Female infertility in supplementary treatment, in combination with gonadotrophins (hMG, FSH, hCG) to induce ovulation with a view to in vitro fertilisation and embryo transfer (I.V.F.E.T.).

Female infertility: in combination with gonadotrophins.
One daily subcutaneous injection from Day 2 of the menstrual cycle (at the same time as ovarian stimulation starts) until the day before the day set for induction, i.e. an average period of 10 to 12 days for each attempt.

The use of GnRH agonists may cause reduction in bone mineral density. 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 0.1 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 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.
DIPHERELINE 0.1 mg contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially “sodium-free”.
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 follicular retrieval induced by the injection of triptorelin combined with gonadotrophins may increase markedly in some predisposed patients and particularly in cases of polycystic ovarian disease.
As with other GnRH analogues there have been reports of ovarian hyperstimulation syndrome associated with the use of triptorelin in combination with gonadotrophins.
The ovarian response to the triptorelin-gonadotrophin association may differ with the same doses from one patient to another, and in certain cases, from one cycle to another in the same patient.
Precautions for use
The induced ovulation should be monitored under rigorous medical supervision with strict and regular biological and clinical controls: fast plasma oestrogen assay and ultrasonography (see section 4.8).
If the ovarian response is excessive, it is recommended to interrupt the stimulation cycle by discontinuing the gonadotrophin injections.

In patients with renal or hepatic impairment, triptorelin has a mean terminal half life of 7-8 hours compared to 3-5 hours in healthy subjects. Despite this prolonged exposure, triptorelin is not expected to be present in circulation at the time of embryo transfer.

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.

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.
When triptorelin is used in this setting, there is no clinical evidence to suggest a causal connection between triptorelin and any subsequent abnormalities of oocyte development or pregnancy or outcome.
However, further studies are necessary to verify the consequences of an exposure during pregnancy.
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.

Clinical Trial experience The adult population enrolled in clinical trials and treated with the triptorelin immediate release formulation included 127 male patients suffering from prostate cancer treated daily for 3 months and about 1000 women who underwent In Vitro Fertilization protocols. The additional detailed safety experience obtained during the clinical studies performed with the 1 Month and 3 Month formulations of triptorelin in men and women has also been included.
The overall analysis of the safety experience reported during the clinical trials included pharmacological class adverse reactions such as a result of hypogonadotrophic hypogonadism or occasionally the initial pituitary–gonadal stimulation.
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); very rare ((<1/10,000).
General tolerance in adults
Very common: mild to severe hot flushes and hyperhidrosis which do not usually require discontinuation of therapy.
General tolerance in women
Very common at the beginning of treatment: When used to treat infertility, the combination with gonadotrophins may result in ovarian hyperstimulation syndrome. Ovarian hypertrophy, dyspnoea, pelvic and/or abdominal pain may be observed ( See section 4.4 ).
Very common at the beginning of treatment with triptorelin 1 Month and 3 Month formulations: Genital haemorrhage including menorrhagia or metrorrhagia may occur in the month following the first injection.
Very common during treatment with triptorelin 1 Month and 3 Month formulations: these adverse reactions showed a general pattern of hypo-oestrogenic events related to pituitary-ovarian blockade such as sleep disorder, headache, mood altered, vulvovaginal dryness and dyspareunia, libido decreased.

Common during treatment with triptorelin 1 Month formulation: breast pain, muscle spasms, arthralgia, weight increased, nausea, abdominal pain/discomfort, asthenia. Depression and mood changes have also been reported with long term use.
Local tolerance
Very rare: pain, erythema and inflammation at the injection site.
Post marketing information
During post-marketing surveillance, additional undesirable effects have been reported in women treated for IVF. The undesirable effects are classified by body system organ categories and by decreasing order of frequency of reported effects:
Skin and subcutaneous tissue disorders: Hypersensitivity reactions including pruritus, urticaria, rash, angioneurotic oedema (see section 4.3).
Nervous system disorders: headache
Eye disorders: episodes of blurred vision or visual disturbance.
Long-term use of GnRH analogues may lead to bone loss which is a risk factor of osteoporosis. These effects are not observed during short duration treatment with 0.1 mg DIPHERELINE.

No adverse effects resulting from an overdose has been reported.

Triptorelin is a synthetic decapeptide analogue of natural GnRH (gonadotrophin-releasing hormone).
Studies conducted in humans and in animals have shown that after initial stimulation, the prolonged administration of triptorelin inhibits gonadotrope secretion with consequent suppression of testicular and ovarian function.
Further studies in animals have suggested another mechanism of action: direct effect on the gonads by decreasing the sensitivity of peripheral receptors to GnRH.
Female infertility
Prolonged treatment with triptorelin inhibits gonadotrope secretion (FSH and LH). The treatment ensures therefore the suppression of the intercurrent endogenous LH peak enabling enhanced quality of folliculogenesis and increased follicular retrieval.

In healthy adult volunteers
Following subcutaneous injection the resorption of triptorelin (0.1 mg) is quick (tmax = 0.63 ± 0.26 hr) with a peak plasma concentration (Cmax = 1.85 ± 0.23 ng/ml).
Elimination is achieved with a biological half-life of 7.6 ± 1.6 hr, after a 3 to 4 hours distribution phase.
Total plasma clearance is: 161 ± 28 ml/min.
Distribution volume is: 1562 ± 158 ml/kg.

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

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Not applicable.

Store in the original package.

Vial or ampoule (glass) containing the powder and ampoule (glass) containing the solvent.

Not applicable.