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Levotyroxin

Klassificering: C

Preparat: Eltroxin, Euthyrox, Levaxin 0,1 mg u/lactose, Levaxin utan lactos, Levaxin®, Levothyroxin, Levothyroxine, Levothyroxine sodium, Levothyroxine Sodium, Levothyroxine Sodium App, Levothyroxinenatrium Teva, Levotyroxin Nycomed, L-Thyrox HEXAL, L-Thyroxin, L-Thyroxin AL, L-Thyroxin Aventis, L-Thyroxin Henning, L-Thyroxin Henning Inject, L-Thyroxine Christiaens, L-Thyroxine Serb, SYNTHROID, Tiche, Tirosint, Tirosintsol

ATC kod: H03AA01

Substanser: levotyroxin, levotyroxinnatrium (hydrat), levotyroxinnatrium, vattenfritt

Sammanfattning

Dosering är individuell och lägsta dos levotyroxin bör eftersträvas. Under graviditet och vid östrogenbehandling ökar vanligen dosbehovet på grund av höjd halt tyroxinbindande globulin vilket leder till minskad serumkoncentration av fritt tyroxin.

Vissa studier indikerar att långtidsanvändning av levotyroxin kan ge minskad bentäthet hos kvinnor, särskilt hos postmenopausala kvinnor. Ingen förändring i bentäthet sågs hos män.

Additional information

The main indication for levothyroxine is for the treatment of hypothyroidism. Patient’s sex is considered a predisposing factor for hypothyroidism (Graves’ disease), as women are affected 4 to 10 times more than men [1-3].

Pharmacokinetics and dosing

Levothyroxine treatment is individualized according to TSH levels.

A retrospective observational study (69 men, 88 premenopausal women, 91 postmenopausal women) showed that premenopausal women had a greater dose requirement (mg/kg bodyweight) of levothyroxine than men and postmenopausal women [4]. All women had a greater dose requirement than men, using ideal body weight [5] instead of actual body weight for dose calculation, in another study [6]. Similar results were also reported in patients with and without heart failure [7].

In a study (8 men, 33 women), the influence of age, weight, and patient’s sex on levothyroxine pharmacokinetics was analyzed. Patient’s sex only affected the median oral clearance rate, apparent volume of distribution, and dose-normalized peak concentration in univariate analyses. However, after adjusting for weight, patient’s sex was no longer a significant covariate. The authors concluded that physicians should consider a patient’s weight, rather than age, for estimating levothyroxine dosage requirement [10]. The sex difference in dosing disappearing when correcting the dose for weight and body surface area is also found in boys and girls [11]. In obese patients, no sex difference in weight-adjusted levothyroxine dosing was found [12].

In women on oral estrogen therapy or pregnant women, adaptation of dosage is necessary because of elevated thyroxine-binding globulin leading to decreased free thyroxine serum concentration [8]. Levothyroxine-treated pregnant women often need to increase the daily dose by 25-30%. Following delivery, levothyroxine dose should be reduced to prepregnancy levels [9].

Effects

The role of patient’s sex in disease presentation and remission rate in patients with Graves’ disease treated with antithyroid drugs (ATD) was assessed in a retrospective study (64 men, 171 women). Patient’s sex was not a predictor of remission in a univariate analysis (p=0.124) [13].

Adverse effects

A review (in total 3279 patients) described that most cross-sectional studies reported adverse effects at a larger number of bone sites in postmenopausal women, suggesting a negative influence on bone mineral density with (BMD) levothyroxine therapy. However, other cross-sectional studies found comparable results in pre- and postmenopausal women, but no effect of levothyroxine on BMD in men. This review reports no dose-response relationship [14]. The original manufacturer reports that long-term levothyroxine therapy might decrease BMD in women, particularly postmenopausal women on higher doses [15].

Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).

Other information 

A cross-sectional retrospective study (33238 men, 87165 women) examined the relationship between TSH and free T4. In individuals not receiving levothyroxine treatment, free T4 concentrations corresponded to higher median TSH in men than in women [18].

No sex differences were found in studies assessing the impact of levothyroxine treatment on depressive symptoms [19] or carotid atherosclerosis [20].

In a retrospective study in patients treated for hypothyroidism (113 men, 602 women), clinical predictors that could identify a subset of patients who might be monitored safely on a less frequent basis, were evaluated. Patient’s sex among other factors were not significantly associated with time to abnormal thyroid-stimulating hormone value (i.e. “stability over time”) [21].

In Taiwanese patients with or without hypothyroidism, patients with hypothyroidism who received thyroxine replacement therapy (TRT) had a lower risk of mortality than patients who did not receive TRT. In the sex-stratified analyses similar results were obtained (1559 men, 2493 women) [16].

Reproductive health issues

Estrogen can increase the concentration of thyroxine-binding globulin in serum. Women using contraceptives containing estrogen or hormone replacement therapy may require higher doses of levothyroxine [17]. Regarding drug-drug interactions aspects, please consult Janusmed Interactions (in Swedish, Janusmed interaktioner).

Försäljning på recept

Fler kvinnor än män hämtade ut tabletter innehållande levotyroxin (ATC-kod H03AA01) på recept i Sverige år 2020, totalt 389 511 kvinnor och 86 133 män. Det motsvarar 76 respektive 17 personer per tusen invånare. Andelen som hämtat ut läkemedel ökade med stigande ålder hos båda könen. I genomsnitt var tabletter innehållande levotyroxin 4,1 gånger vanligare hos kvinnor [22].

Uppdaterat: 2022-03-02

Litteratursökningsdatum: 2021-11-01

Referenser

  1. Weetman AP. Graves' disease. N Engl J Med. 2000;343(17):1236-48. PubMed
  2. Smith TJ, Hegedüs L. Graves' Disease. N Engl J Med. 2016;375(16):1552-1565. PubMed
  3. Marinò M, Latrofa F, Menconi F, Chiovato L, Vitti P. Role of genetic and non-genetic factors in the etiology of Graves' disease. J Endocrinol Invest. 2015;38(3):283-94. PubMed
  4. Devdhar M, Drooger R, Pehlivanova M, Singh G, Jonklaas J. Levothyroxine replacement doses are affected by gender and weight, but not age. Thyroid. 2011;21:821-7. PubMed
  5. Heiat A, National Institutes of Health (NIH: the NIH Consensus Conference on Health Implications of Obesity in 1985), United States Department of Agriculture (the 1990 Department of Agriculture's Dietary Guidelines for Americans), National Heart, Lung, and Blood Institute. Impact of age on definition of standards for ideal weight. Prev Cardiol. 2003;6(2):104-7. PubMed
  6. Jonklaas J. Sex and age differences in levothyroxine dosage requirement. Endocr Pract. 2010;16:71-9. PubMed
  7. Yang T, Ruegger M, Colavecchia AC, Sadhu A, Patham B, Tatara A. Comparison of Levothyroxine Dosing in Patients with and without Heart Failure. Endocr Res. 2020;45(1):50-57. PubMed
  8. Arafah BM. Increased need for thyroxine in women with hypothyroidism during estrogen therapy. N Engl J Med. 2001;344:1743-9. PubMed
  9. Stagnaro-Green A, Abalovich M, Alexander E, Azizi F, Mestman J, Negro R et al. Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid. 2011;21:1081-125. PubMed
  10. Younis IR, Ahmed MA, Burman KD, Soldin OP, Jonklaas J. Stable Isotope Pharmacokinetic Studies Provide Insight into Effects of Age, Sex, and Weight on Levothyroxine Metabolism. Thyroid. 2018;28(1):41-49. PubMed
  11. Singh R. Determinants of levothyroxine dose required to achieve euthyroidism in pediatric population-a hospital-based prospective follow-up study. Eur J Pediatr. 2017;176(8):1027-1033. PubMed
  12. Mele C, Tagliaferri MA, Pagano L, Soranna D, Scacchi M, Aimaretti G et al. Levothyroxine Replacement in Obese Adults: The Role of Metabolic Variables and Aging on Thyroid Testing Abnormalities. J Clin Endocrinol Metab. 2019;104(12):6265-6274. PubMed
  13. Diker-Cohen T, Duskin-Bitan H, Shimon I, Hirsch D, Akirov A, Tsvetov G et al. DISEASE PRESENTATION AND REMISSION RATE IN GRAVES DISEASE TREATED WITH ANTITHYROID DRUGS: IS GENDER REALLY A FACTOR?. Endocr Pract. 2019;25(1):43-50. PubMed
  14. Schneider R, Reiners C. The effect of levothyroxine therapy on bone mineral density: a systematic review of the literature. Exp Clin Endocrinol Diabetes. 2003;111:455-70. PubMed
  15. Levoxyl (levothyroxine). DailyMed [www]. US National Library of Medicine. [updated 2020-12-15, cited 2021-11-10]. länk
  16. Huang HK, Wang JH, Kao SL. Association of Hypothyroidism With All-Cause Mortality: A Cohort Study in an Older Adult Population. J Clin Endocrinol Metab. 2018;103(9):3310-3318. PubMed
  17. LEVAXIN (levotyroxin). Summary of Product Characteristics. Swedish Medical Products Agency [updated 2020-02-04, cited 2021-11-20]
  18. Hadlow NC, Rothacker KM, Wardrop R, Brown SJ, Lim EM, Walsh JP. The relationship between TSH and free T₄ in a large population is complex and nonlinear and differs by age and sex. J Clin Endocrinol Metab. 2013;98:2936-43. PubMed
  19. Wildisen L, Feller M, Del Giovane C, Moutzouri E, Du Puy RS, Mooijaart SP et al. Effect of Levothyroxine Therapy on the Development of Depressive Symptoms in Older Adults With Subclinical Hypothyroidism: An Ancillary Study of a Randomized Clinical Trial. JAMA Netw Open. 2021;4(2):e2036645. PubMed
  20. Blum MR, Gencer B, Adam L, Feller M, Collet TH, da Costa BR et al. Impact of Thyroid Hormone Therapy on Atherosclerosis in the Elderly With Subclinical Hypothyroidism: A Randomized Trial. J Clin Endocrinol Metab. 2018;103(8):2988-2997. PubMed
  21. Pecina J, Garrison GM, Bernard ME. Levothyroxine dosage is associated with stability of thyroid-stimulating hormone values. Am J Med. 2014;127(3):240-5. PubMed
  22. Statistikdatabas för läkemedel. Stockholm: Socialstyrelsen. 2020 [cited 2021-03-10.] länk

Författare: Diana Rydberg, Linnéa Karlsson Lind

Faktagranskat av: Carl-Olav Stiller

Godkänt av: Karin Schenck-Gustafsson