Skip to main content

Advertisement

Log in

Liquid and softgel levothyroxine use in clinical practice: state of the art

  • Review
  • Published:
Endocrine Aims and scope Submit manuscript

Abstract

Levothyroxine is recognized as the treatment of choice for hypothyroidism. So far, the tablet levothyroxine has been the formulation almost exclusively used, even though an optimal daily dose of levothyroxine has been unsuccessfully sought and a consensus not achieved. Due to progressive use of a more individually tailored levothyroxine dose, increasing evidence has instead displayed that many gastrointestinal disorders, polypharmacy, and food interference may raise the daily levothyroxine requirement. In recent years, alternative levothyroxine formulations have become available and have rapidly gained attention because of their pharmacokinetic properties. This study aims to provide an overview regarding the use of softgel capsule and/or liquid levothyroxine solution while performing a review of published studies about such topic. A comprehensive computer literature search of the PubMed/MEDLINE, Scopus, and Google Scholar databases has been conducted to find published articles on this topic. The search algorithm was based on the combinations of the following terms: “oral solution” or “soft gel” or “liquid”, and “levothyroxine”. The computer search resulted in 75 articles; through a critical review of such titles and abstracts and a screening of their references lists, the review included 18 original articles relating to 800 patients treated with alternative formulations. Despite some limits, the results obtained using softgel and liquid levothyroxine were consistent with each other. In selected categories of levothyroxine-treated patients (pediatric, suffering from hypo-achlorhydria, polypharmacy, undergone bariatric surgery, fed through enteric tube) these new formulations have shown promising attributes in improving a treatment that needs to be individually tailored.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. J.R. Garber, R.H. Cobin, H. Gharib, J.V. Hennessey, I. Klein, J.I. Mechanick, R. Pessah-Pollack, P.A. Singer, K.A. Woeber; 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. Thyroid 22, 1200–1235 (2012). doi:10.1089/thy.2012.0205

    Article  CAS  PubMed  Google Scholar 

  2. E. Fiore, T. Rago, M.A. Provenzale, M. Scutari, C. Ugolini, F. Basolo, G. Di Coscio, P. Miccoli, L. Grasso, A. Pinchera, P. Vitti, L-thyroxine-treated patients with nodular goiter have lower serum TSH and lower frequency of papillary thyroid cancer: results of a cross-sectional study on 27914 patients. Endocr. Relat. Cancer 17, 231–239 (2010)

    Article  CAS  PubMed  Google Scholar 

  3. D.S. Cooper, G.M. Doherty, B.R. Haugen, R.T. Kloos, S.L. Lee, S.J. Mandel, E.L. Mazzaferri, B. McIver, F. Pacini, M. Schlumberger, S.I. Sherman, D.L. Steward, R.M. Tuttle; American Thyroid Association (ATA) Guidelines Taskforce on Thyroid Nodules and Differentiated Thyroid Cancer, Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 19, 1167–1214 (2009)

    Article  PubMed  Google Scholar 

  4. L. Hegedus, S.J. Bonnema, F.N. Bennedbæk, Management of simple nodular goiter: current status and future perspectives. Endocr. Rev. 24, 102–132 (2003)

    Article  PubMed  Google Scholar 

  5. Medicine Use and Shifting Costs of Healthcare. Report by the IMS Institute for Healthcare Informatics (2014) http://www.imshealth.com/deployedfiles/imshealth/Global/Content/Corporate/IMSHealthInstitute/Reports/Secure/IIHI_US_Use_of_Meds_for_2013.pdf. Accessed 13 May 2015

  6. W.E. Visser, E.C. Friesema, T.J. Visser, Minireview: thyroid hormone transporters: the knowns and the unknowns. Mol. Endocrinol. 25, 1–14 (2011). doi:10.1210/me.2010-0095

    Article  CAS  PubMed  Google Scholar 

  7. M.T. Hays, Thyroid hormone and the gut. Endocr. Res. 14, 203–224 (1988)

    Article  CAS  PubMed  Google Scholar 

  8. S. Benvenga, L. Bartolone, S. Squadrito, F. Lo Giudice, F. Trimarchi, Delayed intestinal absorption of levothyroxine. Thyroid 5, 249–253 (1995)

    Article  CAS  PubMed  Google Scholar 

  9. B. Biondi, L. Wartofsky, Treatment with thyroid hormone. Endocr. Rev. 35, 433–512 (2014). doi:10.1210/er.2013-1083

    Article  CAS  PubMed  Google Scholar 

  10. B. Biondi, D.S. Cooper, The clinical significance of subclinical thyroid dysfunction. Endocr. Rev. 29, 76–131 (2008). doi:http://dx.doi.org/10.1210/er.2006-0043

    Article  CAS  PubMed  Google Scholar 

  11. G. Mercuro, M.G. Panzuto, A. Bina, M. Leo, R. Cabula, L. Petrini, F. Pigliaru, S. Mariotti, Cardiac function, physical exercise capacity, and quality of life during long-term thyrotropin-suppressive therapy with levothyroxine: effect of individual dose tailoring. J. Clin. Endocrinol. Metab. 85, 159–164 (2000)

    Article  CAS  PubMed  Google Scholar 

  12. S. Benvenga, When thyroid hormone replacement is ineffective? Curr. Opin. Endocrinol. Diabetes Obes. 20, 467–477 (2013)

    Article  CAS  PubMed  Google Scholar 

  13. M. Centanni, L. Gargano, G. Canettieri, N. Viceconti, A. Franchi, G. Delle Fave, B. Annibale, Thyroxine in goiter, Helicobacter pylori infection, and chronic gastritis. N. Engl. J. Med. 354, 1787–1795 (2006)

    Article  CAS  PubMed  Google Scholar 

  14. E. Lahner, C. Virili, M.G. Santaguida, B. Annibale, M. Centanni, Helicobacter pylori infection and drugs malabsorption. World J. Gastroenterol. 20, 10331–10337 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. S. Checchi, A. Montanaro, L. Pasqui, C. Ciuoli, V. De Palo, M.C. Chiappetta, F. Pacini, L-thyroxine requirement in patients with autoimmune hypothyroidism and parietal cell antibodies. J. Clin. Endocrinol. Metab. 93, 465–469 (2008). doi:http://dx.doi.org/10.1210/jc.2007-1544

    Article  CAS  PubMed  Google Scholar 

  16. M. Cellini, M.G. Santaguida, I. Gatto, C. Virili, S.C. Del Duca, N. Brusca, S. Capriello, L. Gargano, M. Centanni, Systematic appraisal of lactose intolerance as cause of increased need for oral thyroxine. J. Clin. Endocrinol. Metab. 99, E1454–E1458 (2014). doi:10.1210/jc.2014-1217

    Article  CAS  PubMed  Google Scholar 

  17. C. Virili, G. Bassotti, M.G. Santaguida, R. Iuorio, S.C. Del Duca, V. Mercuri, A. Picarelli, P. Gargiulo, L. Gargano, M. Centanni, Atypical celiac disease as cause of increased need for thyroxine: a systematic study. J. Clin. Endocrinol. Metab. 97, E419–E422 (2012). doi:10.1210/jc.2011-1851

    Article  CAS  PubMed  Google Scholar 

  18. R. Radaeli, F. de, L.A. Diehl, Increased levothyroxine requirement in a woman with previously well-controlled hypothyroidism and intestinal giardiasis. Arq. Bras. Endocrinol. Metabol. 55, 81–84 (2011)

    Article  Google Scholar 

  19. R. Padwal, D. Brocks, A.M. Sharma, A systematic review of drug absorption following bariatric surgery and its theoretical implications. Obes. Rev. 11, 41–50 (2010). doi:10.1111/j.1467-789X.2009.00614.x

    Article  CAS  PubMed  Google Scholar 

  20. L. Liwanpo, J.M. Hershman, Conditions and drugs interfering with thyroxine absorption. Best Pract. Res. Clin. Endocrinol. Metab. 23, 781–792 (2009)

    Article  CAS  PubMed  Google Scholar 

  21. P. Colucci, C.S. Yue, M.P. Ducharme, S. Benvenga, A review of the pharmacokinetics of levothyroxine for the treatment of hypothyroidism. Eur. J. Endocrinol. 9, 40–47 (2013)

    Article  Google Scholar 

  22. R. Vita, P. Fallahi, A. Antonelli, S. Benvenga, The administration of L-thyroxine as soft gel capsule or liquid solution. Expert Opin. Drug Deliv. 11, 1103–1111 (2014). doi:10.1517/17425247.2014.918101

    Article  CAS  PubMed  Google Scholar 

  23. F. Santini, A. Pinchera, A. Marsili, G. Ceccarini, M.G. Castagna, R. Valeriano, M. Giannetti, D. Taddei, R. Centoni, G. Scartabelli, T. Rago, C. Mammoli, R. Elisei, P. Vitti, Lean body mass is a major determinant of levothyroxine dosage in the treatment of thyroid diseases. J. Clin. Endocrinol. Metab. 90, 124–127 (2005). doi:http://dx.doi.org/10.1210/jc.2004-1306

    Article  CAS  PubMed  Google Scholar 

  24. M. Centanni, Thyroxine treatment: absorption, malabsorption, and novel therapeutic approaches. Endocrine 43, 8–9 (2013). doi:10.1007/s12020-012-9814-9

    Article  CAS  PubMed  Google Scholar 

  25. C.S. Yue, C. Scarsi, M.P. Ducharme, Pharmacokinetics and potential advantages of a new oral solution of levothyroxine vs. other available dosage forms. Arzneimittelforschung 62, 631–636 (2012). doi:10.1055/s-0032-1329951

    Article  CAS  PubMed  Google Scholar 

  26. P. Colucci, P. D’Angelo, G. Mautone, C. Scarsi, M.P. Ducharme, Pharmacokinetic equivalence of a levothyroxine sodium soft capsule manufactured using the new food and drug administration potency guidelines in healthy volunteers under fasting conditions. Ther. Drug Monit. 33, 355–361 (2011). doi:10.1097/FTD.0b013e318217b69f

    Article  CAS  PubMed  Google Scholar 

  27. J.H. von Heppe, H. Krude, D. L’Allemand, D. Schnabel, A. Grüters, 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. 17, 967–974 (2004)

    Google Scholar 

  28. A. Cassio, S. Monti, A. Rizzello, I. Bettocchi, F. Baronio, G. D’Addabbo, M.O. Bal, A. Balsamo, Comparison between liquid and tablet formulations of levothyroxine in the initial treatment of congenital hypothyroidism. J. Pediatr. 162, 1264–1269 (2013). doi:10.1016/j.jpeds.2012.11.070

    Article  CAS  PubMed  Google Scholar 

  29. E. Peroni, M.C. Vigone, S. Mora, L.A. Bassi, C. Pozzi, A. Passoni, G. Weber, Congenital hypothyroidism treatment in infants: a comparative study between liquid and tablet formulations of levothyroxine. Horm. Res. Paediatr. 81, 50–54 (2014). doi:10.1159/000356047

    Article  CAS  PubMed  Google Scholar 

  30. D. Brancato, A. Scorsone, G. Saura, L. Ferrara, A. Di Noto, V. Aiello, M. Fleres, V. Provenzano, Comparison of TSH levels with liquid formulation versus tablet formulations of levothyroxine in the treatment of adult hypothyroidism. Endocr. Pract. 20, 657–662 (2014). doi:10.4158/EP13418.OR

    Article  PubMed  Google Scholar 

  31. R. Negro, R. Valcavi, D. Agrimi, K.A. Toulis, Levothyroxine liquid solution versus tablet for replacement treatment in hypothyroid patients. Endocr. Pract. 20, 901–906 (2014). doi:10.4158/EP13378.OR

    Article  PubMed  Google Scholar 

  32. Fallahi P, Ferrari SM, Antonelli A. Oral L-thyroxine liquid versus tablet in patients with hypothyroidism without malabsorption: a prospective study. Endocrine (2015) doi:10.1007/s12020-015-0836-y

  33. Vita R., Saraceno G., Trimarchi F., Benvenga S.: A novel formulation of L-thyroxine (L-T4) reduces the problem of L-T4 malabsorption by coffee observed with traditional tablet formulations. Endocrine 43, 154-160 (2013) doi:10.1007/s12020-012-9772-2

  34. C. Cappelli, I. Pirola, E. Gandossi, A. Formenti, M. Castellano, Oral liquid levothyroxine treatment at breakfast: a mistake?. Eur. J. Endocrinol. 170, 95–99 (2013). doi:10.1530/EJE-13-0693

    Article  PubMed  Google Scholar 

  35. Morelli S., Reboldi G., Moretti S., Menicali E., Avenia N., Puxeddu E.: Timing of breakfast does not influence therapeutic efficacy of liquid levothyroxine formulation. Endocrine (2015) doi:10.1007/s12020-015-0788-2

  36. C. Cappelli, I. Pirola, L. Daffini, A. Formenti, C. Iacobello, A. Cristiano, E. Gandossi, E. Agabiti Rosei, M. Castellano, A double-blind placebo-controlled trial of liquid thyroxine ingested at breakfast: results of the TICO study. Thyroid 26, 197–202 (2016). doi:10.1089/thy.2015.0422

    Article  CAS  PubMed  Google Scholar 

  37. M.G. Santaguida, C. Virili, S.C. Duca, M. Cellini, I. Gatto, N. Brusca, C. De Vito, L. Gargano, M. Centanni, Thyroxine softgel capsule in patients with gastric-related T4 malabsorption. Endocrine 49, 51–57 (2015). doi:10.1007/s12020-014-0476-7

    Article  CAS  PubMed  Google Scholar 

  38. P. Fallahi, S.M. Ferrari, I. Ruffilli, A. Antonelli, Reversible normalisation of serum TSH levels in patients with autoimmune atrophic gastritis who received L-T4 in tablet form after switching to an oral liquid formulation: a case series. BMC Gastroenterol. 24, 16–22 (2016). doi:10.1186/s12876-016-0439-y

    Google Scholar 

  39. R. Vita, G. Saraceno, F. Trimarchi, S. Benvenga, 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. 99, 4481–4486 (2014). doi:10.1210/jc.2014-2684

    Article  CAS  PubMed  Google Scholar 

  40. M. Giusti, L. Mortara, N. Machello, E. Monti, G. Pera, M. Marenzana, Utility of a liquid formulation of levo-thyroxine in differentiated thyroid cancer patients. Drug Res. 65, 332–336 (2014). doi:10.1055/s-0034-1384535

    Article  Google Scholar 

  41. I. Pirola, A.M. Formenti, E. Gandossi, F. Mittempergher, C. Casella, B. Agosti, C. Cappelli, Oral liquid L-thyroxine (L-T4) may be better absorbed compared to L-T4 tablets following bariatric surgery. Obes. Surg. 23, 1493–1496 (2013). doi:10.1007/s11695-013-1015-y

    Article  PubMed  PubMed Central  Google Scholar 

  42. I. Pirola, L. Daffini, E. Gandossi, D. Lombardi, A. Formenti, M. Castellano, C. Cappelli, Comparison between liquid and tablet levothyroxine formulations in patients treated through enteral feeding tube. J. Endocrinol. Invest. 37, 583–587 (2014). doi:10.1007/s40618-014-0082-9

    Article  CAS  PubMed  Google Scholar 

  43. C. Cappelli, I. Pirola, L. Daffini, E. Gandossi, B. Agosti, M. Castellano, Thyroid hormonal profile in elderly patients treated with two different levothyroxine formulations: A single institute survey. Eur. Geriatr. Med. 5, 382–385 (2014)

    Article  Google Scholar 

  44. C. Cappelli, R. Negro, I. Pirola, E. Gandossi, B. Agosti, M. Castellano, Levothyroxine liquid solution versus tablet form for replacement treatment in pregnant women. Gynecol. Endocrinol. 20, 1–3 (2015)

    Google Scholar 

  45. G. Ford, S.H. LaFranchi, Screening for congenital hypothyroidism: a worldwide view of strategies. Best Pract. Res. Clin. Endocrinol. Metab. 28, 175–187 (2014). doi:10.1016/j.beem.2013.05.008

    Article  CAS  PubMed  Google Scholar 

  46. J.E. Toublanc, J.C. Job, J.L. Chaussain, P. Canlorbe, Treatment of congenital hypothyroidism by L-thyroxine in solution. Posology. Arch. Fr. Pediatr. 40, 379–383 (1983)

    CAS  PubMed  Google Scholar 

  47. G. Touati, J. Léger, J.E. Toublanc, J.P. Farriaux, C. Stuckens, C. Ponte, M. David, P. Rochiccioli, D. Porquet, P. Czernichow, A thyroxine dosage of 8 micrograms/kg per day is appropriate for the initial treatment of the majority of infants with congenital hypothyroidism. Eur. J. Pediatr. 156, 94–98 (1997)

    Article  CAS  PubMed  Google Scholar 

  48. No authors listed, Ethanol in liquid preparations intended for children. Pediatrics 73, 405–407 (1984)

    Google Scholar 

  49. S. Benvenga, L. Bartolone, M.A. Pappalardo, A. Russo, D. Lapa, G. Giorgianni, G. Saraceno, F. Trimarchi, Altered intestinal absorption of L-thyroxine caused by coffee. Thyroid 18, 293–301 (2008). doi:10.1089/thy.2007.0222

    Article  CAS  PubMed  Google Scholar 

  50. A. Magreni, D.V. Bann, J.R. Schubart, D. Goldenberg, The Effects of Race and Ethnicity on Thyroid Cancer Incidence. JAMA Otolaryngol. Head Neck Surg. 141, 319–323 (2015). doi:10.1001/jamaoto.2014.3740

    Article  PubMed  Google Scholar 

  51. K. Boelaert, Thyroid dysfunction in the elderly. Nat. Rev. Endocrinol. 9, 194–204 (2013). doi:10.1038/nrendo.2013.30

    Article  CAS  PubMed  Google Scholar 

  52. L.S. Ward, The difficult patient: drug interaction and the influence of concomitant diseases on the treatment of hypothyroidism. Arq. Bras. Endocrinol. Metabol. 54, 435–442 (2010)

    Article  PubMed  Google Scholar 

  53. P.J. Kim, I. Sachmechi, Levothyroxine malabsorption induced by diabetic gastroparesis exacerbated during pregnancies: effect of intramuscular levothyroxine injections and levothyroxine soft gel capsules. AACE Clin. Case Rep. 1, e73–e78 (2015)

    Article  Google Scholar 

  54. R. Vita, S. Benvenga, Tablet levothyroxine (L-T4) malabsorption induced by proton pump inhibitor; a problem that was solved by switching to L-T4 in soft gel capsule. Endocr. Pract. 20, e38–e41 (2014)

    Article  PubMed  Google Scholar 

  55. R.B. Shah, J.S. Collier, V.A. Sayeed, A. Bryant, M.J. Habib, M.A. Khan, Tablet splitting of a narrow therapeutic index drug: a case with levothyroxine sodium. AAPS PharmSciTech 11, 1359–1367 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. J. Jonklaas, A.C. Bianco, A.J. Bauer, K.D. Burman, A.R. Cappola, F.S. Celi, D.S. Cooper, B.W. Kim, R.P. Peeters, M.S. Rosenthal, A.M. Sawka; American Thyroid Association Task Force on Thyroid Hormone Replacement., Guidelines for the treatment of hypothyroidism: prepared by the american thyroid association task force on thyroid hormone replacement. Thyroid 24, 1670–1751 (2014). doi:10.1089/thy.2014.0028

    Article  PubMed  PubMed Central  Google Scholar 

  57. A.M. Formenti, G. Mazziotti, R. Giubbini, A. Giustina, Treatment of hypothyroidism: all that glitters is gold? Endocrine 2016 Feb 29. [Epub ahead of print] doi:10.1007/s12020-016-0882-0

  58. L.M. Brown, Helicobacter pylori: epidemiology and routes of transmission. Epidemiol. Rev. 22, 283–297 (2000)

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgment

The support of Mrs Valeria Cervetti in revising the manuscript is gratefully acknowledged.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Marco Centanni.

Ethics declarations

Conflict of interest

MC received honorarium from AKRIMAX Pharmaceuticals, LLC, Cranford, NJ 07016 USA. All the remaining authors have no conflict of interest to disclose.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Virili, C., Trimboli, P., Romanelli, F. et al. Liquid and softgel levothyroxine use in clinical practice: state of the art. Endocrine 54, 3–14 (2016). https://doi.org/10.1007/s12020-016-1035-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12020-016-1035-1

Keywords

Navigation