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 of all hormonal therapies was similar (probably because all work through similar mechanisms) and so the Committee considered the adverse effects of the various treatments in making their recommendation, as there are known side effects with hormonal treatments that some women may wish to avoid. In general, the combined oral contraceptive pill or long-acting reversible progestogen contraceptives were considered the most acceptable treatments. It was noted that these would not be appropriate for women who were trying to conceive, although they could be used by women who were planning pregnancy at some time in the future. They also felt it was important to note that GnRHas are only licensed for 6 months due to a loss of bone density.

 European Society of Human Reproduction & Embryology (ESHRE) guideline: management of women with endometriosis 2013 https://www.eshre.eu/Guidelines-and- Legal/Guidelines/Endometriosis-guideline

Related recommendations:  Clinicians are recommended to prescribe hormonal treatment [hormonal contraceptives (evidence level B), progestagens (level A), anti-progestagens (level A), or GnRH agonists (level A)] as one of the options, as it reduces endometriosis-associated pain.  The guideline development group (GDG) recommends that clinicians take patient preferences, side effects, efficacy, costs and availability into consideration when choosing hormonal treatment for endometriosis- associated pain, (expert opinion).

GnRH agonists: Clinical evidence A Cochrane review compared GnRH agonist (GnRHa) at different doses, regimens and routes of administration, with danazol, with intrauterine progestagen, with placebo, and with analgesics for relieving endometriosis-associated pain symptoms (Brown, et al., 2010). The results suggest that GnRHa is more effective than placebo but inferior to the levonorgestrel-releasing intrauterine system or oral danazol. The review found a worse side effect profile for GnRHa in all studies. According to one study, there was no difference for dysmenorrhea, pelvic pain, tenderness and induration when women are treated for 3 or 6 months with GnRHa (leuprolide), but dyspareunia was decreased in the shorter protocol (Hornstein, et al., 1995). No difference in effectiveness exists when GnRHa is administered intramuscularly, subcutaneously or intranasally. Limited evidence suggests an improvement in quality of life for patients receiving nafarelin intranasally compared to intramuscular leuprolide acetate (Zhao, et al., 1999). No studies were available comparing GnRHa

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 3 of 5 with analgesics.

Conclusion and considerations It can be concluded that GnRH agonists, with and without add-back therapy, are effective in the relief of endometriosis-associated pain, but evidence is limited regarding dosage or duration of treatment. No specific GnRHa can be recommended over another in relieving endometriosis-associated pain. There is evidence of severe side effects with GnRHa, which should be discussed with the woman when offering this treatment.

Recommendations  Clinicians are recommended to use GnRH agonists (nafarelin, leuprolide, buserelin, goserelin or triptorelin), as one of the options for reducing endometriosis-associated pain, although evidence is limited regarding dosage or duration of treatment (Brown, et al., 2010) (evidence level A)  The GDG recommends clinicians to give careful consideration to the use of GnRH agonists in young women and adolescents, since these women may not have reached maximum bone density (expert opinion)

 Midlands Therapeutics Review and Advisory Committee – Gonadorelin analogues for the treatment of endometriosis: Verdict & Summary, Nov 2010. https://ccg.centreformedicinesoptimisation.co.uk/download/389e27813165e6982ad57ec5860683ae/Go nadorelin-Verdict-Dec-10.pdf

For the treatment of endometriosis, the gonadorelin analogues (buserelin, goserelin, leuprorelin, nafarelin and triptorelin) are suitable for prescribing in primary care upon the advice of a specialist (or a primary care prescriber with a special interest in womens’ health).

A number of meta-analyses and additional randomised controlled trials (RCTs) found that gonadorelin analogues (considered as a group) were generally as effective as other hormonal treatments, including danazol, combined oral contraceptives and progestogens, in reducing subjective symptoms and objective measures, for up to 6 months. The evidence for efficacy compared with placebo was limited and conflicting. The place in therapy of the gonadorelins was considered to be low, primarily because of their adverse effects, especially their effect on bone mineral density.

Cost of treatment and Cost Effectiveness:

Cost comparator table PRIMARY CARE Drug Dose Unit cost Treatment cost per month Nafarelin nasal spray 2mg/ml 200mcg bd £52.43 £52.43 (60 dose) Buserelin nasal spray 150mcg/dose 300mcg tds £105.16 £105.16 (168 doses) Triptorelin (Decapeptyl SR) 3mg 4 weekly £69 £69 Triptorelin (Decapeptyl SR) 11.25mg 3 monthly £207 £69 Triptorelin (Gonapeptyl) 3.75mg 4 weekly £81.69 £81.69 Primary Care prices as per Drug Tariff November 2020.

It is hard to estimate the potential impact of this change in practice on the primary care prescribing budget as it is unclear how many patients currently being treated with i.m. injections would be switched to the nasal spray and how many new patients are likely to start treatment. Also it is uncertain if current prescribing and administration is all retained by hospital Trusts or if this is transferred to primary care following initiation. If retained by the hospital there will be an activity cost associated with administration.

The needs of the population The needs of the population appear to be low as there are alternative treatment options available. Use of a

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 4 of 5 nasal spray may be preferred by some patients and may also avoid healthcare contact for injections. This may free up appointments for other patients.

The needs of the community The needs of the community appear to be low as there is likely to be little cost impact if nafarelin is available as an alternative to triptorelin in this patient group. There may be some costs associated with transfer of prescribing to primary care if injections are currently retained by specialists. It is uncertain if current prescribing and administration of injections is all retained by hospital Trusts or if this is transferred to primary care following initiation. If retained by the hospital there will be an activity cost associated with administration which will offset costs.

Equity & Equality There is no differential impact expected on one or more equality groups differently to others: Age; Disability; Gender reassignment; Marriage & Civil Partnership; Pregnancy & Maternity; Race; Religion & Belief; Sex; Sexual orientation. As endometriosis only affects females, increasing treatment options may have a positive impact for women.

Policy Drivers Both NHSE & NICE have indicated that reducing unnecessary hospital attendance during the COVID-19 pandemic is desirable. The NICE endometriosis guideline supports referral to a specialist to discuss further treatment options (including GnRH-as) if initial hormonal treatment for endometriosis is not effective, not tolerated or is contraindicated. Other Trust and Joint formularies:  West Essex CCG – nasal spray not on formulary.  Bedfordshire & Luton joint formulary – nasal spray not on formulary.  NCL Joint Formulary – Buserelin (presentation not specified, could be IN or SC): North Middlesex, on formulary no restriction stated. RFL, RNOH, Whittington – non formulary. Nafarelin: Whittington on formulary, no restriction stated. North Middlesex, RFL, RNOH – non formulary.  Cambridge & Peterborough CCG Formulary – nafarelin nasal spray restricted to hospital only at CUFT (obstetrics & gynaecology), non-formulary at other trusts.

Implementability If nafarelin was switched to amber initiation formularies & scriptswitch messages would need to be updated accordingly including safety messages on maximum duration of use (one 6 month course only).

References  Summary of Product Characteristics. Synarel® nasal spray. Pfizer Ltd. Last update on eMC: 17/07/2018. Available online: https://www.medicines.org.uk/emc/product/1149 (accessed 16/11/2020).  Summary of Product Characteristics. Decapeptyl® SR 3mg. Ipsen Ltd. Last update on eMC: 15/09/2017. Available online: https://www.medicines.org.uk/emc/product/963/smpc (accessed 16/11/2020).  HMMC decision: Triptorelin as Decapeptyl SR ® - Gonadorelin analogue of choice within licensed indications. April 2014. https://www.enhertsccg.nhs.uk/sites/default/files/Pharmacy/Local_Decisions/Triptorelin%20%28Decapeptyl%20SR%29%201st%20choice%20gona dorelin%20analogue%20201207%20update%20201404%20%28HMMC%29.pdf  NICE guideline [NG73]: Endometriosis: diagnosis and management, September 2017 https://www.nice.org.uk/guidance/ng73  Dunselman GA, Vermeulen N, Becker C et al. European Society of Human Reproduction & Embryology (ESHRE) guideline: management of women with endometriosis 2013 https://www.eshre.eu/Guidelines-and-Legal/Guidelines/Endometriosis-guideline  Brown J, Pan A, Hart RJ. Gonadotrophin-releasing hormone analogues for pain associated with endometriosis. Cochrane Database Syst Rev 2010:CD008475. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7388859/  Hornstein MD, Yuzpe AA, Burry KA et al. Prospective randomized double-blind trial of 3 versus 6 months of nafarelin therapy for endometriosis associated pelvic pain. Fertil Steril 1995; 63:955–962.  Zhao SZ, Kellerman LA, Francisco CA, Wong JM. Impact of nafarelin and leuprolide for endometriosis on quality of life and subjective clinical measures. J Reprod Med 1999; 44:1000–1006.  Midlands Therapeutics Review and Advisory Committee – Gonadorelin analogues for the treatment of endometriosis: Verdict & Summary, Nov 2010. https://ccg.centreformedicinesoptimisation.co.uk/download/389e27813165e6982ad57ec5860683ae/Gonadorelin-Verdict-Dec-10.pdf

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 5 of 5