Triptorelin

Registered South African indications:

• Treatment of advanced prostate carcinoma for which hormonal therapy is considered
• Symptomatic uterine myomas, when suppression of the ovarian hormonogenesis is indicated as a preoperative measure to reduce the size of individual myomas prior to scheduled myomen nucleation or hysterectomy
• Symptomatic endometriosis confirmed by laparoscopy, when suppression of the ovarian hormonogenesis is indicated to the extent that surgical therapy is not primarily indicated
• Treatment of central precocious puberty (CPP) in previously untreated girls

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Known hypersensitivity to poly-(d,l lactide coglycolide) or dextran
• Hypersensitivity to gonadotrophin-releasing hormone (GnRH) or any other GnRH analogue
• Pregnancy
• Breastfeeding
• Porphyria

Cautions

• Renal impairment
• Hepatic impairment
• Established osteoporosis
• Risk factors for osteoporosis
  - Chronic alcohol abuse
  - 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
• Unknown gonadotroph cell pituitary adenoma
• Depression
• Vertebral metastasis
• Risk of spinal cord compression
• Urinary tract obstruction
• Long-term androgen deprivation either by bilateral orchiectomy or administration of GnRH analogues
• History of or risk factors for QT prolongation
• High risk for metabolic or cardiovascular diseases
• Continuation of regular menstruation once treatment has been initiated (in females)
• Children with progressive brain tumours
• Pseudo-precocious puberty (gonadal or adrenal tumour or hyperplasia)
• Gonadotropin-independent precocious puberty (testicular toxicosis, familial Leydig cell hyperplasia)
• Coadministration with medicinal products that may prolong the QT interval
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: inj

Treatment of hormone-dependent locally advanced or metastatic prostate cancer - men

• SC/IM: 3.75mg, every 4 weeks (28 days)

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In order to continually suppress testosterone levels, it is important to comply with a 4 weekly administration

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Treatment for prostate carcinoma is usually a long-term therapy

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Preoperative reduction of myoma size - women
- To reduce the symptoms of bleeding and pain in women with symptomatic uterine myomas
Symptomatic endometriosis - women
- Confirmed by laparoscopy when suppression of the ovarian hormonogenesis is indicated to the extent that surgical therapy is not primarily indicated

• SC/IM: 3.75mg, every 4 weeks (28 days)

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The treatment must be initiated in the first 5 days of the menstrual cycle

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The duration of treatment for uterine myomas and endometriosis 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

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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

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The product should only be used under the supervision of an appropriate specialist having requisite facilities for regular monitoring of response

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It is important that the injection of the sustained release form be performed strictly in accordance with the instructions. The dosage of one syringe (3.75mg triptorelin) is injected SC (e.g. into the skin of the abdomen, the buttock or thigh) or deep IM. The injection site should be changed each time

Paed. forms avail. in SA and covered in this monograph: inj

Treatment of confirmed central precocious puberty (CPP)
- Girls <9 years
- Boys <10 years

• SC/IM: Dosing at the beginning of treatment should be based on body weight: Initial: 1 injection at day 0, 14 and 28; Maintenance: 1 injection, every 4 weeks (28 days)

Dosing based on body weight for paediatric patients

Body Weight (kg)	Dosing
<20	1.875mg (half dose)
20-30	2.5mg (2/3 dose)
>30	3.75mg (full dose)

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Should the effect be insufficient, the injections may be given every 3 weeks

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The treatment of children with triptorelin should be under the overall supervision of the paediatric endocrinologist or of a paediatrician or endocrinologist with expertise in the treatment of central precocious puberty

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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

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It is important that the injection of the sustained release form be performed strictly in accordance with the instructions. The dosage of one syringe (3.75mg triptorelin) is injected SC (e.g. into the skin of the abdomen, the buttock or thigh) or deep IM. The injection site should be changed each time

Pregnancy

• Contraindicated
• Prior to treatment, potentially fertile women should be examined carefully to exclude pregnancy
• 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 triptorelin should not be used during pregnancy
• Women of childbearing potential should use effective non-hormonal contraception during therapy until menses resume

Breastfeeding

• Contraindicated
• It is not known whether triptorelin is excreted in human milk. Because of the potential for adverse reactions from triptorelin in breastfeeding infants, breastfeeding should be discontinued prior to and throughout administration

Renal Impairment

• Caution; no dose adjustment recommended
  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

Hepatic Impairment

• Caution; no information available
  Triptorelin systemic exposure is elevated in hepatic impairment

Elderly

• No dose adjustment recommended

Porphyria

• Porphyrinogenic (P)

Drugs in Sport

• Prohibited - At all times (in male athletes)

Men
Central Nervous System Disorders

• Decreased libido
• Mood changes
• Depressed mood
• Depression
• Sleep disorder
• Insomnia
• Confusional state
• Decreased activity
• Euphoric mood
• Anxiety
• Loss of libido
• Headache
• Dizziness
• Paraesthesia
• Memory impairment
• Somnolence
• Dysstasia
• Fatigue
• Irritability

Cardiovascular Disorders

• Hot flushes
• Embolism
• Hypertension
  - Increased blood pressure 
• Hypotension
• Chest pain
• QT prolongation

Respiratory Disorders

• Nasopharyngitis
• Aggravated asthma
• Dyspnoea
• Orthopnoea
• Epistaxis

Gastrointestinal Disorders

• Nausea and vomiting
• Dry mouth
• Abdominal pain
  - Upper abdominal pain
• Constipation
• Diarrhoea
• Abdominal distension
• Flatulence
• Gastralgia

Hepatobiliary Disorders

• Increased gamma-glutamyltransferase
• Increased aspartate aminotransferase
• Increased alanine aminotransferase

Genitourinary Disorders

• Dysuria
• Erectile dysfunction
• Gynaecomastia
• Testicular atrophy
• Breast pain
• Testicular pain
• Ejaculation failure
• Increased blood creatinine
• Increased blood urea
• Worsening of signs and symptoms of prostate cancer (tumour flare)
• Urethral obstruction or spinal cord compression by metastasis

Endocrine and Metabolic Disorders

• Decreased appetite
• Increased appetite
• Gout
• Increased weight
• Decreased weight
• Diabetes mellitus
• Increased blood lactate dehydrogenase
• Increased blood alkaline phosphatase

Musculoskeletal Disorders

• Bone pain
• Myalgia
• Arthralgia
• Back pain
• Musculoskeletal pain
• Pain in extremity
• Muscle spasms
• Muscular weakness
• Joint stiffness
• Joint swelling
• Musculoskeletal stiffness
• Osteoarthritis
• Increased bone loss
• Osteoporosis
• Increased risk of bone fracture

Skin and Subcutaneous Tissue Disorders

• Hyperhidrosis
• Hypotrichosis
• Alopecia
• Acne
• Pruritus
• Rash
• Blister
• Angioedema
• Urticaria
• Purpura
• Injection site reaction
• Injection site pain
• Injection site erythema
• Injection site inflammation
• Oedema

Immune, Blood and Lymphatic System Disorders

• Hypersensitivity
• Anaphylactic reaction
• Influenza-like illness
• Fever
• Increased body temperature

Sensory Disorders

• Dysgeusia
• Abnormal sensation in eye
• Visual impairment
• Blurred vision
• Tinnitus
• Vertigo

Others

• Pain

Women
Central Nervous System Disorders

• Decreased libido
• Mood changes
• Sleep disorder
• Depressed mood
• Depression
• Confusional state
• Anxiety
• Headache
• Paraesthesia
• Dizziness
• Fatigue
• Irritability

Cardiovascular Disorders

• Hot flushes
• Increased blood pressure

Respiratory Disorders

• Dyspnoea

Gastrointestinal Disorders

• Abdominal pain
• Nausea and vomiting
• Abdominal discomfort
• Diarrhoea

Hepatobiliary Disorders

• Increased gamma-glutamyltransferase
• Increased aspartate aminotransferase  
• Increased alanine aminotransferase

Genitourinary Disorders

• Vaginal haemorrhage
• Vulvovaginal dryness
• Dyspareunia
• Dysmenorrhoea
• Ovarian hyperstimulation syndrome
• Ovarian hypertrophy
• Pelvic pain
• Breast pain
• Menorrhagia
• Metrorrhagia
• Amenorrhoea
• Exacerbated symptoms of endometriosis

Endocrine and Metabolic Disorders

• Increased weight
• Decreased weight
• Increased blood lactate dehydrogenase
• Increased blood cholesterol

Musculoskeletal Disorders

• Bone pain
• Myalgia
• Arthralgia
• Back pain
• Bone disorder
• Muscle spasms
• Muscular weakness
• Trabecular bone loss

Skin and Subcutaneous Tissue Disorders

• Hyperhidrosis
• Pruritus
• Rash
• Angioedema
• Urticaria
• Injection site reaction
• Injection site pain
• Injection site erythema
• Injection site inflammation

Immune, Blood and Lymphatic System Disorders

• Hypersensitivity
• Anaphylactic reaction
• Fever

Sensory Disorders

• Visual impairment
• Blurred vision
• Vertigo

Children
Central Nervous System Disorders

• Mood changes
• Depression
• Affect lability
• Nervousness
• Headache
• Malaise

Cardiovascular Disorders

• Hot flushes
• Increased blood pressure

Respiratory Disorders

• Epistaxis

Gastrointestinal Disorders

• Nausea and vomiting
• Abdominal discomfort
• Abdominal pain

Genitourinary Disorders

• Vaginal haemorrhage
• Vaginal discharge  
• Genital haemorrhage

Endocrine and Metabolic Disorders

• Increased weight

Musculoskeletal Disorders

• Epiphysiolysis
• Myalgia
• Slipped capital femoral epiphysis

Skin and Subcutaneous Tissue Disorders

• Rash
• Angioneurotic oedema
• Urticaria
• Alopecia
• Erythema
• Injection site erythema
• Injection site inflammation
• Injection site pain

Immune, Blood and Lymphatic System Disorders

• Anaphylactic reaction
• Hypersensitivity reaction

Sensory Disorders

• Blurred vision
• Visual impairment

Others

• Pain

• Agents affecting pituitary secretion of gonadotropins
• QT prolonging agents
• Agents able to induce Torsade de pointes
• Class IA or class III antiarrhythmics
• Quinidine
• Disopyramide
• Amiodarone
• Sotalol
• Dofetilide
• Ibutilide
• Methadone
• Moxifloxacin
• Antipsychotics
• Histamine-liberating agents

None routine. Specific cases may require

• Glucose
• HBA1c
• Electrolytes
• Electrocardiogram
• GnRH agonist stimulation
• Basal luteinising hormone level
• Serum sex steroid levels
• Serum testosterone levels
• Height
• Bone age
• Bone density
• Prostate-specific antigen
• Pregnancy test
• Development, number and size of follicles
• Follicle-stimulating hormone
• Full blood count
• Serum blood urea nitrogen (BUN)
• Creatinine
• Cardiorespiratory status

Additional observations

• Signs and symptoms of:
  - Emerging cardiovascular disease
  - Allergic reaction
• Development or worsening of psychiatric symptoms

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 estrogen 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 estrogen-dependent uterus myomas in women. Regarding uterine myoma, maximal benefit of treatment is observed in women with anaemia (haemoglobin inferior or equal to 8g/dl). In children suffering from central precocious puberty (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.

Injection (per syringe) 3.75mg

• Gonapeptyl (Ferring) originator