Levothyroxine

Levothyroxine sodium is the synthetic sodium salt of L-thyroxine (T4), identical to the hormone produced by the thyroid gland. It has a narrow therapeutic index.

FDA-approved products include oral tablets (Synthroid, Levoxyl, Unithroid, Euthyrox and generics), oral capsules (Tirosint), oral solutions, and levothyroxine sodium for injection for intravenous use.

Oral levothyroxine is FDA-labeled as replacement therapy for primary (thyroidal), secondary (pituitary) and tertiary (hypothalamic) congenital or acquired hypothyroidism, and as an adjunct to surgery and radioiodine for TSH suppression in well-differentiated thyroid cancer.

Labeling states it is not indicated for suppression of benign thyroid nodules or nontoxic diffuse goiter in iodine-sufficient patients, or for transient hypothyroidism during recovery from subacute thyroiditis. Intravenous levothyroxine is labeled for myxedema coma.

Levothyroxine is deiodinated in peripheral tissues to triiodothyronine (T3), the principal active hormone. T3 enters the nucleus and binds thyroid hormone receptors on DNA, regulating gene transcription and protein synthesis. Effects include increased basal metabolic rate and oxygen consumption, and regulation of carbohydrate, lipid and protein metabolism, growth and development, and cardiovascular function.

Oral absorption is 40% to 80%, mainly in the jejunum and upper ileum, and increases with fasting; food, fiber, soy, coffee and binding agents reduce it. Levothyroxine is more than 99% bound to thyroxine-binding globulin, transthyretin and albumin.

It is metabolized mainly by sequential deiodination in liver, kidney and other tissues, with some conjugation and biliary excretion. Elimination is renal, with about 20% excreted in feces. The half-life is 6 to 7 days in euthyroid patients, longer in hypothyroidism and shorter in hyperthyroidism, so steady state takes about 4 to 6 weeks after a dose change.

• Uncorrected adrenal insufficiency.

• Cardiac adverse reactions in the elderly and in patients with underlying cardiovascular disease: start at a lower dose; overtreatment can cause arrhythmias, angina or myocardial infarction.
• Myxedema coma: oral thyroid hormone is not recommended; use intravenous therapy.
• Acute adrenal crisis in patients with concomitant adrenal insufficiency: treat with glucocorticoids before starting levothyroxine.
• Over- or undertreatment: the narrow therapeutic index requires careful dose adjustment, and products may not be interchangeable without monitoring.
• Worsening of diabetic control: antidiabetic requirements may increase.
• Decreased bone mineral density with overreplacement, particularly in postmenopausal women.

• Reduced absorption: calcium carbonate, ferrous sulfate and phosphate binders such as sevelamer and lanthanum; give levothyroxine at least 4 hours apart from these agents. Give levothyroxine at least 4 hours before bile acid sequestrants such as cholestyramine or colesevelam and ion exchange resins, or monitor TSH. Proton pump inhibitors, sucralfate, aluminum- and magnesium-containing antacids and orlistat can also reduce absorption; monitor thyroid function.
• Altered binding: estrogens and oral contraceptives raise thyroxine-binding globulin and may increase requirements; androgens and glucocorticoids may lower them.
• Increased metabolism: phenytoin, carbamazepine, phenobarbital and rifampin may increase requirements. Tyrosine kinase inhibitors such as imatinib may cause hypothyroidism.
• Warfarin: increased anticoagulant effect; monitor INR. Digoxin: levels may fall. Sympathomimetics and ketamine: increased risk of tachycardia and hypertension.
• Biotin can interfere with thyroid immunoassays.

Adverse reactions mainly reflect overtreatment and hyperthyroidism: palpitations, arrhythmias, tachycardia, angina, dyspnea, tremor, nervousness, anxiety, irritability, insomnia, headache, heat intolerance, sweating, increased appetite, weight loss, diarrhea, menstrual irregularities, muscle weakness and decreased bone mineral density. Partial hair loss may occur early in therapy in children; pseudotumor cerebri and slipped capital femoral epiphysis are reported in children. Hypersensitivity to inactive ingredients can occur.

Levothyroxine should not be discontinued in pregnancy; untreated maternal hypothyroidism carries risks for mother and fetus. Requirements often rise. Labeling recommends measuring TSH and free T4 when pregnancy is confirmed and at least each trimester, and returning to the prepregnancy dose after delivery with a TSH check 4 to 8 weeks postpartum.

Levothyroxine is present in human milk in small amounts, and no adverse effects in breastfed infants are reported. Adequate replacement supports normal lactation.

TSH in primary hypothyroidism, reassessed 6 to 8 weeks after any dose or product change and periodically once stable. Free T4 in secondary or tertiary hypothyroidism. TSH and free T4 each trimester in pregnancy. Clinical signs of over- or undertreatment, heart rate and rhythm in cardiac patients, glucose in diabetes, INR on warfarin, and bone health with long-term TSH suppression.

• Synthroid (levothyroxine sodium tablets) Prescribing Information, AbbVie.
• Tirosint (levothyroxine sodium capsules) Prescribing Information, IBSA Pharma.
• Levothyroxine Sodium for Injection Prescribing Information.
• Jonklaas J, et al. Guidelines for the Treatment of Hypothyroidism, American Thyroid Association. Thyroid. 2014.