June 2018 Review: June 2021

Transcription

1 BEDFORDSHIRE AND LUTON JOINT PRESCRIBING COMMITTEE (JPC) Bulletin 264: Liothyronine Guidance Statement June 2018 Review: June 2021 The JPC agreed to support the attached East of England Priorities Advisory Committee (EoEPAC) Guidance Statement with a locally modified set of recommendations. JPC Recommendations (local agreement): 1. Levothyroxine monotherapy is the treatment of choice for hypothyroidism. There is no consistent evidence to support the routine use of liothyronine in the management of hypothyroidism, either alone or in combination with levothyroxine. 2. Liothyronine for treatment of hypothyroidism is not recommended for routine funding unless one of the following criteria applies: a. Post thyroidectomy thyroid cancer patients. Patients who need to receive radioactive iodine treatment (Radioiodine Remnant Ablation RRA) after their surgery will initially be started on liothyronine due to its shorter halflife and therefore faster onset of action than levothyroxine. These patients will remain on liothyronine until the oncologist is confident that they will not need any more radioactive iodine at which point they are switched over to levothyroxine. Prescribing in these circumstances must remain with the secondary care specialist and GPs should not accept prescribing responsibility for these patients. b. In rare cases of levothyroxine induced liver injury, long term liothyronine prescribing may be supported. Initiation and ongoing prescribing and supply should remain in secondary care under the supervision of a secondary care specialist. 3. Initiation and prescribing of liothyronine for patients on levothyroxine who continue to suffer with symptoms despite adequate biochemical correction should remain in secondary care under the supervision of an accredited endocrinologist. The CCGs will not accept any additional activity charges relating to the ongoing supply of the drug. 1

2 4. Funding of unlicensed medicines e.g. Armour Thyroid for the treatment of hypothroidism is not supported. 5. Prescribers in primary care should not initiate or accept clinical responsibility for on-going prescribing of liothyronine for any new patient, including patients who are currently self-funding and obtaining supplies via private prescription or previously prescribed by a secondary care consultant, unless the criteria stated above are met and they have agreed to accept clinical responsibility for prescribing. 6. CCGs should give consideration to providing guidance for GPs to switch existing patients to levothyroxine where clinically appropriate, with support from a consultant NHS endocrinologist where necessary or agree arrangements for appropriate review by a consultant NHS endocrinologist 7. If liothyronine is prescribed, the least costly preparation should be used. (For Primary Care, advice on this will be provided via Scriptswich/Optimise.) 8. These recommendations will be reviewed in the light of new evidence of clinical and cost effectiveness. NB: The full EoEPAC document is attached however clinicians should note that the JPC recommendations outlined above replace the EoEPAC recommendations. 2

3 The East of England Priorities Advisory Committee A function of GUIDANCE STATEMENT Liothyronine (all indications) PAC recommendations 1. Levothyroxine monotherapy is the treatment of choice for hypothyroidism. There is no consistent evidence to support the routine use of liothyronine in the management of hypothyroidism, either alone or in combination with levothyroxine. 2. Liothyronine for treatment of hypothyroidism is not recommended for routine funding unless one of the following criteria applies: a. Post thyroidectomy thyroid cancer patients. Patients who need to receive radioactive iodine treatment (Radioiodine Remnant Ablation - RRA) after their surgery will initially be started on liothyronine due to its shorter half-life and therefore faster onset of action than levothyroxine. These patients will remain on liothyronine until the oncologist is confident that they will not need any more radioactive iodine at which point they are switched over to levothyroxine. Prescribing in these circumstances must remain with the secondary care specialist and GPs should not accept prescribing responsibility for these patients. b. In rare cases of levothyroxine induced liver injury, long term liothyronine prescribing may be supported but only after initiation and stabilisation by a secondary care specialist. Arrangements for individual prior approval, prescribing and supply should be agreed locally, ensuring that appropriate patient monitoring is in place. 3. Initiation and prescribing of liothyronine for patients on levothyroxine who continue to suffer with symptoms despite adequate biochemical correction should remain in secondary care under the supervision of an accredited endocrinologist. 4. Funding of unlicensed medicines, e.g. Armour Thyroid for the treatment of hypothyroidism is not supported. 5. Prescribers in primary care should not initiate or accept clinical responsibility for on-going prescribing of liothyronine for any new patient, including patients who are currently selffunding and obtaining supplies via private prescription or previously prescribed by a secondary care consultant, unless the criteria stated above are met and they have agreed to accept clinical responsibility for prescribing. 6. CCGs should give consideration to providing guidance for GPs to switch existing patients to levothyroxine where clinically appropriate, with support from a consultant NHS endocrinologist where necessary or agree arrangements for appropriate review by a consultant NHS endocrinologist. 7. These recommendations will be reviewed in the light of new evidence of clinical and cost effectiveness. 1 of 10

4 Key points PAC - Liothyronine (all indications) Liothyronine is a synthetic thyroid hormone, which exhibits the actions of the biologically active form of the endogenous thyroid hormone, triiodothyronine (T3). Liothyronine is generally considered to be more active than levothyroxine, the synthetic version of the endogenous thyroid hormone, thyroxine (T4). It has a faster onset of action (usually within a few hours), but with a shorter half-life and therefore requires multiple daily doses to maintain steady state, and more readily crosses the blood brain barrier. Approximately, 80% of circulating triiodothyronine results from peripheral conversion of thyroxine. It has been suggested that peripheral conversion of thyroxine to triiodothyronine may be inhibited during times of stress or illness, or that some individuals are low metabolisers and do not convert thyroxine to triiodothyronine quickly enough. Consequently, combination treatment with both liothyronine and levothyroxine has been advocated. There is no consistent evidence to support the routine use of liothyronine in the management of hypothyroidism, either alone or in combination with levothyroxine. Clinical practice guidelines, worldwide, do not recommend and do not support the routine use of combination levothyroxine and liothyronine therapy for hypothyroidism. There is a lack of evidence to support long term monotherapy with liothyronine. Several safety concerns are associated with liothyronine. Its intestinal absorption can give rise to unusually high post absorption peaks leading to tachycardia and consequently there may be an increased risk of cardiac complications, and fatalities have occurred. In addition, long term therapy with liothyronine is more likely to cause secondary osteoporosis than levothyroxine. The cost of liothyronine is currently significantly higher than alternative treatments, and given the lack of clinical and cost effectiveness, and safety concerns, is considered a low clinical priority and routine funding for any patient group is not recommended. The British Thyroid Association (BTA) recognises a proportion of patients on levothyroxine continue to suffer with symptoms despite adequate biochemical correction, and that a carefully monitored trial of liothyronine under the supervision of an accredited endocrinologist might be warranted in exceptional cases. NHS England guidance on low value medicines which should not routinely be prescribed in primary care recognises the above point. A NICE Clinical Knowledge Summary regarding hypothyroidism management updated in 2016, now states that combination treatment with liothyronine and levothyroxine should not be managed in primary care. In line with guidance from the Royal College of Physicians and BTA, PAC recommends that prescribing for these patients should remain in secondary care. CCGs should have due regard for the NHS England low value medicines guidance and consider these recommendations through their usual processes. There is insufficient evidence to support the routine use of liothyronine for the adjunctive treatment to tricyclic antidepressants in patients with refractory severe depression. Short term treatment with liothyronine for patients with thyroid cancer is included in tariff and prescribing should be retained by the acute provider Trust. Liothyronine is indicated in extremely rare cases of levothyroxine induced liver injury as there is no alternative treatment available. Funding should be provided for ongoing liothyronine treatment for patients with levothyroxine induced liver injury after initiation and stabilisation by a secondary care specialist. Arrangements for prior approval, prescribing and supply should be agreed locally, ensuring that appropriate patient monitoring is in place. 2 of 10

5 In line with NHS guidance on Defining the Boundaries between NHS and Private Healthcare, NHS prescribing should not be routinely offered to patients who are currently self-funding or obtaining supplies via private prescription unless they are clinically exceptional. These patients will retain the option of obtaining liothyronine on private prescription. Background Hypothyroidism is caused by suboptimal circulating concentrations of the thyroid hormones, thyroxine (T4) and triiodothyronine (T3). Liothyronine is a synthetic thyroid hormone, which exhibits the actions of the biologically active form of the endogenous triiodothyronine. 1-4 It is generally considered to be more active than levothyroxine, the synthetic version of the endogenous thyroid hormone, thyroxine. It has a faster onset of action (usually within a few hours), but with a shorter half-life and therefore requires multiple daily doses to maintain steady state. It also more readily crosses the blood brain barrier. 1-4 Whilst these properties are key advantages of liothyronine, it is generally only used routinely where its rapid onset of action is clinically useful, (i.e. the life threatening hypothyroid coma also known as myxoedema). 2 Approximately, 80% of circulating triiodothyronine results from peripheral conversion of thyroxine, by iodothyronine 5 -deiodinase, with the remaining 20% secreted from the thyroid gland. Peripheral conversion of thyroxine to triiodothyronine may be reduced during stress or systemic illness, prolonged fasting and by drugs such as beta blockers or amiodarone. It is also suspected that some patients are low metabolisers and do not convert thyroxine to triiodothyronine quickly enough. 3,4 Consequently, combination treatment with both liothyronine and levothyroxine has been advocated. 3,5-7 Raised plasma thyroid stimulating hormone (TSH), with an associated decreased or normal plasma thyroxine could be indicative of hypothyroidism. Measurement of plasma triiodothyronine concentrations are of no help with respect to diagnosis and ongoing monitoring of thyroid function, as plasma triiodothyronine concentrations are often normal. 8 Management of patients on liothyronine has historically occurred in primary care with supervision and oversight by an appropriate specialist in secondary care. A bulletin by PrescQIPP has highlighted the overall lack of evidence and support in relevant guidance for the use of liothyronine in hypothyroidism and recommended that treatment should be initiated with levothyroxine and that all patients currently receiving liothyronine should be reviewed and a switch to levothyroxine considered where clinically appropriate. 9 Clinical evidence There is no consistent evidence to support the routine use of liothyronine in the management of hypothyroidism, either alone or in combination with levothyroxine. Data from several, small and methodologically limited trials have failed to clearly demonstrate superiority of combination liothyronine and levothyroxine treatment over levothyroxine monotherapy Experience with the use of combined treatment was first published in A small double-blind cross over trial (n=99), compared a combined preparation containing levothyroxine and liothyronine in a 1:4 ratio with levothyroxine alone for two months. At study end, there was no significant difference in biochemical parameters and patients reported no preference to a particular treatment. However, a large number of patients (n=24) had reported unpleasant adverse effects, including palpitations, irritability and nervousness, dizziness and tremor, whilst taking the combined preparation. Subsequent animal studies suggested that combination treatment in thyroidectomised rats, produced complete euthyroidism compared to treatment with levothyroxine alone. 23,24 Only one study in humans has replicated these results to date. 25 In a small study, published by Bunevicius et al in 1999, 33 patients with hypothyroidism received either their usual dose of levothyroxine or a regimen where 50 micrograms of the usual dose of levothyroxine was replaced by 12.5 micrograms of liothyronine for five weeks. The treatments were then switched over. The order in which each patient received the two treatments was randomized. Biochemical, physiological and psychological tests were 3 of 10

6 performed at the end of each treatment period. After five weeks of each treatment, lower serum free, total thyroxine concentrations and higher serum total triiodothyronine concentrations were observed after treatment with levothyroxine plus liothyronine than after levothyroxine alone, whereas the serum thyrotropin concentrations were similar after both treatments. Among 17 scores on tests of cognitive performance and assessments of mood, 6 were cited as better or closer to normal after treatment with levothyroxine plus liothyronine. The study authors concluded that partial substitution of levothyroxine with liothyronine may improve mood and psychological tests. 25 Several recent studies have failed to replicate these results and have concluded that combination treatment with liothyronine and levothyroxine is not superior to levothyroxine alone One study by Siegmund et al, also suggests that combined treatment is associated with subclinical hyperthyroidism causing impaired wellbeing, due to significant fluctuations in the steady state triiodothyronine serum concentrations produced by combination treatment. 15 A systematic review of nine randomized trials also confirms that the only study to report beneficial effects of combination with liothyronine/levothyroxine therapy on mood, quality of life, and psychometric performance when compared to levothyroxine therapy alone is the one by Bunevicius et al. 25,26 Another systematic review by Grozinsky-Glasberg et al concludes that levothyroxine monotherapy is the treatment of choice for clinical hypothyroidism. 27 Several safety concerns are associated with liothyronine. Fast intestinal absorption can give rise to unusually high post absorption peaks leading to tachycardia and consequently there may be an increased risk of cardiac complications and fatalities have occurred. In addition, long term therapy with liothyronine is more likely to cause secondary osteoporosis than levothyroxine. 4,5 The dosage needed to obtain euthyroidism with liothyronine is more difficult to evaluate, owing to unpredictable fluctuations in serum triiodothyronine concentration. 4,5 Place in therapy The overall benefits of combination therapy with levothyroxine and liothyronine are still unproven, with a potential increase in some adverse consequences, such as arrhythmias, osteoporosis and bone fractures. 28 Worldwide clinical practice guidelines do not recommend and do not support the routine use of either combination liothyronine/levothyroxine therapy or liothyronine monotherapy for hypothyroidism. 29 A NICE Clinical Knowledge Summary regarding hypothyroidism management updated in 2016, now states that combination treatment with liothyronine and levothyroxine should not be managed in primary care. 30 The British Thyroid Association (BTA) position statement states that levothyroxine and liothyronine combination therapy in patients with hypothyroidism should not routinely be used, as there is insufficient evidence to show that combination therapy is superior to levothyroxine monotherapy, however it does suggest that a trial of combination therapy may be worth trying in patients who remain symptomatic, despite adequate levothyroxine supplementation. The BTA does not recommend the routine use of thyroid extracts, liothyronine monotherapy, compounded thyroid hormones, iodine containing preparations, dietary supplementation, nutraceuticals and over the counter preparations for the management of hypothyroidism. 28 The British Thyroid Foundation (BTF) Frequently Asked Questions for the management of Primary Hypothyroidism states that levothyroxine alone remains the recommended treatment for thyroid hormone replacement and that patients who want to try alternative treatment should be managed under the supervision of an interested endocrinologist. 31 The Royal College of Physicians in the UK do not recommend the prescribing of additional liothyronine, including Armour thyroid, as it is inconsistent with normal physiology, has not been unequivocally proven to be of benefit to patients and may be harmful. It states that the inclusion of liothyronine in the treatment of hypothyroidism should be reserved for use by accredited endocrinologists in individual patients of 10

7 Separate guidance produced by the American Thyroid Association, American Association of Clinical Endocrinologists and European Thyroid Association also concludes that there is currently insufficient evidence to support the use of liothyronine, either alone or in combination NHS England have recently published guidance regarding medicines of low priority which states that liothyronine could benefit a small group of patients who despite adequate levothyroxine supplementation remain symptomatic, after recommendation of a Consultant Endocrinologist. 36 Their recommendations on prescribing of liothyronine are as follows: Advise CCGs that prescribers in primary care should not initiate liothyronine for any new patient. Advise CCGs that individuals currently prescribed liothyronine should be reviewed by a consultant NHS endocrinologist with consideration given to switching to levothyroxine where clinically appropriate. Advise CCGs that a local decision, involving the Area Prescribing Committee (or equivalent) informed by National guidance (e.g. from NICE or the Regional Medicines Optimisation Committee), should be made regarding arrangements for on-going prescribing of liothyronine. This should be for individuals who, in exceptional circumstances, have an on-going need for liothyronine as confirmed by a consultant NHS endocrinologist. Liothyronine is not used in patients with congenital hypothyroidism; levothyroxine is the treatment of choice in such patients In extremely rare cases of levothyroxine induced liver injury, liothyronine is the only alternative hypothyroid treatment. Long term liothyronine prescribing for these patients should be considered after initiation and stabilisation by a secondary care specialist. Arrangements for individual prior approval, prescribing and supply should be agreed locally, ensuring that appropriate patient monitoring is in place. 40,41 Liothyronine has also been advocated for adjunctive treatment to tricyclic antidepressants in patients with refractory severe depression; however, there is insufficient evidence to support the routine use of liothyronine for these patients Temporary treatment with liothyronine may be appropriate in patients with thyroid cancer who are to undergo radioiodine imaging and possible treatment. To shorten the period of hypothyroidism, the patient s levothyroxine is discontinued and liothyronine is substituted for three to four weeks until the levothyroxine is cleared. 45 All activity including supply of liothyronine is included in tariff and should be retained by the acute provider Trust for such patients. Cost impact and cost effectiveness The recommended dose of liothyronine is initially micrograms daily, gradually increased to 60 micrograms daily in 2 3 divided doses; elderly patients require smaller initial doses. 1,2 Comparative primary care costs May 2017 (emims) 46 Drug Strength Dose Pack cost (28 tablets) Cost per 28 days Cost per year Liothyronine tabs 20mcg 20mcg TDS ,069 Levothyroxine 100mcg 100mcg OD Costs shown are current indicative costs in primary care (VAT excluded) when prescribed on an FP10 prescription. Basic cost of medication to acute provider trusts is generally the same as primary care, however VAT charges are also incurred giving a total billing cost of per patient for 28 days to the acute provider trust. Liothyronine is currently included in the associated outpatient tariff. 47 It is estimated that five patients per 100,000 population are currently receiving liothyronine treatment, either alone or in combination with levothyroxine. 5 of 10

8 The Health Service Medical Supplies (Costs) Act has recently been passed in to law and gained Royal Assent. This new act gives the government the power to instruct pharmaceutical companies to reduce the price of a generic medicine or introduce other controls on their branded products in cases where it thinks drug companies are charging unreasonable prices for generics. The current high cost of liothyronine had been noted in a briefing paper to the House of Commons regarding this Act in October ,49 However, at the time of writing, the likely impact of these developments was unclear and if this will result in a reduction in the cost of liothyronine. At least two new generic versions of liothyronine are anticipated in In line with NHS guidance on Defining the Boundaries between NHS and Private Healthcare, NHS prescribing should not be routinely offered to patients who are currently self-funding or obtaining supplies via private prescription, unless they are clinically exceptional. These patients will retain the option of obtaining liothyronine on private prescription. 50 Document history PAC approval date 10th April 2018 Version 1 Consultation process PAC members East of England clinicians QAprocess Katie Smith, Senior Clinical Pharmacist, PrescQIPP 25th April 2018 References 1. BNF Online. Martin J, editor. British National Formulary London: British Medical Association and The Royal Pharmaceutical Society of Great Britain Accessed 30/04/2017 via www. evidence.nhs.uk 2. Martindale Online. Sweetman S, editor. Martindale: The Complete Drug Reference Liothyronine. Date of revision of the text 20/03/16. Accessed 30/04/2017 via www. medicinescomplete.com 3. Gilman A, Goodman LS, Gilman A, editors. Goodman and Gilman s The Pharmacological Basis of Therapeutics: 6th Ed. Goodman Macmillan, 866 Third Ave., New York, NY Aronson J, Editor. Meyler s Side Effects of Drugs: The International Encyclopaedia of Adverse Drug Reactions and Interactions. Thyroid Hormones, p Accessed 30/04/2017 via 5. Lloyd J, Yerbury P et al. Thyroid Disorders: management. Clinical Pharmacist 2011; (3): Vaidya B. Clinical Review: Management of hypothyroidism in adults. BMJ 2008; 337: a Walsh JP. Dissatisfaction with thyroxine therapy- could the patients be right? Current Opinion in Pharmacology 2002; 2(6): Mayne PD. Clinical Chemistry in diagnosis and treatment. Arnold Publications, London, 6th Edition. Chapter 8 Thyroid Function. 9. PrescQIPP. Drop List Bulletin 121. Liothyronine. December Available via prescqipp.info/liothyronine/viewcategory/404-liothyronine Password may be required. 10. Smith RN, Taylor SA et al. Controlled clinical trial of combined tri-iodothyronine and thyroxine in the treatment of hypothyroidism. British Medical Journal 1970; 4: Escobar-Morreale HFF, Botella-Carretero JI et al. Treatment of hypothyroidism with levothyroxine or a combination of levothyroxine plus L-triiodothyronine. Best Practice and Research: Clinical Endocrinology and Metabolism 2015; 29: of 10

9 12. Jonklaas J, Burman KD. Daily administration of short-acting liothyronine is associated with significant triiodothyronine excursions and fails to alter thyroid-responsive parameters. Thyroid 2016; 26(6): Sawka AM, Gerstein HC, et al. Does a combination regimen of thyroxine (t4) and 3,5,3 -triiodothyronine improve depressive symptoms better than T4 alone in patients with hypothyroidism? Results of a double blind randomised controlled trial. Journal of Clinical Endocrinology & Metabolism 2003; 88 (10): Saravanan P, Simmons DJ et al. Partial substitution of thyroxine with tri-iodothyronine in patients on T4 replacement therapy: results of a large community based randomised controlled trial. Journal of Clinical Endocrinology & Metabolism 2005; 90 (2): Siegmund W, Spieker K et al. Replacement therapy with levothyroxine plus triiodothyronine (bioavailable molar ratio 14: 1) is not superior to thyroxine alone to improve well-being and cognitive performance in hypothyroidism. Clinical Endocrinology (Oxford) 2004; 60: Paz-Filho GJ. Treatment of hypothyroidism with levothyroxine plus triiodothyronine: A randomized, double-blind crossover study Thyroid 2015;25: (1A) Kaminiski J, Miasaki FY et al. Treatment of hypothyroidism with levothyroxine plus liothyronine: a randomised double-blind cross over study. Archives of Endocrinology and Metabolism 2016; 60(6): Escobar-Morreale HF, Botella-Carretero JI et al. Thyroid hormone replacement therapy in primary hypothyroidism: a randomized trial comparing -thyroxine plus liothyronine with -thyroxine alone. Annals of Internal Medicine 2005; 142 (6): Appelhof BC, Fliers E et al. Combined therapy with levothyroxine and liothyronine in two ratios, compared with levothyroxine monotherapy in primary hypothyroidism: a double-blind, randomized, controlled clinical trial. Journal of Clinical Endocrinology & Metabolism 2005; 90 (5): Clyde PW, Harari HE et al. Combined Levothyroxine Plus Liothyronine Compared with Levothyroxine Alone in Primary Hypothyroidism: A Randomized Controlled Trial. Journal of the American Medical Association 2003; 290 (22): Walsh JP, Shiels L et al. Combined thyroxine/liothyronine treatment does not improve well-being, quality of life, or cognitive function compared to thyroxine alone: a randomized controlled trial in patients with primary hypothyroidism. Journal of Clinical Endocrinology & Metabolism 2003; 88 (10): Bunevicius R, Jakuboniene N et al. Thyroxine vs. Thyroxine plus tri-iodothyronine in treatment of hypothyroidism after thyroidectomy for Grave s disease. Endocrine 2002; 18(2): Escobar-Morreale HF, Obregon JM et al. Replacement therapy for hypothyroidism with thyroxine alone does not ensure euthyroidism in all tissues as studied in thyroidectomized rats. Journal of Clinical Investigation 1995; 96: Escobar-Morreale HF, Escobar del Rey F et al. Only the combined treatment with thyroxine and triiodothyronine ensures euthyroidism in all tissues of the thyroidectomised rat. Endocrinology 1996; 137 (6): Bunevicius R, Kazanavicius G et al. Effects of thyroxine as compared with thyroxine plus triiodothyronine in patients with hypothyroidism. New England Journal of Medicine 1999; 340: Escobar-Morreale HF, Botella-Carretero JI et al. Treatment of hypothyroidism with combinations of levothyroxine plus liothyronine. Journal of Clinical Endocrinology & Metabolism 2005; 90 (8): of 10

10 27. Grozinsky-Glasberg S, Fraser A et al. Thyroxine-Triiodothyronine combinations therapy versus thyroxine monotherapy for clinical hypothyroidism: Meta-analysis of randomised controlled trials. Journal of Clinical Endocrinology and Metabolism 2006; 91 (7): Okosieme O, Gilbert J et al. Management of primary hypothyroidism: Statement by the British Thyroid Association Executive Committee. Clinical Endocrinology 2016; 84: First published May Kraut E, Farhani P. A systematic review of Clinical Practice Guidelines recommendations on levothyroxine therapy alone versus combination therapy (LT4 plus LT3) for hypothyroidism. Clinical Investigations & Medicine 2015; 38(6): E305-E NICE Clinical Knowledge Summary. Hypothyroidism. Last updated April Accessed 30th April 2017 via British Thyroid Foundation. FAQ for the management of Primary Hypothyroidism, Royal College of Physicians. The diagnosis and management of primary hypothyroidism. Royal College of Physicians Guidance Original 19th November 2008; updated 14th June Accessed 30th April 2017 via statement_20111.pdf 33. Jonklaas J, Bianco AC et al. Guidelines for the treatment of hypothyroidism: prepared by the American thyroid association task force on thyroid hormone replacement. Thyroid 2014; 24: Garber J, Cobin R, et al. Clinical Practice guidelines for hypothyroidism in adults: co-sponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Endocrine Practice 2012; 18 (6): Weirsinga W, Duntas L et al ETA guidelines: the use of L-T4 + L-T3 in the treatment of hypothyroidism. European Thyroid Journal 2012; 1: NHS England & NHS Clinical Commissioners. Items which should not routinely be prescribed in primary care: Guidance for CCGs. November Accessed via uk/wp-content/uploads/2017/11/items-which-should-not-be-routinely-precscribed-in-pc-ccgguidance.pdf 37. Hypothyroidism in childhood factsheet. British Society for Paediatric Endocrinology and Diabetes. June Accessed 30th April 2017 via NN_HYPOTHYROIDISM(ACQUIRED)june2011.pdf 38. Foley T, Kaplowitz PB et al. Update of newborn screening and therapy for congenital hypothyroidism. Paediatrics 2006; 117 (6): Leger J, Olivieri A et al. European Society for Paediatric Endocrinology consensus guidelines on screening, diagnosis, and management of congenital hypothyroidism. Journal of Clinical Endocrinology and Metabolism 2014; 99(2): Lin H, Yang WL. A rare case of levothyroxine-induced liver injury [P-1002]. Hepatology International 2016; 10 (Suppl 1): S Kawakami T, Tanaka A et al. Liver Injury induced by levothyroxine in a patient with primary hypothyroidism. Internal Medicine 2007; 46(14): Aronson R, Offman HJ, Joffe RT et al. Tri-iodothyronine augmentation in the treatment of refractory depression: A meta-analysis. Archives of General Psychiatry 1996; 53 (9): Cleare A, Pariante CM et al. Evidence based guidelines for treating depressive disorders with antidepressants: A revision of the 2008 British Association for Psychopharmacology guidelines. Journal of PsychoPharmacology 2015; 29 (5): of 10

11 44. Taylor D, Paton C et al. The South London and Maudsley NHS Foundation Trust & Oxleas NHS Foundation Trust Prescribing Guidelines. 11th ed.: Wiley and Blackwell Perros P, Colley S, Boeleart K et al. British Thyroid Association Guidelines for the Management of Thyroid Cancer, 3rd Edition. Clinical Endocrinology 2014; 81 (S1): onlinelibrary.wiley.com/doi/pdf/ /cen emims, Accessed May Monitor and NHS England Statutory guidance. NHS National Tariff Payment System 2017/ nd December Accessed 30/04/ New legislation passed to prevent excessive price hiking of generic drugs. The Pharmaceutical Journal, May 2017, online DOI: /PJ Accessed 25/05/2017 via Barber S, Harker R et al. The Health Service Medical supplies (Costs) Bill (Bill 72 of ). Briefing paper Number 7744, House of Commons Library. 21 October NHS Commissioning Board. Commissioning Policy: Defining the boundaries between NHS and Private Healthcare Reference: NHSCB/CP/12. April 2013 Accessed January 2018 via Appendix 1: Assessment against ethical and commissioning principles Treatment assessed Liothyronine East of England Priorities Advisory Committee Recommendation Levothyroxine monotherapy is the treatment of choice for hypothyroidism. There is no consistent evidence to support the routine use of liothyronine in the management of hypothyroidism, either alone or in combination with levothyroxine. Liothyronine for treatment of hypothyroidism is not recommended for routine funding unless one of the following criteria applies: a. Post thyroidectomy thyroid cancer patients. Patients who need to receive radioactive iodine treatment (Radioiodine Remnant Ablation - RRA) after their surgery will initially be started on liothyronine due to its shorter half-life and therefore faster onset of action than levothyroxine. These patients will remain on liothyronine until the oncologist is confident that they will not need any more radioactive iodine at which point they are switched over to levothyroxine. Prescribing in these circumstances must remain with the secondary care specialist and GPs should not accept prescribing responsibility for these patients. b. In rare cases of levothyroxine induced liver injury, long term liothyronine prescribing may be supported but only after initiation and stabilisation by a secondary care specialist. Arrangements for individual prior approval, prescribing and supply should be agreed locally, ensuring that appropriate patient monitoring is in place. Initiation and prescribing of liothyronine for patients on levothyroxine who continue to suffer with symptoms despite adequate biochemical correction should remain in secondary care under the supervision of an accredited endocrinologist. Funding of unlicensed medicines, e.g. Armour Thyroid for the treatment of hypothroidismhypothyroidism is not supported. Prescribers in primary care should not initiate or accept clinical responsibility for on-going prescribing of liothyronine for any new patient, including patients who are currently self-funding and obtaining supplies via private prescription or previously prescribed by a secondary care consultant, unless the criteria 9 of 10

12 stated above are met and they have agreed to accept clinical responsibility for prescribing. CCGs should give consideration to providing guidance for GPs to switch existing patients to levothyroxine where clinically appropriate, with support from a consultant NHS endocrinologist where necessary or agree arrangements for appropriate review by a consultant NHS endocrinologist. Clinical effectiveness There is no consistent evidence to support the routine use of liothyronine in the management of hypothyroidism, either alone or in combination with levothyroxine. Data from several, small and methodologically limited trials have failed to clearly demonstrate superiority of combination liothyronine and levothyroxine treatment over levothyroxine monotherapy. Results from a small study, which suggested that combination treatment is associated with lower serum free and total thyroxine concentrations and higher serum total triiodothyronine concentrations were observed after treatment with thyroxine plus triiodothyronine than after thyroxine alone and improved mood and cognition scores have not been replicated in more recent studies. Clinical practice guidelines, worldwide, do not recommend and do not support the routine use of combination liothyronine and levothyroxine therapy for hypothyroidism. Cost effectiveness No studies identified. The use of liothyronine is not currently deemed cost-effective, due to the current high cost of liothyronine. Equity No issues identified. Needs of the community Current high cost of treatment with liothyronine associated with a small number of patients represents a financial risk to the whole healthcare economy and will result in cost pressures to other treatment areas. Need for healthcare (incorporates patient choice and exceptional need) Liothyronine is not required by the vast majority of patients with hypothyroidism and an effective standard of care treatment, levothyroxine is easily available. Where treatment with liothyronine is deemed essential (i.e. acute liver injury with levothyroxine, and for patients undergoing treatment for thyroid cancer), management and all prescribing should be retained by the Provider Trust. Policy drivers Clinical practice guidelines worldwide, do not recommend and do not support the routine use of combination levothyroxine and liothyronine therapy for hypothyroidism, including NHS England guidance on items that should not be routinely prescribed in primary care, NICE Clinical Knowledge Summary, BTA, ATA and ETA guidance. Disinvestment None identified. 10 of 10