1. Name Of The Medicinal Product
GONAPEPTYL DEPOT
3.75 mg
Powder and solvent for suspension for injection.
2. Qualitative And Quantitative Composition
One pre-filled syringe contains 3.75 mg triptorelin (as acetate) to be suspended in one ml suspension agent.
For excipients, see 6.1.
3. Pharmaceutical Form
Powder and solvent for suspension for injection
prolonged release in pre-filled syringes.
4. Clinical Particulars
4.1 Therapeutic Indications
Men:
Treatment of advanced, hormone-dependent prostate carcinoma.
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.
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:
At the beginning of treatment one injection with one syringe, equivalent to 3.75 mg triptorelin, 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. Children weighing less than 20 kg are injected with 1.875 mg (half dose), children between 20 and 30 kg receive 2.5 mg (2/3 dose), and children with more than 30 kg body weight are injected with 3.75 mg triptorelin (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.
In men:
− Hormone independent prostate carcinoma
− As sole treatment in prostate cancer patients with spinal cord compression or evidence of spinal metastases (see also section 4.4)
− After orchiectomy (in case of surgical castration Gonapeptyl Depot does not cause further decrease of serum testosterone)
In women:
− Pregnancy
− Clinically manifest osteoporosis
− Lactation period
In children:
− Progressive brain tumours
4.4 Special Warnings And Precautions For Use
Men:
The initial transient increase of serum testosterone has, in few patients, been associated with a temporary aggravation of symptoms of the disease (see 4.8). The patient should be advised to consult the physician, if any of these symptoms aggravates. For that reason, the use of Gonapeptyl Depot has to be carefully evaluated in patients with premonitory signs of medullary compression and the medical surveillance has to be closer in the first weeks of treatment, particularly in patients with urinary tract obstructions due to metastases and/or in patients with spinal metastases.
In order to prevent accentuation of the clinical symptoms, supplementary administration of an appropriate antiandrogen agent should be considered in the initial phase of the treatment.
In order to control the therapeutic effect, the prostate-specific antigen (PSA) and the testosterone plasma levels should be regularly monitored during treatment. Testosterone levels should not exceed 1 ng/ml.
Women:
Gonapeptyl Depot should only be prescribed after careful diagnosis (e.g. laparoscopy). Pregnancy should be precluded prior to treatment.
- Uterine myomas and endometriosis:
Menstruation does not occur during treatment. 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 gonadotrophins. 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.
Treatment with Gonapeptyl Depot over several months can lead to a decrease of bone density (see 4.8). For this reason, therapy should not exceed a duration of 6 months. After withdrawal of treatment, the bone loss is generally reversible within 6 - 9 months.
Particular caution is therefore advised in patients with additional risk factors in view of osteoporosis.
Children:
The chronological age at the beginning of therapy should be under 9 years in girls and under 10 years in boys.
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.
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.
General:
When triptorelin is co-administered with drugs affecting pituitary secretion of gonadotrophins caution should be given and the patient's hormonal status should be supervised.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Oestrogen containing medicinal products should not be used during treatment with Gonapeptyl Depot.
4.6 Pregnancy And Lactation
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. Animal data do not indicate direct or indirect harmful effects with respect to pregnancies or postnatal developments, but there are indications for foetotoxicity and delayed parturition. 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. Women of childbearing potential should use effective non-hormonal contraception. 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.
4.7 Effects On Ability To Drive And Use Machines
Gonapeptyl Depot has no or negligible influence on the ability to drive and use machines.
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 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.
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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.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Gonadorelinanaloga
ATC code: L02AE04
Triptorelin is a synthetic decapeptide analogue of the natural gonadotrophin-releasing hormone (GnRH). GnRH is a decapeptide, which is synthesised in the hypothalamus and regulates the biosynthesis and release of the gonadotrophins LH (luteinising hormone) and FSH (follicle stimulating hormone) by the pituitary. Triptorelin stimulates the pituitary more strongly to secretion of LH and FSH than a comparable dose of gonadorelin, whereas the duration of action is longer. The increase of LH and FSH levels will initially lead to an increase of serum testosterone concentrations in men or serum oestrogen concentrations in women. Chronic administration of a GnRH agonist results in an inhibition of pituitary LH- and FSH-secretion. This inhibition leads to a reduction in steroidogenesis, by which the serum estradiol concentration in women and the serum testosterone concentration in men fall to within the postmenopausal or castrate range, respectively, i.e. a hypogonadotrophic hypogonadal state. In children with precocious puberty, the concentration of estradiol or testosterone will decrease to within the prepubertal range. Plasma DHEAS (dihydroepiandrostenedion sulphate) levels are not influenced. Therapeutically, this leads to a decrease in growth of testosterone-sensitive prostate tumours in men, and to reduction of endometriosis foci and oestrogen-dependent uterus myomas in women. Regarding uterine myoma, maximal benefit of treatment is observed in women with anaemia (haemoglobin inferior or equal to 8 g/dl). In children suffering from CPP triptorelin treatment leads to a suppression of the secretion of gonadotropins, estradiol, and testosterone to prepubertal levels. This results in arrest or even regression of pubertal signs and an increase in adult height prediction in CPP patients.
5.2 Pharmacokinetic Properties
After intramuscular administration of Gonapeptyl Depot, the plasma concentrations of triptorelin are determined by the (slow) degradation of the poly-(d,l lactide coglycolide) polymer. The mechanism inherent to this administration form enables this slow release of triptorelin from the polymer.
After I.M. or S.C. application of a triptorelin depot-formulation (sustained-release microcapsules), a rapid increase in the concentration of triptorelin in plasma is recorded, with a maximum in the first hours. Then the triptorelin concentration declines notably within 24 hours. On day 4 the value reaches a second maximum, falling below the detection limit in a biexponential course after 44 days. After S.C. injections the triptorelin increase is more gradual and in a somewhat lower concentration than after I.M. injections. After S.C. injection, the decline in the triptorelin concentration takes longer, with values falling below the detection limit after 65 days.
During treatment over a period of 6 months and an administration every 28 days, there was no evidence of triptorelin accumulation in both modes of administration. Plasma triptorelin values decreased to approx. 100 pg/ml before the next application after I.M. or S.C. application (median values). It is to be assumed that the non-systemically available proportion of triptorelin is metabolized at the injection site, e.g. by macrophages.
In the pituitary, the systemically available triptorelin is inactivated by N-terminal cleavage via pyroglutamyl-peptidase and a neutral endopeptidase. In the liver and the kidneys, triptorelin is degraded to biologically inactive peptides and amino acids.
40 minutes after the end of an infusion of 100 μg triptorelin (over 1 hour) 3-14% of the administered dose has already been eliminated by the kidney.
For patients with an impaired renal function, adaptation and individualization of therapy with the triptorelin depot-formulation seems to be unnecessary, on account of the subordinate significance of the renal elimination route and the broad therapeutic range of triptorelin as an active component.
Bioavailability:
Men:
The systemic bioavailability of the active component triptorelin from the intramuscular depot is 38.3% in the first 13 days. Further release is linear at 0.92% of the dose per day on average. Bioavailability after S.C. application is 69% of I.M. availability.
Women:
After 27 test days, 35.7% of the applied dose can be detected on average, with 25.5% being released in the first 13 days and further release being linear at 0.73% of the dose per day on average.
General:
Calculation of the model-depending kinetic parameters (t½, Kel, etc.) is inapplicable in presentations with a strongly protracted release of the active component.
5.3 Preclinical Safety Data
In rats, but not in mice treated over a long period of time with triptorelin, an increase in pituitary tumors has been detected. The influence of triptorelin on pituitary abnormalities in humans is unknown. The observation is considered not to be relevant to humans. Pituitary tumors in rodents in connection with other LHRH analogues have also been known to occur. Triptorelin has been shown to be embryo-/foetotoxic and to cause a delay in embryo-/foetal development as well as delay in parturition in rats. Preclinical data reveal no special hazard to humans based on repeat dose toxicity and genotoxicity studies. Single I.M. or S.C. injection of Gonapeptyl Depot or its suspension agent produced delayed foreign body reactions at the injection site. Within 8 weeks, these late reactions were nearly reversed after I.M. injection but only slightly reversed after S.C. injection. Local tolerance of Gonapeptyl Depot after I.V. injection was limited
6. Pharmaceutical Particulars
6.1 List Of Excipients
One pre-filledsyringe with powder contains:
Poly-(d,l lactide coglycolide)
Propyleneglycol octanoate decanoate
One pre-filledsyringe with one ml suspension agent contains:
Dextran 70
Polysorbate 80
Sodium chloride
Sodium hydrogen phosphate dihydrate
Sodium hydroxide
Water for injection
6.2 Incompatibilities
In the absence of compatibility studies this medicinal product should not be mixed with other medicinal products.
6.3 Shelf Life
3 years
Reconstituted suspension: 3 minutes
6.4 Special Precautions For Storage
Store at 2°C - 8°C (in a refrigerator). Keep the container in the outer carton.
6.5 Nature And Contents Of Container
Powder: Pre-filled syringe
Solvent: Pre-filled syringe
Pre-filled syringes (borosilicate glass type I, clear) with a connector (polypropylene), black chlorobutyl rubber stopper (plunger stopper, type I) and injection needle.
Pack sizes:
1 pre-filled syringe (powder) plus
1 pre-filled syringe (solvent)
3 pre-filled syringes (powder) plus
3 pre-filled syringes (solvent)
6.6 Special Precautions For Disposal And Other Handling
GonapeptylDepot is for single use only and any unused suspension should be discarded.
1. Preparation
Instructions for the physician how to prepare the suspension.
Since successful treatment depends upon correct preparation of the suspension, the following instructions must be strictly followed.
- Take the package of Gonapeptyl Depot from the refrigerator.
- Remove the cap from the disposable syringe containing the powder. Keep upright to prevent spilling.
- Open the package with the connector without removing the connector.
- Screw the syringe containing the sustained release microparticles on the connector in the package, then remove it.
Screw the syringe containing the suspension agent tightly on the free end of the connector and ensure that it fits tightly.
2. Reconstitution of a suspension
Empty the liquid into the syringe with the powder, then shoot it back and forth into the first syringe – the first two or three times without pushing the injection rod all the way in. Repeat this about 10 times or until you have a homogeneous milky-like suspension. While preparing the suspension, you might possibly create some foam. It is important that the foam be dissolved or removed from the syringe before giving the injection.
Mixing
Mix approximately 10 times
3. Injection
- Remove the connector together with the empty syringe.
- Mount the injection needle on the syringe with the ready-to-use suspension.
- Inject subcutaneously or deep into the muscle immediately.
7. Marketing Authorisation Holder
Ferring Pharmaceuticals Ltd.
The Courtyard
Waterside Drive
Langley
Berkshire SL3 6EZ
United Kingdom
8. Marketing Authorisation Number(S)
PL 03194/0085
9. Date Of First Authorisation/Renewal Of The Authorisation
14th May 2003
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