Decapeptyl: Indications, Dosage, Precautions, Adverse Effects
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Decapeptyl - Product Information

Manufacture: Ferring Pharmaceuticals
Country: Canada
Condition: Amenorrhea, Endometriosis, Prostate Cancer, Uterine Fibroids
Class: Gonadotropin releasing hormones, Hormones/antineoplastics
Form: Liquid solution, Subcutaneous (SC)
Ingredients: Triptorelin acetate, are sodium chloride, acetic acid (glacial), water for injection.

Summary Product Information

Route of
Administration
Dosage Form /
Strength
Clinically Relevant Nonmedicinal
Ingredients
Subcutaneous InjectionSolution for InjectionSodium Chloride
0.1 mg/mLGlacial Acetic Acid
Water for Injection

Indications and Clinical Use

DECAPEPTYL is indicated for:

  • downregulation and prevention of premature luteinizing hormone (LH) surges in women undergoing controlled ovarian hyperstimulation for assisted reproductive technologies (ART).

In clinical trials DECAPEPTYL 0.1 mg/mL has been used in cycles where urinary and recombinant human follicle stimulating hormone (FSH) as well as human menopausal gonadotrophin (HMG) were used for stimulation.

DECAPEPTYL should be initiated under the supervision of a physician experienced in the treatment of infertility.

DECAPEPTYL is not indicated during pregnancy.

Contraindications

DECAPEPTYL is contraindicated in cases of

  • Hypersensitivity to the active substance or to any of the excipients
  • Hypersensitivity to gonadotrophin-releasing hormone (GnRH) or any other GnRH analogue
  • Pregnancy and lactation period

Warnings and Precautions

General

Before initiating treatment with DECAPEPTYL, pregnancy must be ruled out (see Special Population-Pregnant Women)

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.

No specific dose recommendations are given for subjects with renal or hepatic impairment. A clinical study indicated that the risk of accumulation of triptorelin in patients with severe hepatic or renal impairment is small. 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 subiects. Despite this prolonged exposure, triptorelin is not expected to be present in circulation at the time of embryo transfer.

ART is associated with an increased risk of multiple pregnancies, pregnancy wastage, ectopic pregnancies and congenital malformations. These risks are also valid with usage of DECAPEPTYL 0.1 mg/1 mL as adjunct therapy in controlled ovarian hyperstimulation. The use of DECAPEPTYL in controlled ovarian hyperstimulation may increase the risk of ovarian hyperstimulation syndrome (OHSS) and ovarian cysts.

Follicular recruitment, induced by the use of GnRH analogues and gonadotrophins, may be markedly increased in a minority of predisposed patients, particularly in case of Polycystic Ovarian Syndrome.

As with other GnRH analogues, there have been reports of ovarian hyperstimulation syndrome (OHSS) associated with the use of triptorelin in combination with gonadotrophins.

Ovarian stimulation should be done under strict medical supervision.

Ovarian Hyperstimulation Syndrome (OHSS)

OHSS is a medical event distinct from uncomplicated ovarian enlargement. OHSS is a syndrome that can manifest itself with increasing degrees of severity. It comprises marked ovarian enlargement, high serum sex steroids, and an increase in vascular permeability which can result in an accumulation of fluid in the peritoneal, pleural and, rarely, in the pericardial cavities.

The following symptoms may be observed in severe cases of OHSS: abdominal pain, abdominal distension, severe ovarian enlargement, weight gain, dyspnoea, oliguria and gastrointestinal symptoms including nausea, vomiting and diarrhoea. Clinical evaluation may reveal hypovolaemia, haemoconcentration, electrolyte imbalances, ascites, haemoperitoneum, pleural effusions, hydrothorax, acute pulmonary distress, and thromboembolic events.

Excessive ovarian response to gonadotrophin treatment seldom gives rise to OHSS unless hCG is administered to trigger ovulation. Therefore, in cases of OHSS it is prudent to withhold hCG and advise the patient to refrain from coitus or to use barrier methods for at least 4 days. OHSS may progress rapidly (within 24 hours to several days) to become a serious medical event, therefore patients should be followed for at least two weeks after the hCG administration.

OHSS may be more severe and more protracted if pregnancy occurs. Most often, OHSS occurs after hormonal treatment has been discontinued and reaches its maximum severity at about seven to ten days following treatment. Usually, OHSS resolves spontaneously with the onset of menses. If severe OHSS occurs, gonadotrophin treatment should be stopped if still ongoing, the patient hospitalized and specific therapy for OHSS started e.g. with rest, intravenous infusion of electrolyte solutions or colloids and heparin.

This syndrome occurs with higher incidence in patients with polycystic ovarian disease. The risk of OHSS might be higher with use of GnRH agonists in combination with gonadotrophins than with use of gonadotrophins alone.

Cardiovascular

Effects on QT/QTc Interval

Gonadotrophin-releasing hormone receptors superagonists and antagonists have been associated with QTc prolongation in male patients receiving these drugs as long-term treatment for prostate cancer. QTc prolongation is believed to be related to the decreased plasma levels of testosterone. Triptorelin has not been studied for QTc prolongation in female subjects. Particular care should be exercised when administering Decapeptyl to patients with risk factors for Torsade de Pointes, including, but not limited to, congenital long QT syndrome, cardiac disease; history of arrhythmias; hypokalemia, hypocalcemia, and/or hypomagnesemia;bradycardia; and eating disorders.

Endocrine and Metabolism

Loss of bone mineral density

The use of GnRH agonists is likely to cause reduction in bone mineral density averaging 1% per month during six months treatment period. Every 10% reduction in bone mineral density is linked with about a two to three times increased fracture risk. In 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 abuse smokers, long term therapy with drugs that reduce bone mineral density, e.g. anti -convulsants or corticoids, family history of osteoporosis, malnutrition, e.g. anorexia nervosa). Since reduction in bone density is likely to be 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 to counteract loss of bone mineral density.

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

Psychiatric

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

Renal / Hepatic/Biliary/Pancreatic

No specific dose recommendations are given for subjects with renal or hepatic impairment. A clinical study indicated that the risk of accumulation of triptorelin in patients with severe or renal impairment is small.

Sensitivity/Resistance

Special care should be taken in women with signs and symptoms of active allergic conditions or known history of allergic predisposition. Treatment with DECAPEPTYL is not advised in women with severe allergic conditions.

Sexual Function/Reproduction

Ovarian Cysts

Ovarian cysts may occur during the initial phase of treatment with GnRH agonist. They are usually asymptomatic and non-functional.

Special Populations

Pregnant Women

DECAPEPTYL is not indicated during pregnancy. Pregnancy must be excluded before initiation of fertilization treatment. Non-hormonal methods of contraception should be employed during therapy until menses resume. If a patient becomes pregnant while receiving triptorelin, therapy should be discontinued.

When triptorelin is used for fertilization treatment, there is no clinical evidence to suggest a causal connection between triptorelin and any subsequent abnormalities of oocyte development or pregnancy or outcome.

Very limited data on the use of triptorelin during pregnancy does not indicate an increased risk of congenital malformations. Based on the pharmacological effects disadvantageous influence on the pregnancy and the offspring cannot be excluded.

Pregnant rats were treated by subcutaneous administration of triptorelin at dose levels of 0.4, 2 or 10 μg/kg/day during the period of organogenesis. No signs of maternal toxicity or teratogenicity were seen. However, a substantial increase in the number of luteal bodies was seen in all treated groups. Treatment with 2 μg/kg caused a slight increase in the mean placental weight while treatment with 10 μg/kg caused a marked increase in placental weight.

Pregnant rabbits were treated by subcutaneous administration of triptorelin to at dose levels of 0.5, 5 or 50 μg/kg/day during the period of organogenesis. Pre-implantation losses were observed in rabbits treated with the highest dose. When compared with the control group, a higher incidence of resorptions and abortions were observed at 50.0 µg/kg/day dosage. Fetal survival, growth and morphological development were unaffected at dose-levels up to 50.0 µg/kg/day.

Pregnant Cynomolgus monkeys were given single intramuscular injections of 1500 μg triptorelin/animal (ca. 375 μg/kg) as a slow release formulation on day 10 and day 40 post-coitum The treatment did not affect parturition and had no maternal or embryotoxic effects.

Nursing Women

DECAPEPTYL is not indicated for use during lactation.

Monitoring and Laboratory Tests

Before starting therapy with DECAPEPTYL, pregnancy must be excluded.

Adverse Reactions

Adverse Drug Reaction Overview

Frequently (≥ 2%) reported adverse events during the treatment with DECAPEPTYL in clinical trials, either before or during co-administration with gonadotrophins, are listed in the table below. The most frequent adverse events are headache (27%), vaginal bleeding/spotting (24%), abdominal pain (15%), injection site inflammation (12%) and nausea (10%).

Mild to severe hot flushes and hyperhidrosis may occur which do not usually require discontinuation of therapy.

At the beginning of treatment with DECAPEPTY, the combination with gonadotrophins may result in ovarian hyperstimulation syndrome. Ovarian enlargement, dyspnoea, pelvic and/or abdominal pain may be observed (See Warnings and Precautions). Genital haemorrhage including menorrhagia and metrorrhagia may occur at the beginning of treatment with DECAPEPTYL.

Ovarian cysts have been reported to occur commonly (1%) during the initial phase of treatment with DECAPEPTYL.

During treatment with triptorelin some adverse reactions showed a general pattern of hypo-oestrogenic events related to pituitary-ovarian blockade such as sleep disorder, headache, mood alteration, vulvovaginal dryness, dyspareunia and decreased libido..

Breast pain, muscle spasms, arthralgia, weight increased, nausea, abdominal pain, abdominal discomfort, asthenia and episodes of blurred vision and visual disturbances may occur during treatment with DECAPEPTYL.

Single cases of allergic reactions, localized or generalized, have been reported after injection of DECAPEPTYL.

Frequency (> 2%) Reported Adverse Events with DECAPEPTYL in Clinical Trials
MedDRA System
Organ Class
Very common
(≥ 1/10)
Common (≥ 1/100 or
< 1/10)
Not known
Infection and InfestationsUpper respiratory tract infection, pharyngitis
Immune system disorderHypersensitivity
Psychiatric DisordersSleep disorder, mood altered, libido decreased
Nervous system disorderHeadacheDizziness
Eye disordersVisual impairment, vision blurred
Vascular disordersHot flushes
Respiratory, thoracic and mediastinal disordersDyspnoea
Gastrointestinal disordersAbdominal pain, nauseaAbdominal distension, vomitingAbdominal discomfort
Skin and subcutaneous tissue disordersHyperhidrosis, pruritus, rash, angioedema, urticaria
Musculoskeletal and connective tissue disordersBack painMuscle spasms, arthralgia
Pregnancy, puerperium and perinatal conditionsAbortion
Reproductive system and breast disordersVaginal haemorrhagePelvic pain, ovarian hyperstimulation syndrome, dysmenorrhoea, ovarian cystOvarian enlargement, menorrhagia, metrorrhagia, vulvovaginal dryness, dyspareunia, breast pain
General disorders and administration site conditionsInjection site inflammationInjection site pain, injection site reaction, fatigue, influenza like symptomsAsthenia, injection site erythema
InvestigationsWeight increased

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Treatment-Emergent AEs Reported by at Least 1% of the IVF/ICSI Patients Receiving DECAPEPTYL in Studies MFK/IVF/0399E and FE999906 CS003
MedDRA Preferred TermMFK/IVF/0399E
n (%)
FE999906 CS003
n (%)
Onset During
Downregulation
N=133
Onset During
Stimulation
N=113
Onset During
Downregulation
N=781
Onset During
Stimulation
N=731
Headache30 (27%)31 (27%)29 (4%)36 (5%)
Dizziness5 (4%)6 (5%)
Dysmenorrhoea7 (6%)2 (2%)20 (3%)
Vaginal Haemorrhage2 (2%)176 (24%)
Pelvic Pain43 (6%)
Leukorrhoea2 (2%)
Application site Disorders
All events
Inj. Site Inflammation
Inj. Site Pain
Inj. Site Bruising
Injection Site Reaction


16 (14%)
13 (12%)
5 (4%)
--
2 (2%)


20 (18%)
11 (10%)
8 (7%)
3 (3%)
3 (3%)
Abdominal Pain10 (9%)17 (15%)
Abdominal Distension18 (2%)
Nausea6 (5%)11 (10%)20 (3%)
Vomiting3 (3%)
Diarrhea2 (2%)
Ovarian Cyst10 (1%)8 (1%)
Abortion Spontaneous48 (7%)
Abortion Missed15 (2%)
OHSS23 (3%)
Adnexa Uteri Pain12 (2%)
Upper Resp. Tract Infection4 (4%)4 (4%)
Dyspnea2 (2%)
Influenza-like Symptoms3 (3%)
Pharyngitis3 (3%)
Rhinitis2 (2%)
Fatigue3 (3%)4 (4%)
Hot Flushes2 (2%)
Malaise2 (2%)
Back Pain3 (3%)3 (3%)
Flushing4 (4%)
Post Procedural Pain26 (4%)
Post-operative Pain3 (3%)

Post-Market Adverse Drug Reactions

Since 1 January 1990, a total of 35 adverse events in concerning DECAPEPTYL have been reported. Thirty-two cases were reported in females of reproductive age, and in the remaining three cases information on either age or gender were not available. There were six serious adverse events reported: two reports of hypersensitive reactions and four cases of OHSS.

There were two cases of injection site necrosis, two cases of injection site pain (one of them associated with injection site haemorrhage) and one case of each of the following: diarrhea, injection site reaction, injection site bruising, circulatory collapse and lack of efficacy.

Exposure to DECAPEPTYL during pregnancy has been reported for a total of 35 cases. 6 case reports concern Triptorelin daily formulation, 29 concern Triptorelin depot formulations. The outcome of the 35 pregnancy cases with Triptorelin formulations were as follows: eight abortions (7 spontaneous and 1 elective), four cases of congenital anomalies (Down’s syndrome, cleft palate, hypospadias and multiple anomalies), three cases of ectopic pregnancies, and one case each of hyperemesis gravidarum, non-acute porphria and pre-eclampsia. A total of 21 pregnancies were unintended pregnancies. A total of 18 healthy infants were delivered (including 1 twin pregnancy).

Drug Interactions

Drug-Drug Interactions

Interactions of DECAPEPYL with other medicines have not been investigated for this indication. The possibility of interactions with commonly used medicinal products, including histamine liberating products, cannot be excluded.

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.

Dosage and Administration

Dosing Considerations

DECAPEPTYL is intended for subcutaneous injection once daily into the lower abdominal wall. Following the first administration, it is advised that the patient be kept under medical supervision for 30 minutes to ensure there is no allergic/pseudo-allergic reaction to the injection. Facilities for the treatment for such reactions should be immediately available. The following injections may be self-administered as long as the patient is made aware of the signs and symptoms that may indicate hypersensitivity, the consequences of such a reaction and the need for immediate medical intervention. The injection site should be varied to prevent lipoatrophy.

Treatment with DECAPEPTYL should be initiated under the supervision of a physician experienced in the treatment of infertility. Treatment can be started in the early follicular phase (day 2 or 3 of the menstrual cycle) or in the mid-luteal phase (day 21-23 of the menstrual cycle or 5-7 days before expected start of menses). Controlled ovarian hyperstimulation with gonadotrophins should be started after approximately 2-4 weeks of DECAPEPTYL treatment. Ovarian response should be monitored clinically (including ovarian ultrasound alone or in combination with measurement of oestradiol levels) and the dose of gonadotrophins adjusted accordingly. When a suitable number of follicles have reached an appropriate size, treatment with DECAPEPTYL and gonadotrophin is stopped and a single injection of hCG is administered to induce the final follicular maturation.

If downregulation is not confirmed after 4 weeks (determined by oestradiol levels or ultrasound documentation of a shedded endometrium), discontinuation of DECAPEPTYL should be considered. The total duration of treatment is usually 4-7 weeks. When using DECAPEPTYL, luteal phase support should be provided. Luteal phase support should be given according to the reproductive medical centre's practice.

Recommended Dose and Dosage Adjustment

The usual dosage is one injection (0.1 mg) under the skin of the lower abdomen once daily. Treatment can be started on day 2 or 3 or day 21 to 23 of the menstrual cycle (or 5-7 days before expected start of menstruation). After 2 to 4 weeks other hormones are given to stimulate follicle growth. In general DECAPEPTYL treatment continues until follicles have reached a suitable size. This usually last 4-7 weeks.

Ovarian response should be monitored clinically (including ovarian ultrasound alone or preferably in combination with measurement of oestradiol levels) and the dose of gonadotrophins adjusted accordingly.

No specific dose recommendations are given for subjects with renal or hepatic impairment. A clinical study indicated that the risk of accumulation of triptorelin in patients with severe liver and renal impairment is small.

Missed Dose

If the patient misses a dose, the patient should be advised to take the missed dose if it is on the same day and not to double dose.

Administration

DECAPEPTYL is intended for subcutaneous injection once. Inject the entire contents of a pre-filled disposable syringe subcutaneously to the lower abdomen once daily.

Overdosage

Overdose in humans may result in a prolonged duration of action. In case of overdose, DECAPEPTYL treatment should be (temporarily) discontinued.

No adverse reaction has been reported as a consequence of overdose.

For management of a suspected drug overdose, contact your regional Poison Control Centre.

Action and Clinical Pharmacology

Mechanism of Action

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 gives a greater stimulation of the pituitary to secrete LH and FSH than a comparable dose of gonadorelin, and has a longer duration of action. The increase of LH and FSH levels will initially lead to an increase of serum testosterone concentrations in men or serum estrogen concentrations in women. Chronic administration of a GnRHagonist 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. 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 estrogen-dependent uterus myomas in women. The assisted reproduction procedure of IVF requires a suppression of plasma concentration of luteinizing hormone. This suppression assists the treatment protocol and may prevent cancellation of IVF treatment due to a premature rise in the luteinizing hormone.

Pharmacodynamics

Continuous administration of triptorelin has a biphasic effect at the pituitary level. After an initial large sudden increase in LH and FSH levels (flare-up), circulating LH and FSH levels decrease due to the pituitary GnRH-receptor desensitization, with a consequent marked reduction in the gonadal production. The exact duration of action of DECAPEPTYL has not been established, but pituitary suppression is maintained for at least 6 days after stopping administration. After discontinuation of DECAPEPTYL, a further drop in circulating LH levels should be expected, with LH levels returning to baseline after approximately 2 weeks.

The DECAPEPTYL induced downregulation of the pituitary can prevent the LH surge and thereby premature ovulation and/or follicular luteinisation. The use of the downregulation with GnRH agonist reduces the cycle cancellation rate and improves the pregnancy rate in ART cycles.

Pharmacokinetics

The pharmacokinetic data suggest that after subcutaneous administration of DECAPEPTYL the systemic bioavailability of triptorelin is close to 100%. The elimination half-life of triptorelin is approximately 3-5 hours, indicating that triptorelin is eliminated within 24 hours and therefore will not be present in circulation at the time of embryo transfer. Metabolism to smaller peptides and amino acids primarily occurs in the liver and kidneys. Triptorelin is predominantly excreted in the urine.

The clinical studies indicated that the risk of accumulation of triptorelin in patients with severe liver and renal impairment is small (i.e. half-life of approximately 8 hours in these patients).

Absorption

Triptorelin is not active when given orally. Following a single dose of DECAPEPTYL 0.25 mg SC in healthy male subjects, the mean maximum plasma concentration of triptorelin was 5.68 ng/mL. Maximum plasma concentrations were reached approximately 45 minutes after SC administration. The mean terminal elimination half-life was 3.3 hours and the total clearance was 9.24 L/hour and these parameters were quite similar to those determined after IV administration.

Distribution & Metabolism

Human distribution and metabolism after administration of DECAPEPTYL have not been studied. It is known that after injection, GnRH agonist progressively accumulate in the anterior pituitary and the main inactivating organs, the liver and kidneys. In the pituitary, GnRH agonists are inactivated by N-terminal cleavage by peptidases. In the liver and kidneys, GnRH agonists are degraded to biologically inactive C-terminal metabolites.

Following IV infusion of DECAPEPTYL 0.1 mg, disappearance of triptorelin from the plasma has two components: an initial fast component of approximately 19 minutes and a second slower component of approximately 50 minutes. Protein binding has not been investigated.

Excretion

Triptorelin, as all other GnRH agonists, is predominantly excreted in urine. Information on the elimination of triptorelin is available in female subjects. DECAPEPTYL 0.5 mg was administered as an IV bolus to 19 female subjects. The mean half-life for terminal elimination was 5.1 hours (range: 2.5-13.81 hours). The elimination of triptorelin in urine was investigated in eight of the female subjects. Renal clearance over 24 hours was on average 25.3 mL/min (range: 5.3-45.4 mL/min). The mean percentage of the dose recovered in urine over the 24 hours was 16.7% (range: 3.4-34.6%). This indicates that approximately 17% of the dose is eliminated unchanged in the urine within 24 hours. This figure is similar to that reported for other GnRH agonists.

Special Populations and Conditions

Nursing Women

DECAPEPTYL is not indicated for use during lactation.

Pregnant women

DECAPEPTYL is not indicated for use during pregnancy.

Hepatic Insufficiency / Renal Insufficiency

No specific dose recommendations are given for subjects with renal or hepatic impairment. A clinical study indicated that the risk of accumulation of triptorelin in patients with severe liver and renal impairment is small.

Storage and Stability

Store in a refrigerator (2oC – 8oC). Do not freeze. Store in the original package, to protect from light.

Special Handling Instructions

No special requirements for disposal.

Dosage Forms, Composition and Packaging

Each pre-filled syringe of 1 mL solution for injection contains 100 micrograms triptorelin acetate equivalent to 95.6 micrograms triptorelin free base.

Each box contains 1 mL solution in a pre-filled syringe (glass) with plunger stopper (chlorobutyl rubber), plunger rod (polystyrene), integrated needle and rigid needle shield in pack sizes of 7 or 28.