Tower Hamlets GPs and Barts Health NHS Trust Shared Care Guidelines. TRIPTORELIN Central Precocious Puberty. Patient Name : Date of Birth: NHS No:

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1 DOCUMENT TO BE SCANNED INTO ELECTRONIC RECORDS AND FILED IN NOTES Patient Name : Date of Birth: NHS No: Name of Referring Consultant: Contact number: INTRODUCTION Indication and Licensing Gonadotrophin Releasing Hormone (GnRH) Analogue Therapy The decision to start treatment should always be initiated by the Paediatric Endocrinologist. Administration of GnRH analogues results in an initial increase in circulating levels of gonadotrophins which leads to a transient increase in gonadal steroid concentrations in males and females. These hormonal changes occur predominantly within the first month of treatment. This is due to an initial stimulation of the GnRH receptors before they are blocked. In females with advanced precocious puberty vaginal bleeding may occur. (Parents are warned of this). Such patients can be treated with an anti-androgen drug such as cyproterone acetate starting 3 days before and continuing for 2 weeks after commencement of GnRH analogue therapy. This has been reported to prevent the sequelae of an initial rise in sex steroids but is not necessary in every patient. The endocrinologist will prescribe the full course of anti-androgen therapy, when the decision to initiate GnRH analogue therapy is made. Chronic administration of GnRH analogue results in an inhibition of gonadotrophin production and subsequent suppression of ovarian and testicular steroid secretion. The effect is reversible on discontinuation of therapy. Triptorelin (Gonapeptyl ) is licensed in children for the treatment of confirmed central precocious puberty (girls under 9 years, boys under 10 years). Triptorelin SR (Decapeptyl ) is licensed in children for precocious puberty (before 8 years in girls and 10 years in boys). Typically the child starts treatment at 6-7 years of age nad continues until they start secondary school. PATIENT PATHWAY Clinical Speciality/ Indication Paediatric Endocrinology Prescribing Initiated by Prescribing Continued by (detail when suitable for transfer to occur) Consultant Paediatric Endocrinologist. GP after day 56 of treatment when pt is ready to continue on long acting preparation Monitored by (detail when suitable for transfer to occur IF APPROPRIATE) Paediatric Endocrinology team baseline and 3-6 monthly Duration of treatment 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. Decision to stop is assessed at each clinic appointment 6 monthly. No monitoring by local GP is required Page 1 of 7

2 DOSE AND ADMINISTRATION Injection: Gonapeptyl (triptorelin) 3.75 mg on days 0, 14 & 28 Then Decapeptyl SR (triptorelin SR) mg on day 56 Continue Decapeptyl SR (triptorelin SR) 12 weekly (interval may be reduced where clinically assessed appropriate by paediatric endocrinologist) Gonapeptyl mg. Powder and solvent for suspension for injection. One pre-filled syringe contains 3.75mgs triptorelin (as acetate) to be suspended in one ml suspension agent. Injection on days 0, 14 and 28. Dosing based on body weight. < 20 kg mg (half reconstituted syringe) kg mg (two-thirds reconstituted syringe) > 30 kg mg (full reconstituted syringe) Inject subcutaneously or intramuscularly within 3 minutes of reconstitution. Prior use of local anaesthetic cream at site of injection is optional. Decapeptyl SR mg Powder and solvent for suspension for injection. One vial contains mg (as acetate) to be suspended in suspension agent. Inject intramuscularly mg at interval as advised by paediatric endocrinologist, usually every weeks, immediately after reconstitution. MONITORING STANDARDS FOR MEDICATION AT BARTS AND THE LONDON NHS TRUST The purpose of GnRH therapy is to dampen down the progression of secondary sexual development and its associated rapid bone maturation. It is aimed at alleviating the social consequences of developing puberty at an age inappropriate time or reducing the rate of pubertal progress if this is deemed inappropriately fast, by freezing the process until a more age appropriate time is reached. To monitor the effectiveness of therapy there are parameters available against which the desired clinical outcome can be rated. Firstly adequate history is paramount. This should include age at presentation, progression and development of pubertal and/or behavioural changes. The height and weight of the child, along with same for parents and age of onset of puberty in the parents. Growth and auxological measurements 4-6 monthly. Pubertal rating, at time of referral and again every 4-6 months until control is established, or if treatment is being given due to problems of rate of pubertal progression. Thereafter at each clinic visit. Pelvic ultrasound in females, repeated if there is a doubt over suppression. Unstimulated serum gonadotrophin concentrations and Oestrogen/Testosterone levels, repeated if there is any indication of breakthrough of symptoms. Debate still exists as to whether testing should be routinely undertaken to determine if full suppression has been achieved but may be of value if progression is clinically apparent. Usually clinical findings are sufficient to direct the physician. Bone age assessment - undertaken initially, then as clinically indicated to observe that bone maturation is not progressing. Parameter Target level Frequency of monitoring Action Pubertal staging No progression 4 to 6 monthly Refer to Paediatric Endocrinologists Page 2 of 7

3 KEY ADVERSE EFFECTS & ACTIONS Adverse effects Symptoms/signs Actions Gastrointestinal Administration site symptoms Investigations Musculoskeletal and connective tissue disorders Nervous system disorders Psychiatric disorders Reproductive system and breast disorders Vascular disorders Respiratory, thoracic and mediastinal disorders Eye disorders Skin and subcutaneous tissue disorders Immune system disorders Vomiting Abdominal pain Abdominal discomfort Pain Erythema Injection site erythema Injection site inflammation Injection site pain Malaise Blood pressure increased by > 10mm Hg Weight increased by >10% Myalgia Headache Affect lability Nervousness Genital haemorrhage Vaginal bleeding Hot flush Epistaxis Vision blurred Visual disturbance Angioneurotic oedema Rash Urticaria Hypersensitivity reaction Refer to Paediatric Endocrinologist There are no known contra-indications to the use of GnRH analogue therapy in children with central precocious puberty. Whilst the development of pituitary adenomas has been noted in chronic toxicity studies at high doses in some animal species, this has not been observed in long term clinical studies with GnRH analogues. The more commonly reported side effects are headaches, hot flushes, mood swings and sometimes sweating. These are much more common in adults and are a consequence of oestrogen withdrawal. Bruising and rashes or itching around the injection site have been reported making it advisable to vary the injection site periodically. Peripheral oedema, fatigue, nausea, GI disturbances, arthralgia/myalgia, sleep disorders and hair loss have been reported infrequently. Rarely, anaphylaxis with swollen face and breathing difficulties has been reported. Long term use may be linked to polycystic ovarian syndrome (PCOS). This only lists the key important ADRs-For comprehensive information on cautions, contra-indications and interactions please refer to the current British National Formulary and Summary of Product Characteristics. PREGNANCY AND BREAST FEEDING Not applicable For comprehensive information please refer to the current British National Formulary and Summary of Product Characteristics Page 3 of 7

4 SHARED CARE Shared care guideline: is a document which provides information allowing patients to be managed safely by primary care, secondary care and across the interface. It assumes a partnership and an agreement between a hospital specialist, GP and the patient and also sets out responsibilities for each party. The intention to shared care should be explained to the patient and accepted by them. Patients are under regular follow-up and this provides an opportunity to discuss drug therapy. Intrinsic in the shared care agreement is that the prescribing doctor should be appropriately supported by a system of communication and cooperation in the management of patients. The doctor who prescribes the medicine has the clinical responsibility for the drug and the consequence of its use. Consultant 1. Ensure that the patient/carer is an informed recipient in therapy. 2. Ensure that patient/carer understands their treatment regimen and any monitoring or follow up that is required (using advocacy if appropriate). Issue any local patient information leaflets where appropriate. 3. Ensure baseline investigations are normal before commencing treatment. Give the patient a patient held booklet for result monitoring if appropriate. 4. Initiate treatment and prescribe until the GP formally agrees to share care (as a minimum, supply the first month of treatment or until patient is stabilised). 5. Send a letter to the GP requesting shared care for this patient. 6. Clinical and laboratory supervision of the patient by blood monitoring and routine clinic follow-up on a regular basis. 7. Send a letter/results notification to the GP after each clinic attendance ensuring current dose, most recent results and frequency of monitoring are stated. 8. Where the GP is not performing the phlebotomy, the blood test form MUST be annotated to request that blood results are also copied to the GP 9. Evaluation of any reported adverse effects by GP or patient. 10. Advise GP on review, duration or discontinuation of treatment where necessary. Where urgent action is required following tests the hospital team will telephone the patient and inform GP. 11. Inform GP of patients who do not attend clinic appointments. 12. Counsel the patient on contraception and what to do if pregnancy occurs. Document in the notes. 13. Ensure that backup advice is available at all times. General Practitioner 1. Ensure that the patient understands the nature, effect and potential side effects of the drug before prescribing it as part of the shared care programme and contact the specialist for clarification where appropriate. 2. Monitor patient s overall health and well-being. 3. Report any adverse events to the consultant, where appropriate. 4. Report any adverse events to the MHRA, where appropriate. 5. Help in monitoring the progression of disease 6. Maintain a patient held monitoring booklet where used 7. Prescribe the drug treatment as described. 8. Administer the triptorelin injection. PCT 1. To provide feedback to trusts via Trust Medicines Committee. 2. To support GPs to make the decision whether or not to accept clinical responsibility for prescribing. 3. To support trusts in resolving issues that may arise as a result of shared care. Patient/ Carer 1. Report any adverse effects to their GP and/or specialist 2. Ensure they have a clear understanding of their treatment. 3. Report any changes in disease symptoms to GP and/or specialist Page 4 of 7

5 4. Alert GP and/or specialist of any changes of circumstance which could affect management of disease e.g. plans for pregnancy 5. Take/ administer the medication as prescribed 6. Undertake any monitoring as requested by the GP and/or specialist Costs Drug Product Cost in primary care per dose (add VAT in hospital) Gonapeptyl mg Decapeptyl SR mg for approximately 3 months duration Based on BNF edition 63 March 2012 RESOURCES AVAILABLE Bart s and The London NHS Trust Consultant via switchboard Registrar on-call out of hours Switchboard Aircall via switchboard Clinical Nurse Specialist NHS Tower hamlets Prescribing Team To confirm new number References Adapted from GOSH Shared Care Guidelines,, June 2010 Adapted from United Bristol Healthcare NHS Trust, Gonadotrophin Releasing Hormone Analogue Therapy (Shared Care Guideline), June 2007 Ipsen Ltd. Decapeptyl SR 11.25mg Summary of Product Characteristics last updated on the emc: 21/06/2011 Ferring Pharmaceuticals. Gonapeptyl depot 3.75 mg Summary of Product Characteristics last updated on the emc: 08/09/2003 BNFc Page 5 of 7

6 Patient Support Groups The Child Growth Foundation: 2 Mayfield Avenue, Chiswick, London, W4 1PW Tel: Medical Society Information BSPED: NICE: ESPE: Refer to the NHS Tower Hamlets intranet to obtain the latest version of this guideline FURTHER INFORMATION PUBERTY Puberty arises as a result of an increase in release of the gonadotrophins (hormones that control puberty and reproduction), luteinising hormone (LH) and follicle stimulating hormone (FSH), from the pituitary gland. The hormones are controlled from the hypothalamus by a hormone called gonadotrophin releasing hormone (GnRH) which is secreted in bursts every 90 minutes. Puberty arises from an increase in the amplitude of these bursts. The bursts of GnRH are critical to the system because if secretion takes place continuously the pituitary gland becomes unresponsive to the GnRH. The observation of reduced gonadotrophin release when GnRH is applied continuously, led to the development of GnRH analogues which occupy the GnRH receptor for long periods of time, thereby reducing gonadotrophin secretion from the pituitary. The purpose of GnRH analogue therapy is to dampen down and freeze the secretion, until a more appropriate time is reached. CENTRAL PRECOCIOUS PUBERTY Early puberty is considered as any girl between 8-9 years of age or any boy between 9-10 years of age with secondary sexual characteristics. True Central Precocious puberty is defined as any girl less than 8 years or boy less than 9 years with secondary sexual characteristics. In girls - Breast development before 8 years of age Menarche before 9 years of age In boys -Genital development (including testicular enlargement) before 9 years of age Associated Symptoms Development of pubic and axillary hair. Tall stature, especially in relation to parental heights. Rapid growth rate and loss of final height. Advanced skeletal maturation (assessed by bone age) Behavioural problems. The incidence is 1 in 5,000 to 10,000. Causes of Idiopathic - sporadic, familial. Organic o Hypothalamic hamartoma o CNS tumours - astrocytoma, craniopharyngioma, ependymoma, glioma, pinealoma Page 6 of 7

7 o CNS malformations - arachnoid + suprasellar cysts, phakomatosis, hydrocephalus o congenital midline anomalies - septo-optic dysplasia Acquired disease - CNS infection or abscess, radiation, chemotherapy, trauma, hydrocephalus Other - ethnic origin (adopted children), abuse Gonadotrophin independent puberty (pseudo-precocious puberty) e.g. Congenital Adrenal Hyperplasia, adrenal/gonadal tumours. The treatment for these is more specialised and they do not respond to GnRH analogue therapy. However, with time, true central precocious puberty can be secondarily triggered. MANAGEMENT OF CENTRAL PRECOCIOUS PUBERTY Treatment aims to hold pubertal development in an emotionally immature child, by de-activating the hypothalamic-pituitarygonadal axis. Any girl less than 8 years or boy less than 9 years with confirmed central precocious puberty in whom it is felt that it is inappropriate for puberty to continue can be treated. Occasionally girls and boys with a diagnosis of early puberty may benefit from arresting pubertal development. Any underlying cause should be identified and treated e.g. intracranial tumours. Bone age assessment is undertaken. Girls should also have a pelvic ultrasound scan and both boys and girls should have a MRI scan of the pituitary and hypothalamus, unless aetiology is obvious such as in Congenital Adrenal Hyperplasia. Pubertal staging is documented, along with unstimulated serum concentrations of LH, FSH, oestradiol/testosterone. GnRH analogue treatment of children with gonadotrophin dependent sexual precocity suppresses gonadotrophin secretion resulting in arrest and/or regression of physical pubertal development and a slowing of the accelerated pubertal growth rate and bone maturation. Growth rate and bone maturation during treatment slows depending upon skeletal maturation at onset of treatment. Adult height potential can be preserved as a result of therapy if treatment is begun early enough. Height lost however cannot be regained and so prompt treatment is essential. The analogue is stopped when it is appropriate for puberty to continue. The decision is made jointly by the patient/parents and Endocrinologist. Other indications for therapy When puberty needs to be delayed in order to maximise growth e.g. CAH, growth arrest following cranial irradiation. Page 7 of 7