open access

Vol 71, No 5 (2020)
Review paper
Published online: 2020-10-30
Submitted: 2020-09-05
Accepted: 2020-09-06
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Expert opinion on liquid L-thyroxine usage in hypothyroid patients and new liquid thyroxine formulation — Tirosint SOL [Opinia ekspertów dotycząca stosowania płynnej postaci lewotyroksyny oraz nowego preparatu Tirosint SOL u chorych na niedoczynność tarczycy]

Małgorzata Gietka-Czernel, Alicja Hubalewska-Dydejczyk, Beata Kos-Kudła, Andrzej Lewiński, Marek Ruchała, Anhelli Syrenicz, Wojciech Zgliczyński
DOI: 10.5603/EP.a2020.0065
·
Pubmed: 33202031
·
Endokrynologia Polska 2020;71(5):441-465.

open access

Vol 71, No 5 (2020)
REVIEWS — Postgraduate Education
Published online: 2020-10-30
Submitted: 2020-09-05
Accepted: 2020-09-06

Abstract

Hypothyroidism is a common endocrine disorder affecting 3–15% of the adult population in subclinical form and 0.3–0.8% as overt disease. The mainstay of treatment is replacement monotherapy with levothyroxine (LT4). Currently several oral LT4 formulations including tablets, softgel capsules, and liquid formulations are available. Liquid LT4 is manufactured as LT4 solution in 85% glycerol and 96% ethanol and as LT4 solution in purified water and glycerol. The latest formulation, Tirosint SOL, gained FDA approval in 2017. To evaluate the clinical utility of liquid LT4 we reviewed the literature using three databases: PubMed/MEDLINE, Scopus, and Embase and found 405 articles among which 23 prospective and two retrospective studies were further evaluated. Finally, several case reports on rare clinical conditions were discussed. Our review demonstrated that liquid LT4 was more effective than tablet formulation in patients with malabsorption caused by interfering diseases, drugs, and bariatric surgery. The better pharmacokinetics of liquid LT4 was also confirmed in subjects without malabsorption: patients on replacement or suppressive therapy, who switched from tablet to liquid formulation in equivalent dose, gained better hormonal control, and required less frequent TSH measurements. The drug also appeared effective and easy to handle in patients fed by enteric tube. Liquid LT4 appeared equally effective whenever taken before or during breakfast. The analysis of the drug utility in particular populations including newborns, pregnant women, and the elderly confirmed the high value and safety of liquid LT4. However, in neonates the higher incidence of TSH suppression on liquid in comparison to tablet LT4 therapy was noted, and particular attention to avoid over-treatment must be paid. Concluding: the literature review revealed that liquid LT4 is especially advantageous in patients with malabsorption and the critically ill, but it seems also very promising in common therapy. The lack of alcohol content in the new formulation makes Tirosint SOL especially attractive.

Abstract

Hypothyroidism is a common endocrine disorder affecting 3–15% of the adult population in subclinical form and 0.3–0.8% as overt disease. The mainstay of treatment is replacement monotherapy with levothyroxine (LT4). Currently several oral LT4 formulations including tablets, softgel capsules, and liquid formulations are available. Liquid LT4 is manufactured as LT4 solution in 85% glycerol and 96% ethanol and as LT4 solution in purified water and glycerol. The latest formulation, Tirosint SOL, gained FDA approval in 2017. To evaluate the clinical utility of liquid LT4 we reviewed the literature using three databases: PubMed/MEDLINE, Scopus, and Embase and found 405 articles among which 23 prospective and two retrospective studies were further evaluated. Finally, several case reports on rare clinical conditions were discussed. Our review demonstrated that liquid LT4 was more effective than tablet formulation in patients with malabsorption caused by interfering diseases, drugs, and bariatric surgery. The better pharmacokinetics of liquid LT4 was also confirmed in subjects without malabsorption: patients on replacement or suppressive therapy, who switched from tablet to liquid formulation in equivalent dose, gained better hormonal control, and required less frequent TSH measurements. The drug also appeared effective and easy to handle in patients fed by enteric tube. Liquid LT4 appeared equally effective whenever taken before or during breakfast. The analysis of the drug utility in particular populations including newborns, pregnant women, and the elderly confirmed the high value and safety of liquid LT4. However, in neonates the higher incidence of TSH suppression on liquid in comparison to tablet LT4 therapy was noted, and particular attention to avoid over-treatment must be paid. Concluding: the literature review revealed that liquid LT4 is especially advantageous in patients with malabsorption and the critically ill, but it seems also very promising in common therapy. The lack of alcohol content in the new formulation makes Tirosint SOL especially attractive.
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Keywords

hypothyroidism; liquid levothyroxine; Tirosint SOL

About this article
Title

Expert opinion on liquid L-thyroxine usage in hypothyroid patients and new liquid thyroxine formulation — Tirosint SOL [Opinia ekspertów dotycząca stosowania płynnej postaci lewotyroksyny oraz nowego preparatu Tirosint SOL u chorych na niedoczynność tarczycy]

Journal

Endokrynologia Polska

Issue

Vol 71, No 5 (2020)

Article type

Review paper

Pages

441-465

Published online

2020-10-30

DOI

10.5603/EP.a2020.0065

Pubmed

33202031

Bibliographic record

Endokrynologia Polska 2020;71(5):441-465.

Keywords

hypothyroidism
liquid levothyroxine
Tirosint SOL

Authors

Małgorzata Gietka-Czernel
Alicja Hubalewska-Dydejczyk
Beata Kos-Kudła
Andrzej Lewiński
Marek Ruchała
Anhelli Syrenicz
Wojciech Zgliczyński

References (60)
  1. Peeters RP. Subclinical Hypothyroidism. N Engl J Med. 2017; 376(26): 2556–2565.
  2. Garmendia Madariaga A, Santos Palacios S, Guillén-Grima F, et al. The incidence and prevalence of thyroid dysfunction in Europe: a meta-analysis. J Clin Endocrinol Metab. 2014; 99(3): 923–931.
  3. Taylor PN, Albrecht D, Scholz A, et al. Global epidemiology of hyperthyroidism and hypothyroidism. Nat Rev Endocrinol. 2018; 14(5): 301–316.
  4. Almandoz JP, Gharib H. Hypothyroidism: etiology, diagnosis, and management. Med Clin North Am. 2012; 96(2): 203–221.
  5. Burch HB. Drug Effects on the Thyroid. N Engl J Med. 2019; 381(8): 749–761.
  6. Kluczyński Ł, Gilis-Januszewska A, Rogoziński D, et al. Hypophysitis - new insights into diagnosis and treatment. Endokrynol Pol. 2019; 70(3): 260–269.
  7. Pearce SHS, Brabant G, Duntas LH, et al. 2013 ETA Guideline: Management of Subclinical Hypothyroidism. Eur Thyroid J. 2013; 2(4): 215–228.
  8. Jonklaas J, Bianco A, Bauer A, et al. Guidelines for the Treatment of Hypothyroidism: Prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement. Thyroid. 2014; 24(12): 1670–1751.
  9. Garber JR, Cobin RH, Gharib H, et al. American Association of Clinical Endocrinologists and American Thyroid Association Taskforce on Hypothyroidism in Adults. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Endocr Pract. 2012; 18(6): 988–1028.
  10. Rodondi N, den Elzen WPJ, Bauer DC, et al. Thyroid Studies Collaboration. Subclinical hypothyroidism and the risk of coronary heart disease and mortality. JAMA. 2010; 304(12): 1365–1374.
  11. Ning Yu, Cheng YJ, Liu LiJ, et al. What is the association of hypothyroidism with risks of cardiovascular events and mortality? A meta-analysis of 55 cohort studies involving 1,898,314 participants. BMC Med. 2017; 15(1): 21.
  12. Dayan C, Panicker V. Management of hypothyroidism with combination thyroxine (T4) and triiodothyronine (T3) hormone replacement in clinical practice: a review of suggested guidance. Thyroid Res. 2018; 11: 1.
  13. 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): 770–778.
  14. Celi FS, Zemskova M, Linderman JD, et al. Metabolic effects of liothyronine therapy in hypothyroidism: a randomized, double-blind, crossover trial of liothyronine versus levothyroxine. J Clin Endocrinol Metab. 2011; 96(11): 3466–3474.
  15. Duntas LH, Jonklaas J. Levothyroxine Dose Adjustment to Optimise Therapy Throughout a Patient's Lifetime. Adv Ther. 2019; 36(Suppl 2): 30–46.
  16. Dora J, Machado W, Rheinheimer J, et al. Association of the type 2 deiodinase Thr92Ala polymorphism with type 2 diabetes: case–control study and meta-analysis. Eur J Endocrinol. 2010; 163(3): 427–434.
  17. Hoermann R, Midgley JEM, Larisch R, et al. Individualised requirements for optimum treatment of hypothyroidism: complex needs, limited options. Drugs Context. 2019; 8: 212597.
  18. Virili C, Antonelli A, Santaguida MG, et al. Gastrointestinal Malabsorption of Thyroxine. Endocr Rev. 2019; 40(1): 118–136.
  19. Skelin M, Lucijanić T, Amidžić Klarić D, et al. Factors Affecting Gastrointestinal Absorption of Levothyroxine: A Review. Clin Ther. 2017; 39(2): 378–403.
  20. Bellastella G, Caputo M, Maiorino MI, et al. EMPATHY: A New Tool for Identifying the Most Suitable Thyroxine Formulation in Hypothyroid Patients. Thyroid. 2019; 29(7): 928–933.
  21. Benvenga S, Carlé A. Levothyroxine Formulations: Pharmacological and Clinical Implications of Generic Substitution. Adv Ther. 2019; 36(Suppl 2): 59–71.
  22. Yue CS, Scarsi C, Ducharme MP. Pharmacokinetics and potential advantages of a new oral solution of levothyroxine vs. other available dosage forms. Arzneimittelforschung. 2012; 62(12): 631–636.
  23. Formenti AM, Mazziotti G, Giubbini R, et al. Treatment of hypothyroidism: all that glitters is gold? Endocrine. 2016; 52(3): 411–413.
  24. Laurent I, Tang S, Astère M, et al. Liquid L-thyroxine versus tablet L-thyroxine in patients on L- thyroxine replacement or suppressive therapy: a meta-analysis. Endocrine. 2018; 61(1): 28–35.
  25. Fallahi P, Ferrari SM, Antonelli A. Oral L-thyroxine liquid versus tablet in patients with hypothyroidism without malabsorption: a prospective study. Endocrine. 2016; 52(3): 597–601.
  26. Ribichini D, Fiorini G, Repaci A, et al. Tablet and oral liquid L-thyroxine formulation in the treatment of naïve hypothyroid patients with Helicobacter pylori infection. Endocrine. 2017; 57(3): 394–401.
  27. Fallahi P, Ferrari SM, Antonelli A. In patients with subclinical hypothyroidism while in therapy with tablet L-T4, the liquid L-T4 formulation is more effective in restoring euthyroidism. Endocr Pract. 2017; 23(2): 170–174.
  28. Ferrara R, Ientile V, Arcoraci V, et al. Treatment pattern and frequency of serum TSH measurement in users of different levothyroxine formulations: a population-based study during the years 2009-2015. Endocrine. 2017; 58(1): 143–152.
  29. Benvenga S. Liquid and softgel capsules of l-thyroxine results lower serum thyrotropin levels more than tablet formulations in hypothyroid patients. J Clin Transl Endocrinol. 2019; 18: 100204.
  30. Giusti M, Mortara L, Machello N, et al. Utility of a Liquid Formulation of Levo-thyroxine in Differentiated Thyroid Cancer Patients. Drug Res (Stuttg). 2015; 65(6): 332–336.
  31. Cappelli C, Pirola I, Gandossi E, et al. TSH Variability of Patients Affected by Differentiated Thyroid Cancer Treated with Levothyroxine Liquid Solution or Tablet Form. Int J Endocrinol. 2017; 2017: 7053959.
  32. Fallahi P, Ferrari SM, Materazzi G, et al. Oral L-thyroxine liquid versus tablet in patients submitted to total thyroidectomy for thyroid cancer (without malabsorption): A prospective study. Laryngoscope Investig Otolaryngol. 2018; 3(5): 405–408.
  33. Cappelli C, Pirola I, Gandossi E, et al. Oral liquid levothyroxine treatment at breakfast: a mistake? Eur J Endocrinol. 2014; 170(1): 95–99.
  34. Morelli S, Reboldi G, Moretti S, et al. Timing of breakfast does not influence therapeutic efficacy of liquid levothyroxine formulation. Endocrine. 2016; 52(3): 571–578.
  35. Cappelli C, Pirola I, Daffini L, et al. A Double-Blind Placebo-Controlled Trial of Liquid Thyroxine Ingested at Breakfast: Results of the TICO Study. Thyroid. 2016; 26(2): 197–202.
  36. Guglielmi R, Grimaldi F, Negro R, et al. Shift from Levothyroxine Tablets to Liquid Formulation at Breakfast Improves Quality of Life of Hypothyroid Patients. Endocr Metab Immune Disord Drug Targets. 2018; 18(3): 235–240.
  37. Pirola I, Gandossi E, Brancato D, et al. TSH evaluation in hypothyroid patients assuming liquid levothyroxine at breakfast or 30 min before breakfast. J Endocrinol Invest. 2018; 41(11): 1301–1306.
  38. Vita R, Saraceno G, Trimarchi F, et al. Switching levothyroxine from the tablet to the oral solution formulation corrects the impaired absorption of levothyroxine induced by proton-pump inhibitors. J Clin Endocrinol Metab. 2014; 99(12): 4481–4486.
  39. Fallahi P, Ferrari SM, Camastra S, et al. TSH Normalization in Bariatric Surgery Patients After the Switch from L-Thyroxine in Tablet to an Oral Liquid Formulation. Obes Surg. 2017; 27(1): 78–82.
  40. Benvenga S, Di Bari F, Vita R. Undertreated hypothyroidism due to calcium or iron supplementation corrected by oral liquid levothyroxine. Endocrine. 2017; 56(1): 138–145.
  41. Vita R, Di Bari F, Benvenga S. Oral liquid levothyroxine solves the problem of tablet levothyroxine malabsorption due to concomitant intake of multiple drugs. Expert Opin Drug Deliv. 2017; 14(4): 467–472.
  42. Ribichini D, Fiorini G, Repaci A, et al. Tablet and oral liquid L-thyroxine formulation in the treatment of naïve hypothyroid patients with Helicobacter pylori infection. Endocrine. 2017; 57(3): 394–401.
  43. Benvenga S. Liquid and softgel capsules of l-thyroxine results lower serum thyrotropin levels more than tablet formulations in hypothyroid patients. J Clin Transl Endocrinol. 2019; 18: 100204.
  44. von Heppe JH, Krude H, L'Allemand D, et al. The use of L-T4 as liquid solution improves the practicability and individualized dosage in newborns and infants with congenital hypothyroidism. J Pediatr Endocrinol Metab. 2004; 17(7): 967–974.
  45. Cassio A, Monti S, Rizzello A, et al. Comparison between liquid and tablet formulations of levothyroxine in the initial treatment of congenital hypothyroidism. J Pediatr. 2013; 162(6): 1264–9, 1269.e1.
  46. Peroni E, Vigone MC, Mora S, et al. Congenital hypothyroidism treatment in infants: a comparative study between liquid and tablet formulations of levothyroxine. Horm Res Paediatr. 2014; 81(1): 50–54.
  47. Cappelli C, Negro R, Pirola I, et al. Levothyroxine liquid solution versus tablet form for replacement treatment in pregnant women. Gynecol Endocrinol. 2016; 32(4): 290–292.
  48. Cappelli C, Pirola I, Daffini L, et al. Thyroid hormonal profile in elderly patients treated with two different levothyroxine formulations: A single institute survey. Eur Geriatr Med. 2014; 5(6): 382–385.
  49. Morini E, Catalano A, Lasco A, et al. In thyroxine-replaced hypothyroid postmenopausal women under simultaneous calcium supplementation, switch to oral liquid or softgel capsule L-thyroxine ensures lower serum TSH levels and favorable effects on blood pressure, total cholesterolemia and glycemia. Endocrine. 2019; 65(3): 569–579.
  50. Ruchała M, Szczepanek-Parulska E, Zybek A. The influence of lactose intolerance and other gastro-intestinal tract disorders on L-thyroxine absorption. Endokrynol Pol. 2012; 63(4): 318–323.
  51. Fallahi P, Ferrari SM, Marchi S, et al. Patients with lactose intolerance absorb liquid levothyroxine better than tablet levothyroxine. Endocrine. 2017; 57(1): 175–178.
  52. Benvenga S, Capodicasa G, Perelli S, et al. Increased Requirement of Replacement Doses of Levothyroxine Caused by Liver Cirrhosis. Front Endocrinol (Lausanne). 2018; 9: 150.
  53. Benvenga S, Capodicasa G, Perelli S. l-Thyroxine in an Oral Liquid or Softgel Formulation Ensures More Normal Serum Levels of Free T4 in Patients with Central Hypothyroidism. Front Endocrinol (Lausanne). 2017; 8: 321.
  54. Pirola I, Daffini L, Gandossi E, et al. Comparison between liquid and tablet levothyroxine formulations in patients treated through enteral feeding tube. J Endocrinol Invest. 2014; 37(6): 583–587.
  55. Virili C, Trimboli P, Romanelli F, et al. Liquid and softgel levothyroxine use in clinical practice: state of the art. Endocrine. 2016; 54(1): 3–14.
  56. Hepp Z, Lage MJ, Espaillat R, et al. The association between adherence to levothyroxine and economic and clinical outcomes in patients with hypothyroidism in the US. J Med Econ. 2018; 21(9): 912–919.
  57. Castellana M, Castellana C, Giovanella L, et al. Prevalence of gastrointestinal disorders having an impact on tablet levothyroxine absorption: should this formulation still be considered as the first-line therapy? Endocrine. 2020; 67(2): 281–290.
  58. Negro R, Attanasio R, Nagy EV, et al. Use of Thyroid Hormones in Hypothyroid and Euthyroid Patients; the 2019 Italian Survey. Eur Thyroid J. 2020; 9(1): 25–31.
  59. Virili C, Giovanella L, Fallahi P, et al. Levothyroxine Therapy: Changes of TSH Levels by Switching Patients from Tablet to Liquid Formulation. A Systematic Review and Meta-Analysis. Front Endocrinol (Lausanne). 2018; 9: 10.
  60. Léger J, Olivieri A, Donaldson M, et al. ESPE-PES-SLEP-JSPE-APEG-APPES-ISPAE, Congenital Hypothyroidism Consensus Conference Group. European Society for Paediatric Endocrinology consensus guidelines on screening, diagnosis, and management of congenital hypothyroidism. J Clin Endocrinol Metab. 2014; 99(2): 363–384.

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