Triptorelin

Triptorelin is a synthetic decapeptide analogue of natural gonadotropin-releasing hormone (GnRH). Given continuously, it first stimulates and then suppresses the pituitary release of luteinising hormone (LH) and follicle-stimulating hormone (FSH). This switches off testicular and ovarian hormone production, which is the basis of its use in hormone-dependent cancers, gynaecological disorders, assisted reproduction and early puberty.

Mechanism of Action

• GnRH agonist: after an initial stimulation, continued administration inhibits the secretion of gonadotropins and so suppresses testicular and ovarian function. In animal studies triptorelin was 13 times more active than natural GnRH at releasing LH and 21 times more active at releasing FSH.
• Initial flare: the first dose is followed by a temporary rise in FSH, LH, oestradiol and testosterone. In prostate cancer this is why symptoms can briefly worsen, and why an antiandrogen may be added at the start.
• Castrate hormone levels: in prostate cancer, prolonged treatment lowers LH and FSH until testosterone reaches castrate levels after about 2 to 3 weeks, and it stays there for as long as the medicine is given. A temporary rise in acid phosphatase can be seen at the start.
• Direct gonadal effects: further animal studies suggest an additional action on the gonads themselves, lowering the sensitivity of peripheral GnRH receptors.
• Reversibility: the effects can usually be reversed once treatment stops.
• IVF protocols: in the daily-injection protocol, pituitary desensitisation is shown by an oestradiol level below 50 pg/mL, usually about day 15 of treatment, when stimulation with gonadotropins begins.

Pharmacokinetics

• Absorption, Decapeptyl Mensual in men: after intramuscular injection, the drug on the surface of the microparticles is released first, followed by a steady release (peak concentration 0.32 ± 0.12 ng/mL) at a mean rate of 46.6 ± 7.1 µg a day. The bioavailability of the microparticle suspension is about 53% over one month.
• Absorption, Decapeptyl Mensual in women: peak blood levels, up to about 11 ng/mL, are reached 2 to 6 hours after injection. There was no sign of accumulation after 6 monthly injections, and trough levels range from 0.1 to 0.2 ng/mL. The bioavailability of the sustained-release product is about 50%.
• Distribution: after a single intravenous dose of 0.5 mg in healthy men, the volume of distribution was 30 to 33 L. Triptorelin does not bind to plasma proteins at clinically relevant concentrations.
• Metabolism: not well understood. It probably does not involve CYP enzymes, and no metabolites have been identified.
• Elimination: involves both the kidneys and the liver. Total clearance in healthy men was about 212 mL/min, and the fall in plasma levels follows three phases with half-lives of about 6 minutes, 45 minutes and 3 hours.

Triptorelin is authorised nationally, not centrally, so the indications depend on the product and the country. This page follows the two Spanish SmPCs (AEMPS) of Ipsen Pharma S.A.U.

Decapeptyl Mensual 3.75 mg (monthly prolonged-release depot)

• Prostate cancer: hormone-dependent, locally advanced or metastatic prostate cancer; and hormone-dependent, high-risk localised or locally advanced prostate cancer in combination with radiotherapy. The favourable effect is more marked and more frequent in men who have not had other hormone treatment before.
• Endometriosis: genital and extragenital. Treatment is limited to 6 months, and a second course with triptorelin or any other GnRH analogue is not recommended.
• Uterine fibroids.
• Female infertility: as an adjunct to gonadotropins (HMG, FSH, hCG) during ovulation induction for in vitro fertilisation and embryo transfer (IVF-ET).
• Early breast cancer: adjuvant treatment, in combination with tamoxifen or an aromatase inhibitor, of hormone-sensitive early-stage breast cancer in women at high risk of recurrence who are confirmed premenopausal after completing chemotherapy.
• Central precocious puberty: treatment is to start before the age of 8 years in girls and before 10 years in boys.

Decapeptyl Diario 0.1 mg (daily injection)

• Female infertility: as an adjunct to gonadotropins (HMG, FSH, hCG) during ovulation induction for IVF-ET. This is its only indication.

Other nationally authorised triptorelin products, such as the three-monthly and six-monthly depots (Decapeptyl Trimestral and Decapeptyl Semestral), have their own SmPCs with their own strengths, dosing intervals and indications. They are not described here.

• Hypersensitivity to triptorelin, to GnRH or other GnRH analogues, or to any of the excipients.
• Pregnancy and breastfeeding.
• Decapeptyl Mensual in premenopausal breast cancer: starting an aromatase inhibitor before adequate ovarian suppression has been achieved with triptorelin.

Most reactions follow from the lower sex-hormone levels that the medicine produces. In men with prostate cancer the most frequent were hot flushes and reduced libido. More than 90% of men in the trials reported reactions, but they were mostly older men with other illnesses, so the cause is often hard to assess. Apart from allergic reactions (rare) and injection-site reactions (fewer than 5%), all reactions in men are known to be linked to changes in testosterone levels. In women, the most frequent reactions (expected in 10% or more) were headache, decreased libido, sleep disorders, mood changes, dyspareunia, dysmenorrhoea, genital bleeding, ovarian hyperstimulation syndrome, ovarian hypertrophy, pelvic pain, abdominal pain, vulvovaginal dryness, hyperhidrosis, hot flush and asthenia. The lists below are those of the Decapeptyl Mensual SmPC.

Men (Prostate Cancer)

Very common (≥1/10): asthenia, back pain, paraesthesia in the lower limbs, decreased libido, erectile dysfunction (including ejaculation failure and ejaculation disorder), hyperhidrosis, hot flush.

Common (≥1/100 to <1/10): dry mouth, nausea, injection-site reaction (erythema, swelling and pain), oedema, hypersensitivity, weight increased, musculoskeletal pain, pain in extremity, dizziness, headache, depression, loss of libido, mood changes, pelvic pain, hypertension.

Uncommon (≥1/1,000 to <1/100): thrombocytosis, palpitations, tinnitus, vertigo, visual impairment, abdominal pain, constipation, diarrhoea, vomiting, lethargy, peripheral oedema, pain, chills, somnolence, increased alanine aminotransferase, aspartate aminotransferase, blood creatinine, blood urea and gamma-glutamyltransferase, increased blood pressure, weight decreased, anorexia, diabetes mellitus, gout, hyperlipidaemia, increased appetite, arthralgia, bone pain, muscle cramps, muscular weakness, myalgia, paraesthesia, insomnia, irritability, nocturia, urinary retention, gynaecomastia, breast pain, testicular atrophy, testicular pain, dyspnoea, epistaxis, acne, alopecia, erythema, pruritus, rash, urticaria.

Rare (≥1/10,000 to <1/1,000): abnormal sensation in the eye, visual disturbance, abdominal distension, dysgeusia, flatulence, chest pain, influenza-like illness, pyrexia, anaphylactic reaction, nasopharyngitis, increased blood alkaline phosphatase, joint stiffness, joint swelling, musculoskeletal stiffness, osteoarthritis, memory impairment, confusional state, decreased activity, euphoric mood, orthopnoea, blisters, purpura, hypotension.

Not known (cannot be estimated from the available data): anaemia, QT prolongation, pituitary apoplexy, malaise, anaphylactic shock, anxiety, urinary incontinence, angioedema.

Pituitary apoplexy was reported after the first dose in patients with a pituitary adenoma. The frequencies given for QT prolongation, depression and mood changes are class-effect frequencies common to all GnRH analogues.

Women (Endometriosis, Fibroids, IVF)

Very common (≥1/10): asthenia, headache, decreased libido, mood changes, sleep disorders (including insomnia), breast disorders, dyspareunia, genital bleeding (including vaginal haemorrhage and withdrawal bleeding), ovarian hyperstimulation syndrome, ovarian hypertrophy, pelvic pain, vulvovaginal dryness, acne, hyperhidrosis, seborrhoea, hot flush.

Common (≥1/100 to <1/10): abdominal pain, abdominal discomfort, nausea, injection-site reaction (pain, swelling, erythema and inflammation), peripheral oedema, hypersensitivity, weight increased, arthralgia, muscle spasms, pain in extremity, dizziness, depression (long-term use), nervousness, breast pain.

Uncommon (≥1/1,000 to <1/100): palpitations, vertigo, dry eye, visual impairment, abdominal distension, dry mouth, flatulence, mouth ulceration, vomiting, weight decreased, decreased appetite, fluid retention, back pain, myalgia, dysgeusia, hypoaesthesia, syncope, memory impairment, disturbance in attention, paraesthesia, tremor, affect lability, anxiety, depression (short-term use), disorientation, coital bleeding, cystocele, menstrual disorder (including dysmenorrhoea, metrorrhagia and menorrhagia), ovarian cyst, vaginal discharge, dyspnoea, epistaxis, alopecia, dry skin, hirsutism, nail breakage, pruritus, rash.

Not known (cannot be estimated from the available data): pituitary apoplexy, visual disturbance, diarrhoea, malaise, pyrexia, anaphylactic shock, increased blood alkaline phosphatase, increased blood pressure, muscular weakness, convulsions, confusional state, amenorrhoea, angioedema, urticaria, hypertension.

At the start of treatment for endometriosis, pelvic pain and dysmenorrhoea can be exacerbated (very commonly) while oestradiol briefly rises; these symptoms are temporary and usually fade within one or two weeks. Genital bleeding, including menorrhagia and metrorrhagia, can occur in the month after the first injection. When used for infertility together with gonadotropins, ovarian hyperstimulation syndrome can occur, with ovarian hypertrophy and pelvic or abdominal pain.

Women With Early Breast Cancer (With Tamoxifen or an Aromatase Inhibitor)

In the TEXT and SOFT studies, five years of triptorelin with tamoxifen (2,325 women) or exemestane (2,318 women) most often caused hot flushes, musculoskeletal disorders, fatigue, insomnia, hyperhidrosis, vulvovaginal dryness and depression. These reactions are in addition to those in the men’s and women’s lists above.

Very common (≥1/10): nausea, fatigue, musculoskeletal disorder, osteoporosis, insomnia, decreased libido, depression, urinary incontinence, dyspareunia, vulvovaginal dryness, hyperhidrosis, hot flush, hypertension.

Common (≥1/100 to <1/10): injection-site reaction, hypersensitivity, diabetes mellitus (glucose intolerance), hyperglycaemia, fracture, embolism.

Uncommon (≥1/1,000 to <1/100): myocardial ischaemia, cerebral ischaemia, central nervous system haemorrhage.

Rare (≥1/10,000 to <1/1,000): QT prolongation.

Osteoporosis was more frequent with exemestane than with tamoxifen (39% vs 25%), as were musculoskeletal disorders (89% vs 76%) and fractures (6.8% vs 5.2%). Hypertension affected 23% (exemestane) and 22% (tamoxifen) of women. Hyperglycaemia (2.6% and 3.4%) and diabetes (2.3% in both groups) were common.

Children (Central Precocious Puberty)

Very common (≥1/10): vaginal bleeding (including vaginal haemorrhage, withdrawal bleeding, uterine haemorrhage, vaginal discharge and spotting).

Common (≥1/100 to <1/10): abdominal pain, injection-site reaction (pain, erythema and inflammation), hypersensitivity, weight increased, headache, acne, hot flush.

Uncommon (≥1/1,000 to <1/100): visual impairment, vomiting, constipation, nausea, malaise, obesity, neck pain, mood altered, breast pain, epistaxis, pruritus, rash, urticaria.

Not known (cannot be estimated from the available data): visual disturbance, anaphylactic shock, increased blood prolactin, increased blood pressure, myalgia, idiopathic intracranial hypertension (pseudotumour cerebri), convulsions, affect lability, depression, nervousness, angioedema, hypertension.

An increase in lymphocyte numbers has been described in patients on GnRH analogues. It seems to be related to GnRH-induced castration and suggests that gonadal hormones play a part in involution of the thymus.

Decapeptyl Diario (Daily Injection)

Its SmPC reports clinical-trial experience with the immediate-release formulation in 127 men with prostate cancer treated daily for 3 months and about 1,000 women in IVF protocols. The reactions listed are similar to those in the women’s list above. The most frequent were vaginal bleeding, decreased libido, pelvic pain, dyspareunia, vulvovaginal dryness, seborrhoea and hot flushes, all due to the expected pharmacological effect.

Important Serious or Notable Reactions

• Tumour flare: in up to 5% of men, prostate cancer signs and symptoms worsen temporarily in the first week or two (urinary symptoms in fewer than 2%, metastatic pain in 5%). Isolated cases of urethral obstruction or spinal cord compression have occurred.
• Bone loss: GnRH analogues can cause bone loss, osteoporosis and a higher risk of fracture. Osteoporosis was more frequent with exemestane than with tamoxifen in breast cancer.
• Allergic reactions: hypersensitivity is common, and anaphylactic reactions and shock have been reported.
• Pituitary apoplexy, convulsions and depression: see Special Instructions.
• Radiotherapy: men on long-term GnRH analogue treatment together with radiotherapy may have more side effects, mainly gastrointestinal and radiotherapy-related.

• Medicines that affect pituitary gonadotropin secretion: use caution and monitor the patient’s hormonal status.
• QT-prolonging medicines: androgen deprivation therapy can prolong the QT interval, so combining Decapeptyl Mensual with medicines known to prolong it or to induce torsades de pointes needs careful assessment. Examples named in the SmPC are class IA antiarrhythmics (quinidine, disopyramide), class III antiarrhythmics (amiodarone, sotalol, dofetilide, ibutilide), methadone, moxifloxacin and antipsychotics.
• Anticoagulants: take care with intramuscular injection, because of the risk of a haematoma at the injection site.
• Medicines that lower bone density or lower the seizure threshold: anticonvulsants and corticosteroids add to the risk of bone loss, and medicines known to carry a risk of convulsions add to the risk of seizures (see Special Instructions).
• Abiraterone acetate or enzalutamide (castration-resistant metastatic prostate cancer): in men who have not had surgical castration and are eligible for these, the GnRH analogue is continued.
• Aromatase inhibitors (premenopausal breast cancer): the aromatase inhibitor must not be started before adequate ovarian suppression with triptorelin, and triptorelin is not stopped during aromatase inhibitor treatment.
• Add-back therapy (endometriosis): an oestrogen plus a progestogen can be given with the GnRH analogue to reduce bone loss and vasomotor symptoms.
• Gonadotropins (HMG, FSH, hCG): given together with triptorelin in IVF on purpose; the combination can cause ovarian hyperstimulation syndrome.

Triptorelin is given by injection under the supervision of a doctor. Dose, route and interval depend on the product. The figures below are those of the two Spanish SmPCs and must not be applied to other triptorelin products. Other nationally authorised products, for example the three-monthly and six-monthly depots (Decapeptyl Trimestral and Decapeptyl Semestral), have their own SmPCs with their own doses and intervals; the product actually prescribed must be followed.

Decapeptyl Mensual 3.75 mg: Prolonged-Release Depot, Every 4 Weeks

• How it is given: deep intramuscular injection only, by or under the supervision of a doctor. The injection site is changed regularly. The product is a suspension of microgranules, so accidental injection into a blood vessel must be strictly avoided. The powder is reconstituted with the solvent before use (see section 6.6 of the SmPC) and given immediately.
• Prostate cancer: one injection every 4 weeks. For high-risk localised or locally advanced disease given with radiotherapy, radiotherapy followed by long-term androgen deprivation is preferred to short-term deprivation; guidelines recommend 2 to 3 years. In castration-resistant metastatic prostate cancer in men who have not had surgical castration and are eligible for abiraterone acetate or enzalutamide, the GnRH analogue is continued.
• Endometriosis: start during the first five days of the cycle. One injection every 4 weeks, usually for four to six months depending on the initial severity and the clinical response. A second course with Decapeptyl Mensual or another GnRH analogue is not advised. Where appropriate, add-back therapy (an oestrogen and a progestogen) is given with it to reduce bone mineral density loss and vasomotor symptoms.
• Uterine fibroids: start during the first five days of the cycle. One injection every 4 weeks for at least four and at most six months, guided by fibroid volume on ultrasound. A second course is not advised.
• Female infertility (IVF-ET): one injection on day 2 of the cycle. Stimulation with gonadotropins is generally started when plasma oestrogen is below 50 pg/mL, usually around day 15 of the cycle.
• Early breast cancer: one injection every 4 weeks together with tamoxifen or an aromatase inhibitor, starting after chemotherapy once premenopausal status is confirmed. Start triptorelin at least 6 to 8 weeks before an aromatase inhibitor, with at least two injections (4 weeks apart) before the aromatase inhibitor begins. Do not stop triptorelin during aromatase inhibitor treatment, to avoid a rebound rise in circulating oestrogen. The recommended duration of adjuvant treatment with other hormone therapy is up to 5 years.
• Central precocious puberty: treatment is supervised by a paediatric endocrinologist, or a paediatrician or endocrinologist experienced in this condition. Children over 30 kg receive one injection every 4 weeks (28 days). At 20 to 30 kg, two-thirds of the dose (two-thirds of the volume of the reconstituted suspension) every 28 days. Under 20 kg, half a dose (half the volume) every 28 days. Stop at the physiological age of puberty. Continuing is not recommended in girls with bone maturation above 12 to 13 years. In boys, data on the best time to stop are limited, and stopping is recommended at a bone maturation age of 13 to 14 years.

Decapeptyl Diario 0.1 mg: Daily Injection

• How it is given: one subcutaneous injection a day of one 0.1 mg vial, given immediately after the solution is reconstituted. It is used only as an adjunct to gonadotropins in IVF-ET.
• Short protocol: daily from day 2 of the cycle (together with the start of ovarian stimulation) until the day before the planned ovulation induction. The average course is 10 to 12 days per cycle.
• Long protocol: daily from day 2 of the cycle. When pituitary desensitisation appears (oestradiol below 50 pg/mL), about day 15 after starting, stimulation with gonadotropins begins and Decapeptyl Diario continues until the day before the planned induction. A course can last 18 to 25 days per cycle.

Special Populations

• Children: Decapeptyl Mensual is used for central precocious puberty (see above). Decapeptyl Diario is not indicated in children.
• Women who could become pregnant: pregnancy must be excluded before treatment (see Special Instructions).

Tumour Flare and Monitoring in Prostate Cancer

Triptorelin first raises serum testosterone, so in the first weeks signs and symptoms of prostate cancer can temporarily worsen (tumour flare), including more cancer-related bone pain, which can be treated symptomatically. A suitable antiandrogen may be added during the initial phase to counter the surge. Isolated cases of spinal cord compression or urethral obstruction have occurred. Patients with vertebral metastases or urinary tract obstruction need close monitoring in the first weeks. If spinal cord compression or renal impairment develops, the standard treatment for these complications is given and, in extreme cases, immediate orchiectomy is considered.

Bone Loss

Long-term use of GnRH analogues in adults can cause bone loss and raise the risk of osteoporosis. In men, preliminary data suggest a bisphosphonate may reduce bone mineral loss. Take special care with extra risk factors for osteoporosis: chronic alcohol abuse, smoking, long-term use of medicines that reduce bone density such as anticonvulsants or corticosteroids, a family history of osteoporosis, or malnutrition. In women, GnRH analogues are likely to lower bone mineral density by about 1% a month over six months of treatment; each 10% fall is linked to a two- to three-fold higher fracture risk. For endometriosis, add-back therapy can reduce the loss.

Mood Changes and Depression

The risk of depression, which can be severe, is higher in patients on GnRH analogues. Patients should be informed and treated if symptoms appear, and those with known depression need close monitoring during treatment.

Pituitary Adenoma

Rarely, GnRH analogues reveal a previously unknown gonadotroph pituitary adenoma. Pituitary apoplexy can follow, with sudden headache, vomiting, visual changes and ophthalmoplegia.

Convulsions

Convulsions have been reported with GnRH analogues, mostly in women and children. Some patients had risk factors (epilepsy, intracranial tumours, or medicines known to carry a risk of seizures), but others had none.

Injection Precautions

Care is needed with intramuscular injection in patients on anticoagulants, because of the risk of a haematoma at the injection site. Decapeptyl Mensual must not be injected into a blood vessel.

QT Interval

Androgen deprivation therapy can prolong the QT interval (see Drug Interactions).

Endometriosis and Fibroids

Treatment is limited to 6 months: in principle four to six months for endometriosis, and four to six months for fibroids (guided by fibroid volume). A second course with triptorelin or another GnRH analogue is not advised.

Early Breast Cancer

Premenopausal status must be confirmed after chemotherapy before starting. The aromatase inhibitor must not be started until adequate ovarian suppression has been achieved with triptorelin.

IVF

Pregnancy must be excluded before treatment. With gonadotropins, ovarian hyperstimulation syndrome can occur. In Decapeptyl Diario’s SmPC, no specific data are available for women with established osteoporosis or risk factors for it.

Children With Central Precocious Puberty

Treatment is supervised by a paediatric endocrinologist or a paediatrician or endocrinologist experienced in the condition. Idiopathic intracranial hypertension (pseudotumour cerebri) and convulsions have been reported in children on GnRH analogues (frequency not known).

Pregnancy, Breastfeeding and Fertility

• Pregnancy: triptorelin must not be used in pregnancy, because GnRH analogues carry a theoretical risk of miscarriage or foetal abnormality. Women who could become pregnant must be examined to exclude pregnancy before treatment. Non-hormonal contraception should be used during treatment until menstruation returns.
• Breastfeeding: triptorelin must not be used while breastfeeding.
• Fertility: pregnancy must be excluded before using triptorelin in fertility treatment. When used for that purpose, there is no clinical evidence of a causal link between triptorelin and later abnormalities in oocyte development, pregnancy or outcome.

Sodium

Each vial contains less than 1 mmol (23 mg) of sodium, so the medicine is essentially sodium-free.

Effect on Driving

No studies of the effect on the ability to drive and use machines have been done. However, certain side effects of treatment or of the underlying disease, such as dizziness, drowsiness or visual disturbances, could impair these abilities.

Do not store Decapeptyl Mensual or Decapeptyl Diario above 25 °C. No refrigeration is needed. Use the reconstituted suspension or solution immediately. The Decapeptyl Mensual pack holds everything needed for one injection: a vial of powder, an ampoule with 2 mL of solvent, two 0.90 × 40 mm needles (one to draw up the solvent and one for the intramuscular injection) and a 3 mL polypropylene syringe.

• Decapeptyl Mensual: 3 years.
• Decapeptyl Diario: 2 years.

After reconstitution, the suspension or solution must be used immediately.

Prescription only (Rx). Treatment is started and supervised by a doctor experienced in the condition treated, and in children with central precocious puberty by a paediatric endocrinologist or a paediatrician or endocrinologist experienced in this condition. Decapeptyl Mensual is a depot injection given under medical supervision, and Decapeptyl Diario is used in IVF cycles, so both are supplied on prescription to the hospital or clinic that administers or supervises the injections.