HERTFORDSHIRE MEDICINES MANAGEMENT COMMITTEE (HMMC) NAFARELIN FOR ENDOMETRIOSIS AMBER INITIATION – RECOMMENDED FOR RESTRICTED USE Name: What it is Indication Date Decision NICE / SMC generic decision status Guidance (trade) last revised Nafarelin A potent agonistic The hormonal December Final NICE NG73 2mg/ml analogue of management of 2020 Nasal Spray gonadotrophin endometriosis, (Synarel®) releasing hormone including pain relief and (GnRH) reduction of endometriotic lesions HMMC recommendation: Amber initiation across Hertfordshire (i.e. suitable for primary care prescribing after specialist initiation) as an option in endometriosis Background Information: Gonadorelin analogues (or gonadotrophin-releasing hormone agonists [GnRHas]) include buserelin, goserelin, leuprorelin, nafarelin and triptorelin. The current HMMC decision recommends triptorelin as Decapeptyl SR® injection as the gonadorelin analogue of choice within licensed indications (which include endometriosis) link to decision. A request was made by ENHT to use nafarelin nasal spray as an alternative to triptorelin intramuscular injection during the COVID-19 pandemic. The hospital would provide initial 1 month supply, then GPs would continue for further 5 months as an alternative to the patient attending for further clinic appointments for administration of triptorelin. Previously at ENHT, triptorelin was the only gonadorelin analogue on formulary for gynaecological indications. At WHHT buserelin nasal spray 150mcg/dose is RED (hospital only) for infertility & endometriosis indications. Nafarelin nasal spray 2mg/ml is licensed for: . The hormonal management of endometriosis, including pain relief and reduction of endometriotic lesions. Use in controlled ovarian stimulation programmes prior to in-vitro fertilisation, under the supervision of an infertility specialist. Use of nafarelin in endometriosis aims to induce chronic pituitary desensitisation, which gives a menopause-like state maintained over many months. The recommended daily dose is 200 mcg taken twice daily as one spray to one nostril in the morning and one spray into the other nostril in the evening. Treatment should be started between days 2 and 4 of the menstrual cycle. The recommended duration of therapy is six months; only one 6 month course is advised. ASSESSMENT AGAINST THE ETHICAL FRAMEWORK Evidence of Clinical Effectiveness: NICE guideline [NG73]: Endometriosis: diagnosis and management, September 2017 https://www.nice.org.uk/guidance/ng73 Recommendations related to hormonal treatments: Pharmacological pain management – hormonal treatments Explain to women with suspected or confirmed endometriosis that hormonal treatment for endometriosis can reduce pain and has no permanent negative effect on subsequent fertility. Offer hormonal treatment (for example, the combined oral contraceptive pill or a progestogen) to women with suspected, confirmed or recurrent endometriosis. If initial hormonal treatment for endometriosis is not effective, not tolerated or is contraindicated, refer the woman to gynaecology service, specialist endometriosis service (endometriosis centres) or paediatric and This HMMC recommendation is based upon the evidence available at the time of publication. The recommendation will be reviewed upon request in the light of new evidence becoming available. Page 1 of 5 adolescent gynaecology service for investigation and treatment options. Surgical management As an adjunct to surgery for deep endometriosis involving the bowel, bladder or ureter, consider 3 months of gonadotrophin-releasing hormone agonists before surgery, (noting not all licensed for this indication. Combination treatments After laparoscopic excision or ablation of endometriosis, consider hormonal treatment (with, for example, the combined oral contraceptive pill), to prolong the benefits of surgery and manage symptoms, (noting not all licensed for this indication). Nafarelin is a recognised treatment for endometriosis. The NICE evidence evaluation considered all the GnRHas (including leuprorelin, triptorelin & goserelin injections and nafarelin & buserelin nasal sprays), but does not appear to differentiate between them. The NICE review highlighted that there may be concerns related to adherence with the twice daily nasal spray versus an injection and also that patients would need to be counselled on the correct administration of the spray. The full evidence document for the endometriosis guideline can be found here: https://www.nice.org.uk/guidance/ng73/evidence/full-guideline-pdf-4550371315 Relevant extracts below: Hormonal medical treatments Endometriosis is considered a predominantly oestrogen-dependent condition. Thus, ovarian suppression with hormones is currently offered as an alternative to surgical excision to treat the disease and its symptoms. However, clinical practice with regards to hormonal treatment varies widely, because of the implications of each option. None of the hormones used to manage endometriosis are free of side effects, but the severity and tolerability of the side effects can vary quite significantly. Many of the hormones used to manage endometriosis-associated pain will also reduce menstrual bleeding and this may be advantageous. Similarly, the contraceptive properties of the hormones may be welcome if the woman does not wish to become pregnant at this moment in time, or unwanted if fertility is an issue. All these factors should be taken into consideration when prescribing hormones to women for the treatment of endometriosis. Key conclusions The Committee concluded that women should be offered the oral combined contraceptive pill or progestogens as the first-line treatment for pain relief. However, if these were contraindicated or if women did not tolerate them, or found the treatments to be ineffective, they should be referred to a gynaecologist to discuss the alternative management options of hormonal treatment or laparoscopy. Consideration of clinical benefits and harms The evidence reviewed supported the use of hormonal treatments for pain relief in women with endometriosis and the committee highlighted that the benefit from hormonal treatments was due to their efficacy in stopping or reducing periods. The desire to reduce the number of repeated operations for women with endometriosis, further supports maintenance of pain relief using hormonal treatments wherever possible. Although they chose not to be specific about recommending a particular hormonal treatment in the recommendations, they stated that the first-line hormonal treatment would generally be the oral combined contraceptive pill or progestogens as they have good efficacy and typically have side effects that women may find more tolerable. The Committee recommended that if first-line hormonal treatment was contraindicated or not tolerated, then women should be referred to a gynaecologist for possible further treatment which could include other hormonal treatments (for example, with a Gonadotropin-Releasing Hormone agonist [GnRHa]) or surgery. The Committee discussed the results of clinical effectiveness of other hormonal treatments such as GnRHas and danazol. Even though highly effective, use of GnRHas requires guidance from a specialist as evidence showed that they had higher risk of withdrawal due to adverse events and the Committee identified them as having more serious adverse events (e.g. bone density changes). The Committee noted that GnRHas are only licensed for a 6 month period and therefore require special considerations to ensure that women do not stay on This HMMC recommendation is based upon the evidence available at the time of publication. The recommendation will be reviewed upon request in the light of new evidence becoming available. Page 2 of 5 this treatment indefinitely. They also discussed that to negate their adverse events add-back therapy using oestrogens, progestogens or both would usually be prescribed as well. The Committee’s view was that women found the androgenic adverse events related to other hormonal treatments such as danazol in particular to be very unpleasant (e.g. voice alteration, hair growth). The Committee therefore decided not to be prescriptive about which treatment path to follow when first line treatment is not effective, not tolerated or is contraindicated and that clinical judgement was required to weigh up the benefits and harms of options that could be used. Adverse events were very varied across different types of hormonal treatments but were consistent within the classes of hormonal treatments. Potential adverse events should be discussed with women alongside the potential benefit for pain relief. Hormonal treatment as an adjunct to surgery Key conclusions Although there was no evidence available regarding the use of GnRH agonists prior to surgery, a recommendation was made to support this based on the clinical experience and knowledge that pre-operative GnRH agonists can reduce surgical complications such as bleeding. The decision to use GnRH agonists pre- operatively should be made on an individual patient basis and only in severe deep disease. Hormonal treatment after surgery Key conclusions As there was evidence that post-surgical hormonal therapy gave additional benefit over surgery alone, the Committee recommended that this be offered after surgery (laparoscopic excision or ablation). It reduces the risk of recurrence and symptoms, so it should be offered to women post-surgery unless they want to conceive. Based on the evidence, the beneficial effect