treatment of hyperglycaemia or diabetes.

Other identified precautions

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

Adjustment of antihypertensive therapy may be required in patients receiving such medication.

Caution is required with intramuscular injection in patients treated with anticoagulants, due to the potential risk of haematomas at the site of injection.

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 a GnRH agonist may therefore be misleading.

Pseudotumour cerebri (PTC)/Benign intracranial hypertension (BIH) has been reported in women and children receiving GnRH analogues including triptorelin. Monitor patients for signs and symptoms of PTC/BIH, including headache, papilledema, blurred vision, diplopia, loss of vision, pain behind the eye or pain with eye movement, tinnitus, dizziness, and nausea. Refer the patient to an ophthalmologist to confirm the presence of papilledema. If PTC/BIH is confirmed, treat the patient in accordance with established treatment guidelines and permanently discontinue use of triptorelin.

All formulations of Diphereline contain less than 1 mmol (23 mg) sodium per dose.

Use in the elderly

No data available.

Paediatric use

The Diphereline 22.5mg 6 month formulation is indicated for use in children 2 years and older with central precocious puberty (CPP).

The safety and efficacy of triptorelin embonate 3.75mg (1 month) and 11.25mg (3 month) formulations have not been reviewed in neonates, infants, children and adolescents, and are therefore not indicated for use in these populations.

Effects on laboratory tests

No data available.

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 PRECAUTIONS).

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

In the absence of relevant data, there is a theoretical risk that treatment with drugs that increase serum prolactin may decrease the efficacy of GnRH agonists as hyperprolactinaemia reduces the number of pituitary GnRH receptors.

Effects on fertility

In chronic toxicity studies at clinically relevant doses, triptorelin induced changes in the reproductive organs of male rats, dogs and monkeys. These were considered to reflect the suppressed gonadal function caused by the pharmacological activity of the compound. These changes would be expected to cause a profound impairment of fertility but, were partly reversed (males) or largely reversed (females) after cessation of treatment. In males, changes included decreases in weight and atrophic histological changes in the testes, epididymis, seminal vesicle and prostate gland, with suppression of spermatogenesis. In females, changes included ovarian atrophy and suppression of ovarian function, with arrest of follicular development and cessation of oestrus cycling; uterine weights were also reduced.

Use in pregnancy (Category D)

Safe use of Diphereline 22.5mg in pregnancy has not been established in clinical studies. It should be confirmed that the patient is not pregnant before prescription of Diphereline 22.5 mg.

Diphereline should not be used during pregnancy since concurrent use of GnRH agonists is associated with a theoretical risk of abortion or foetal abnormality.

After subcutaneous administration of 10 micrograms/kg/day to rats on days 6 to 15 of gestation, triptorelin did not elicits any embryotoxicity or teratogenicity. At 100 micrograms/kg/day, a reduction in maternal body weight gain and an increased number of resorptions were observed.

Use in lactation

Diphereline is not recommended for use during lactation.

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, epileptic seizures and visual disturbances being possible undesirable effects of treatment, or resulting from the underlying disease.

Reporting suspected adverse effects

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting- problems.

General tolerance in men

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, most of the patients included in clinical trials reported adverse events. 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 (4%) and decreased libido (3%).

With the exception of immuno-allergic reactions (0.2%) and injection site reactions (3%), all adverse reactions are known to be related to testosterone changes.

Tabulated list of adverse reactions in men

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.

In Table 1, the frequency of the adverse reactions is classified as follows: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10000, <1/1000). No very rare (<1/10000) adverse reactions were reported.

Table 1. Adverse reactions in men:

^* This frequency is based on class-effect frequencies common for all GnRH agonists.
^** Reported following initial administration in patients with pituitary adenoma

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. 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 PRECAUTIONS).

The use of synthetic 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. This may also lead to an incorrect diagnosis of bone metastases.

General tolerance in children

Tabulated list of adverse reactions in children

The frequency of the adverse reactions is classified as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000, <1/100).

Table 2. Adverse reactions in children:

General

Increased lymphocyte count has been reported with patients undergoing GnRH analogue treatment. This secondary lymphocytosis is apparently related to GnRH induced castration and seems to indicate that gonadal hormones are involved in thymic involution.

Uncommonly pressure sensitive infiltrations at the injection site have been reported in other triptorelin products after subcutaneous injection.

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.