Consumer medicine information

Diphereline

Triptorelin

BRAND INFORMATION

Brand name

Diphereline

Active ingredient

Triptorelin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Diphereline.

WHAT IS IN THIS LEAFLET

Please read this leaflet carefully before you are given DIPHERELINE.

This leaflet answers some common questions about DIPHERELINE. It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Sometimes new risks are found even when a medicine has been used for many years.

Your doctor has weighed the risks of you being given DIPHERELINE against the benefits they expect it will have for you.

If you have any concerns about being given this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

WHAT DIPHERELINE IS USED FOR

The name of your medicine is DIPHERELINE. It contains the active ingredient triptorelin embonate.

In adult men, DIPHERELINE is used to treat prostate cancer that has spread into surrounding tissue and/or to other parts of the body. It is not a cure for prostate cancer.

In children, DIPHERELINE 22.5 mg is used to treat puberty that occurs at a very young age (Precocious Puberty). This is called “early puberty” in the rest of this leaflet.

DIPHERELINE belongs to a group of medicines called Gonadotrophin Releasing Hormone agonists (GnRHa).

In males, DIPHERELINE works by lowering the production of testosterone. Testosterone is the natural male sex hormone.

In some types of prostate cancer, testosterone may help the cancer cells to grow. By lowering testosterone, DIPHERELINE may slow or stop the growth of cancer.

In females, DIPHERELINE lowers the levels of the hormone oestrogen.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

BEFORE YOU ARE GIVEN DIPHERELINE

When you must not be given it

DIPHERELINE should not be given to pregnant or lactating women.

Do not be given DIPHERELINE if you are allergic to:

  • triptorelin embonate, the active ingredient in DIPHERELINE
  • any of the other ingredients listed at the end of this leaflet, in particular, polysorbate 80
  • Gonadotropin Releasing Hormone (GnRH) or any other Gonadotrophin Releasing Hormone agonists (GnRHa)

Signs of an allergic reaction may include itchy skin rash, shortness of breath and swelling of the face or tongue.

Do not be given the medicine if:

  • the expiry date printed on the pack has passed
  • the packaging is torn or shows signs of tampering.

In men:

  • you have severe back pain as a result of your prostate cancer spreading and pressing into the nerves of your backbone

Before you are given it

Tell your doctor if:

In men:

  • you have cancer related pain (metastatic pain)
  • you experience difficulty or pain when passing urine
  • you have osteoporosis, a family history of osteoporosis or risk factors for developing osteoporosis (such as heavy drinking, smoking, a diet low in calcium, poor mobility, a slight build or treatment with steroid medicines or anticonvulsants)
  • you get sudden headaches , and/or have blurred vision
  • you are allergic to food, dyes, preservatives or any other medicines
  • you have high blood sugar or diabetes
  • you have heart or vascular problems or other cardiovascular risk factors
  • you have any heart or blood vessel conditions, including heart rhythm problems (arrhythmia), or are being treated with medicines for these conditions. The risk of heart rhythm problems may be increased when using DIPHERELINE
  • you are taking medicines to lower your blood pressure.

There have been reports of mood changes and depression in patients taking GnRH analogues, such as DIPHERELINE, which may be severe. If you are taking DIPHERELINE and develop depressed mood, inform your doctor.

In children:

  • If your child has progressive brain tumour, tell their doctor. This may affect the way your doctor decides to treat your child.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

There are some medicines which may interfere with the action of DIPHERELINE. These include:

  • medicines used to prevent blood clots (anti-coagulants), including warfarin, as there is a possible risk of haematoma (bruising, bleeding) formation at the site of intramuscular injection
  • medicines that increase levels of another hormone, prolactin
  • medicines affecting secretion of gonadotrophins.

DIPHERELINE might interfere with some medicines used to treat heart rhythm problems (e.g. quinidine, disopyramide, amiodarone, and sotalol) or might increase the risk of heart rhythm problems when used with some other drugs (e.g. methadone (used for pain relief and part of drug addiction detoxification), moxifloxacin (an antibiotic), antipsychotics used for serious mental illnesses).

Your doctor or pharmacist have more information on medicines to be careful with or avoid while you are receiving this medicine.

HOW IS DIPHERELINE GIVEN

How it is given

DIPHERELINE is given as an injection into your muscle (intramuscular) by your doctor or nurse.

How much and how often it is given

DIPHERELINE is available in 3 dose formulations:

  • a 3.75 mg injection given once a month
  • a 11.25 mg injection given once every 3 months (4 times a year)
  • a 22.5 mg injection given every 6 months (2 times a year).

Your doctor will prescribe which dose formulation is most suitable for you.

In children:

Only the 22.5 mg injection is used to treat early puberty in children with one injection every 6 months. Your child's doctor will decide when treatment should be stopped (normally when your child is about 12-13 if they are a girl and about 13-14 if they are a boy).

If you forget to have it

Make sure you keep a diary of when your doses are due. You will have made a doctor's appointment for your next date so you will not forget it.

If you are given too much (overdose)

As DIPHERELINE is given to you under the supervision of your doctor, it is very unlikely that you or your child will receive too much.

However, if you feel you or your child have been given too much, contact the Poisons Information Centre on 131126 for advice.

WHILE YOU ARE BEING GIVEN DIPHERELINE

Things you must do

In men:

At the start of treatment, you will have an increased amount of testosterone in your body which may cause the symptoms of your cancer to get worse.

If you experience any of the following symptoms within the first few weeks of treatment, tell your doctor:

  • pain in the bones or backbone
  • difficulty passing urine
  • weakness, tingling or numbness in your arms and legs.

These symptoms usually only happen with the first treatment with DIPHERELINE. You should not experience them with further treatments. Your doctor may give you additional medicines with your first dose to treat these symptoms.

If you continue to experience them, tell your doctor immediately as it may mean that the cancer is growing.

In children:

Girls who have early puberty may have some vaginal bleeding in the first month of treatment.

All patients:

Keep follow-up appointments with your doctor. It is important to have your follow-up doses at the appropriate times to get the best effects from your treatments.

If you feel that your medicine is not helping your condition (or your child's condition), talk to your doctor.

Tell any other doctors, dentists, and pharmacists who are treating you that you (or your child) are being treated with DIPHERELINE.

Things you must not do

Do not stop your treatment with DIPHERELINE unless you have discussed it with your doctor first.

Things to be careful of

Be careful driving or operating machinery until you know how DIPHERELINE affects you. Make sure you know how you react to it before you drive a car, operate machinery, or do anything else that could be dangerous if you are dizzy or light-headed, sleepy or have blurred vision or seizures, which are possible side effects of treatment or due to the underlying disease. If this occurs do not drive. If you drink alcohol, dizziness or light-headedness may be worse.

Children should be careful when riding bicycles or climbing trees until you know how DIPHERELINE affects them.

SIDE EFFECTS

Tell your doctor or pharmacist as soon as possible if you or your child do not feel well while you are receiving DIPHERELINE

DIPHERELINE helps most men with prostate cancer and most children with early puberty, but it may have unwanted side effects in a few people.

In men, it can be hard to work out whether side effects are caused by DIPHERELINE or prostate cancer.

Like all medicines, DIPHERELINE can have side effects. Generally, these are mild but you may need medical attention if you or your child get some of the side effects.

If you get any side effects, do not cancel your follow-up dose of DIPHERELINE without first talking to your doctor.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

In men:

Tell your doctor immediately or go to Accident and Emergency at your nearest hospital if any of the following happen. You may need urgent medical attention. (These side effects are rare.)

  • sudden signs of allergy such as rash, itching or hives on the skin, swelling of the face, lips, tongue or other parts of the body, shortness of breath, wheezing or trouble breathing
  • chest pain
  • sharp, stabbing pain or swelling in your lower leg
  • swelling and redness along a vein which is extremely tender when touched
  • seizures or convulsions.

Tell your doctor as soon as possible if you notice any of the following.

These side effects may be serious. You may need medical attention.

  • sudden headaches
  • severe back pain
  • difficulty breathing
  • temporary worsening of symptoms of your cancer (tumour flare)
  • high blood pressure
  • gout (disease with painful swollen joints, particularly in the big toe)
  • inability to pass urine.

Tell your doctor if you notice any of the following side effects and they worry you:

Very common side effects affecting more than 1 in 10 patients:

  • hot flushes
  • weakness
  • back pain
  • pins and needles sensation in the legs
  • excess sweating
  • reduced libido
  • impotence

Common side effects affecting more than 1 in 100 patients:

  • nausea
  • dry mouth
  • mood changes, depression
  • pain, bruising, redness and swelling at injection site
  • oedema (build up of fluid in the body tissues)
  • muscle and bone pain, pain in the arms and legs, lower abdominal pain
  • dizziness, headache
  • allergic reactions
  • loss of libido
  • hypersensitivity
  • high blood pressure
  • increase in weight

The following side effects have also been reported since DIPHERELINE was approved for use: general discomfort, anxiety, urinary incontinence, rapid formation of wheals due to swelling of the skin or mucous membranes, anaphylactic shock and changes in ECG (QT prolongation).

If you have an enlargement (benign tumour) of the pituitary gland that you were unaware of, this may be discovered during treatment with DIPHERELINE. Symptoms include sudden headache, vomiting, problems with eye sight and paralysis of the eyes.

An increase in white blood cell count may be found, as with other GnRH analogues, in patients being treated with DIPHERELINE.

Other side effects not listed above may also occur in some people.

Your doctor will monitor you during treatment to check that you do not develop high blood sugar or diabetes. You will also be monitored for any symptoms or signs of cardiovascular disease.

Some side effects (for example, high blood pressure or changes in liver function) can only be found when your doctor does tests to check on your progress.

Always tell your doctor or pharmacist if you notice anything that is making you feel unwell.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

In children:

Tell your child's doctor immediately or go to Accident and Emergency at your nearest hospital if any of the following happen. Your child may need urgent medical attention. (These side effects are rare.)

  • sudden signs of allergy such as rash, itching or hives on the skin, swelling of the face, lips, tongue or other parts of the body, shortness of breath, wheezing or trouble breathing
  • changes to vision
  • increased pressure in the head or brain
    Monitor/watch your child for signs and symptoms of increased pressure in the head or brain including: headache, blurred vision, double vision, loss of vision, pain behind the eye or pain with eye movement, ringing in the ears, dizziness, nausea.

Tell your child's doctor if you notice any of the following side effects and they worry you:

Very common side effects which may affect more than 1 in 10 patients:

  • vaginal bleeding which may occur in girls in the first month of treatment.

Common side effects which may affect up to 1 in 10 patients:

  • pain in abdomen
  • pain, redness and swelling at injection site
  • headache
  • hot flushes
  • weight gain
  • acne
  • hypersensitivity reactions.

Uncommon side effects which may affect up to 1 in 100 patients:

  • blurred vision
  • vomiting, constipation, nausea
  • general discomfort
  • overweight,
  • neck pain
  • changes in mood
  • pain in breast
  • nosebleeds
  • itching, rash or hives in the skin.

Always tell your doctor or pharmacist if you notice anything that is making your child feel unwell.

AFTER BEING GIVEN DIPHERELINE

Storage

DIPHERELINE is usually stored in the doctor's surgery or clinic, or at the pharmacy. However, if you need to store it at home:

Keep it in a cool, dry place where the temperature stays below 25°C

Keep your medicine where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines

Keep it in the original container until it is time for it to be given. If you take your medicine out of the original container, it will not keep well.

Disposal

Any DIPHERELINE which is not used will be disposed in a safe manner by your doctor.

PRODUCT DESCRIPTION

What it looks like

DIPHERELINE 3.75mg
1 month formulation

DIPHERELINE 11.25mg
3 month formulation

DIPHERELINE 22.5mg
6 month formulation

Each pack contains 1 vial of DIPHERELINE (3.75, 11.25 or 22.5 mg triptorelin), 1 ampoule, and 1 blister pack containing 1 empty polypropylene syringe and 2 needles.

The vial contains a small pellet of white to slightly yellow powder which must be mixed with the contents of the ampoule (solvent) before injection.

Ingredients

Active ingredients:

  • triptorelin embonate

Other ingredients:

  • polyglactin
  • mannitol
  • carmellose sodium
  • polysorbate 80
  • The solvent is composed of water for injections

SPONSOR

Ipsen Pty Ltd
Level 5
627 Chapel Street
South Yarra, Victoria 3141

Australian Registration Numbers:

AUST R 109854 (DIPHERELINE 3.75mg 1 month formulation)

AUST R 109856 (DIPHERELINE 11.25mg 3 month formulation)

AUST R 159173 (DIPHERELINE 22.5mg 6 month formulation)

Date of preparation of this leaflet:

March 2023

Published by MIMS April 2023

BRAND INFORMATION

Brand name

Diphereline

Active ingredient

Triptorelin

Schedule

S4

 

1 Name of Medicine

Triptorelin embonate.

2 Qualitative and Quantitative Composition

Diphereline 3.75 mg 1 month formulation.

Each vial contains a triptorelin content which allows the administration of an effective dose of 3.75 mg triptorelin. After reconstitution in 2 mL of solvent, 1 mL of reconstituted suspension contains 1.875 mg of triptorelin.

Diphereline 11.25 mg 3 month formulation.

Each vial contains a triptorelin content which allows the administration of an effective dose of 11.25 mg triptorelin. After reconstitution in 2 mL of solvent, 1 mL of reconstituted suspension contains 5.625 mg of triptorelin.

Diphereline 22.5 mg 6 month formulation.

Each vial contains a triptorelin content which allows the administration of an effective dose of 22.5 mg triptorelin. After reconstitution in 2 mL of solvent, 1 mL of reconstituted suspension contains 11.25 mg of triptorelin.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Powder and solvent for suspension for injection, prolonged release granules.
White to off-white powder.

4 Clinical Particulars

4.1 Therapeutic Indications

Diphereline is indicated for the treatment of hormone dependent locally advanced or metastatic prostate cancer.

Diphereline 22.5 mg 6 month formulation only.

Diphereline 22.5 mg is indicated for the treatment of children 2 years and older with central precocious puberty (CPP).

4.2 Dose and Method of Administration

Diphereline 3.75 mg - 1 month formulation.

The recommended dose of Diphereline is 3.75 mg triptorelin (1 vial) administered once a month as a single intramuscular injection.

Diphereline 11.25 mg - 3 month formulation.

The recommended dose of Diphereline is 11.25 mg triptorelin (1 vial) administered every three months as a single intramuscular injection.

Diphereline 22.5 mg - 6 month formulation.

The recommended dose of Diphereline is 22.5 mg triptorelin (1 vial) administered every six months as a single intramuscular injection.
The lyophilised microgranules are to be reconstituted using 2 mL sterile water for injection (see Section 4.2 Dose and Method of Administration). The injection site should be varied periodically.
Since Diphereline is a suspension of microgranules, inadvertent intravascular injection must be strictly avoided.

Special populations.

Patients with renal or hepatic impairment. No dosage adjustment is necessary for patients with renal or hepatic impairment (also see Section 5.2 Pharmacokinetic Properties). Diphereline must be administered under the supervision of a physician.
Paediatric population.

Precocious puberty (before 8 years in girls and 9 years in boys).

Prior to initiation of treatment a clinical diagnosis of CPP should be confirmed by measurement of blood concentrations of LH (basal or stimulated with a GnRH analogue), sex steroids, and assessment of bone age versus chronological age. Baseline evaluations should include height and weight measurements, diagnostic imaging of the brain (to rule out intracranial tumour), pelvic/testicular/adrenal ultrasound (to rule out steroid secreting tumours), human chorionic gonadotropin levels (to rule out a chorionic gonadotropin secreting tumour), and adrenal steroid measurements to exclude congenital adrenal hyperplasia.
The treatment of children with Diphereline 22.5 mg should be under the overall supervision of a paediatric endocrinologist or of a paediatrician or an endocrinologist with expertise in the treatment of central precocious puberty.
Treatment should be stopped around the physiological age of puberty in boys and girls and should not be continued in girls with a bone maturation of more than 12-13 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.

Method of administration.

The solvent for suspension should be drawn into the injection syringe and transferred to the vial containing the powder. The vial should be gently shaken to thoroughly disperse particles and obtain a uniform suspension. The suspension will appear milky. The suspension obtained should be drawn back into the injection syringe. The injection needle has to be changed and the produced suspension for injection should be administered immediately.
The suspension should be discarded if not used immediately after reconstitution.
Diphereline contains no antimicrobial agent. The product is for treatment of one patient only on one occasion. Discard any remaining contents. Used injection needles should be disposed in a designated sharp container. Any remaining product should be discarded.
Diphereline must be administered under the supervision of a healthcare professional.

4.3 Contraindications

Diphereline is contraindicated in patients with known hypersensitivity to the active substance triptorelin, GnRH, other GnRH agonist analogues or to any of the excipients (see Section 6.1 List of Excipients). Note that polysorbate 80 has been observed to induce hypersensitivity reactions in some patients.
Diphereline is contraindicated in patients with spinal cord compression secondary to prostate cancer metastases.
Diphereline is contraindicated in pregnancy and during lactation.

4.4 Special Warnings and Precautions for Use

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 antiandrogen 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 Section 4.5 Interactions with Other Medicines and Other Forms of Interactions) physicians should assess the benefit risk ratio including the potential for torsades 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. Patients may experience metabolic changes (e.g. glucose intolerance, fatty liver). 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)/ idiopathic intracranial hypertension has been reported in women and children receiving GnRH analogues including triptorelin. Monitor patients for signs and symptoms of PTC/ idiopathic intracranial hypertension, including severe or recurrent 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/ idiopathic intracranial hypertension 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 22.5 mg 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 3.75 mg (1 month) and 11.25 mg (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.

4.5 Interactions with Other Medicines and Other Forms of Interactions

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 torsades 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 Special Warnings and Precautions for Use).
When triptorelin is coadministered 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.

4.6 Fertility, Pregnancy and Lactation

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.
(Category D)
Safe use of Diphereline 22.5 mg 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 microgram/kg/day to rats on days 6 to 15 of gestation, triptorelin did not elicits any embryotoxicity or teratogenicity. At 100 microgram/kg/day, a reduction in maternal bodyweight gain and an increased number of resorptions were observed.
 Diphereline is not recommended for use during lactation.

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

4.8 Adverse Effects (Undesirable Effects)

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 immunoallergic 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 (≥ 1/10,000, < 1/1000). No very rare (< 1/10,000) adverse reactions were reported.
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 Section 4.4 Special Warnings and Precautions for Use).
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). See Table 2.

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.

4.9 Overdose

For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).
The pharmaceutical properties of Diphereline and its route of administration make accidental or intentional overdose unlikely. There is no experience of overdose from clinical trials. Animal tests suggest that no effect other than the intended therapeutic effects on sex hormone concentration and on the reproductive tract will be evident with higher doses of Diphereline.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Hormones and related agents, gonadotropin releasing hormone analogues.
ATC code: L02AE04.

Mechanism of action.

Triptorelin, a gonadotrophin releasing hormone (GnRH) agonist, inhibits gonadotrophin secretion when given continuously and in therapeutic doses. Male animal and human studies show that after the administration of triptorelin there is an initial and transient increase in circulating levels of luteinizing hormone (LH), follicle stimulating hormone (FSH), and testosterone. However, chronic and continuous administration of triptorelin results in decreased LH and FSH secretion and suppression of testicular and ovarian steroidogenesis. A reduction of serum testosterone levels into the range normally seen in surgically castrated men occurs approximately 2 to 4 weeks after initiation of therapy. This results in accessory sexual organ atrophy. These effects are generally reversible upon discontinuation of the medicinal product.
In animals, administration of triptorelin resulted in the inhibition of growth of some hormone sensitive prostate tumours in experimental models.

Clinical trials.

Prostate cancer.

One pivotal, long-term (9 months), controlled, phase III, multicentre study (DEB-96-TRI-01, first phase) compared the 3.75 mg (1 month) and 11.25 mg (3 month) embonate formulations in 348 patients with advanced prostatic cancer. Patients in this study had histologically confirmed stage C (52.9% of patients) or D (46.8% of patients) prostate cancer with testosterone levels greater than 5 nanomol/L at baseline. The mean age of the 348 patients in the safety population was 70.5 years (range 45 to 96 years); mean age at onset of prostate cancer was 69.8 years (range 44 to 96 years) and the mean disease duration was 6.9 months (range 0 to 155 months).
Per protocol and intent to treat analyses produced similar results. The 3 month formulation was noninferior (no worse than 10 percentage point difference in incidence) to the 1 month formulation in inducing and maintaining chemical castration (see Table 3).
The second phase of study DEB-96-TRI-01 (9 months) compared the efficacy of the 1 month formulation of triptorelin 3.75 mg and the US 1 month formulation of leuprorelin acetate 7.5 mg in patients with advanced prostatic cancer (the US formulation of leuprorelin acetate is not the same as the Australian registered formulation). This study involved 284 patients who had histologically confirmed stage C or D prostatic cancer.
Per protocol and intent to treat analyses produced similar results. Whilst the 1 month formulation was slower in inducing chemical castration than the US 1 month leuprorelin acetate formulation, it was noninferior in maintaining chemical castration (no worse than 10 percentage point difference in incidence). See Table 4.
With continuous use, desensitisation of the pituitary gonadotrophin receptors had generally occurred by 84 days of exposure making a surge in serum testosterone unlikely after this time. Tables 3 and 4 show that most patients had minimal increases in serum LH (≤ 1.0 IU/L) at days 85 and 169.
In trial DEB-TRI6M-301, 120 patients with advanced prostate cancer received Diphereline 22.5 mg 6-month formulation IM on days 1 and 169 and were followed until day 337 (48 weeks). The median age of patients was 70 years (range 50-92). The primary efficacy endpoints were the percentage of patients achieving the castrate level of testosterone (≤ 1.735 nanomol/L) by day 29 and percentage of patients maintaining this level from day 57 to Week 48. 115 patients (96%) completed the study. Three patients died, one was lost to follow-up and one withdrew consent. Of the patients completing the trial, 93% maintained castrate serum testosterone levels from day 57 to week 48 (Table 5 per protocol population). Intent to treat results were similar.

Precocious puberty.

Inhibition of the increased hypophyseal gonadotropic activity in children with precocious puberty leads to lowering of the LH levels following GnRH (or GnRH agonist) stimulation test and to suppression of oestradiol and testosterone secretion in girls and boys, respectively.
In a non-comparative clinical study, 44 children with central precocious puberty (39 girls and 5 boys) were treated with a total of two intramuscular injections of Diphereline 22.5 mg over 12 months (48 weeks). Suppression of stimulated LH concentrations to prepubertal levels (serum LH ≤ 5 IU/L) was achieved in 95.5% of subjects by month 3, and in 93.2% and 97.7% of subjects at months 6 and 12, respectively.
The consequence is a regression or stabilisation of secondary sex characteristics and slowing down of accelerated bone maturation and growth.
In girls, initial ovarian stimulation at treatment initiation, followed by the treatment-induced oestrogen increase, may lead, in the first month, to uterine 'withdrawal' bleeding of mild or moderate intensity.
The mean chronological age was 94.6 months (range: 31.0 to 118.0 months). The Tanner stage was stable or reduced in 90.9% of patients between baseline and Month 6 and in 88.6% patients between baseline and Month 12. See Table 6.
The percentage of children with no increase, i.e. reduction or stabilisation, of bone age/chronological age ratio on-treatment was 63.6% at Month 6 and 95.5% at Month 12.

5.2 Pharmacokinetic Properties

Absorption.

In a substudy of the pivotal efficacy trial DEB-96-TRI-01 of the 1 and 3 month doses in patients with prostate cancer, triptorelin exposure based on plasma AUC was comparable after intramuscular doses of the 1 month (x 3 doses at 28-day intervals) and 3-month formulations of triptorelin embonate (Table 7). Triptorelin did not accumulate over 9 months of treatment.
In a substudy in 15 patients with prostate cancer from the efficacy trial of the 6 month formulation (DEB-TRI6M-301), the plasma Cmax after the first injection was comparable to that obtained previously with the 3-month formulation and higher than the 1-month formulation; however, the AUC over 6 months (resulting from an overall dose of 22.5 mg for all 3 formulations) was about half that after the 3-month and 1-month formulations.
The three sustained release formulations of Diphereline cannot be considered strictly bioequivalent and this is due to differences in polymeric matrix which confers different release rate for each of the three strengths. Nonetheless, the three formulations were demonstrated to be pharmacodynamically equivalent.
The relationship between serum triptorelin and serum testosterone is not linear but on/off, so the level of serum triptorelin rather than AUC is important in maintaining castrate serum testosterone levels. After an initial surge, mean ± SD serum testosterone remained below the castrate level (≤ 1.735 nanomol/L) for the 336 days of the trial, except at day 336 when the upper limit of the standard deviation was above the castrate level.
In a study in healthy volunteers, the absolute bioavailability of an intramuscular dose of the 1 month formulation was 83%.
In children with precocious puberty median tmax was 4 (2-8) hours and Cmax following the first injection was 39.9 (19.1-107.0) nanogram/mL.

Distribution.

Results of pharmacokinetic investigations conducted in healthy men indicate that after intravenous bolus administration, triptorelin is distributed and eliminated according to a 3 compartment model and corresponding half-lives are approximately 6 minutes, 45 minutes, and 3 hours.
The volume of distribution at steady state of triptorelin following intravenous administration of 0.5 mg triptorelin is approximately 30 L in healthy male volunteers. Since there is no evidence that triptorelin at clinically relevant concentrations binds to plasma proteins, medicinal product interactions involving binding site displacement are unlikely.

Metabolism.

Metabolites of triptorelin have not been determined in humans. However, human pharmacokinetic data suggest that C-terminal fragments produced by tissue degradation are either completely degraded within tissues or are rapidly further degraded in plasma, or cleared by the kidneys.

Excretion.

Triptorelin is eliminated by both the liver and the kidneys. Following intravenous administration of intermediate release triptorelin acetate 0.5 mg to 6 young healthy adult males (mean Clcreat 150 mL/min), 42% of the dose was excreted in the urine as intact triptorelin. The mean triptorelin clearance was 212 mL/min.

Pharmacokinetics in special patient populations.

Renal and hepatic impairment.

In the intravenous study referred to under Excretion, patients with renal and liver impairment were also studied. There were 6 subjects in each group. Compared to young healthy adult males, mean triptorelin clearance was reduced by 43% in subjects with moderate renal impairment (mean Clcreat 40 mL/min), 58% in subjects with severe renal impairment (mean Clcreat 8.9 mL/min) and 73% in subjects with hepatic impairment (Child Pugh score 5-9) and a lower mean Clcreat (90 mL/min) than young healthy adult males. Triptorelin exposure was increased 2- to 4-fold in patients with renal or hepatic impairment.
The effects of age and race on triptorelin pharmacokinetics have not been systematically studied. However, pharmacokinetic data obtained in young healthy male volunteers aged 20 to 22 years with an elevated creatinine clearance (approximately 150 mL/min) indicated that triptorelin was eliminated twice as fast in the young population. This is related to the fact that triptorelin clearance is correlated to total creatinine clearance, which is well known to decrease with age.
Because of the large safety margin of triptorelin and since Diphereline is a sustained release formulation, no dose adjustment is recommended in patients with renal or hepatic impairment.

Pharmacokinetic/pharmacodynamic relationship(s).

The pharmacokinetics/pharmacodynamics relationship of triptorelin is nonlinear and time dependent. Thus, after acute administration in naive subjects, triptorelin induces a dose dependent increase of LH and FSH responses.
When administered as a sustained release formulation, triptorelin stimulates LH and FSH secretion during the first days postdosing and, in consequence, testosterone secretion. As shown by the results of the different bioequivalence studies, the maximal increase in testosterone is reached after around 4 days with an equivalent Cmax which is independent from the release rate of triptorelin. This initial response is not maintained despite continuous exposure to triptorelin and is followed by a progressive decrease of testosterone levels. In this case too, the extent of triptorelin exposure can vary markedly without affecting the overall effect on testosterone serum levels.

5.3 Preclinical Safety Data

Genotoxicity.

In vitro genotoxicity tests for gene mutations and chromosomal damage, and a mouse micronucleus test have provided no evidence for genotoxic effects.

Carcinogenicity.

Carcinogenicity studies were conducted in mice (18 months) and rats (23 months) with triptorelin embonate microgranules administered once monthly IM. In mice, no oncogenic effect was observed at triptorelin doses of up to 6000 microgram/kg/month. In rats, an almost 100% incidence of pituitary tumours was observed at each dose level (120, 600 and 3000 microgram/kg/month), leading to premature death. There were increased incidences of both pituitary adenomas and carcinomas at all dose levels. The increased incidence of pituitary tumours in rats is a common effect associated with GnRH agonist treatment. The clinical relevance of this is not known.

6 Pharmaceutical Particulars

6.1 List of Excipients

Composition of the powder.

Polyglactin, mannitol, carmellose sodium, polysorbate 80.

Composition of the solvent.

Water for injections.

6.2 Incompatibilities

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

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

After opening.

Chemical and physical in-use stability has been demonstrated for 24 hours at 25°C.
From a microbiological point of view, the prepared suspension should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C.
Contains no antimicrobial preservative. Use each ampoule in one patient on one occasion only. Discard any residue.

6.4 Special Precautions for Storage

Store below 25°C.
For storage conditions after first opening of the medicinal product, see Section 6.3 Shelf Life.

6.5 Nature and Contents of Container

Diphereline 3.75 mg 1 month formulation.

6 mL type I brown tint glass vial with grey bromobutyl stopper and purple aluminium flip-off capsule.

Diphereline 11.25 mg 3 month formulation.

6 mL type I brown tint glass vial with grey bromobutyl stopper and yellow green aluminium flip-off capsule.

Diphereline 22.5 mg 6 month formulation.

6 mL type I brown tint glass vial with grey bromobutyl stopper and dark green aluminium flip-off capsule.
Solvent: Type I glass ampoule containing 2 mL of sterile solvent for suspension.
Each box contains 1 vial, 1 ampoule and 1 blister containing 1 empty polypropylene injection syringe and 2 injection needles.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.

[(L-Pyr)-(L-His)-(L-Trp)-(L-Ser)-(L-Tyr)-(D-Trp)-(L-Leu)-(L-Arg)-(L-Pro)-(Gly-NH2)].
Molecular formula: C64H82N18O13 (triptorelin). C23H16O6 (embonate).
Molecular weight: 1311.5 (triptorelin) + 388.4 (embonate).

CAS number.

57773-63-4.

7 Medicine Schedule (Poisons Standard)

S4.

Summary Table of Changes