Levothyroxine (T4 / Synthroid) — Standard Thyroid Replacement — Thyroid Hormones
Prodrug thyroid hormone and the most prescribed hormone in the world. FDA-approved for hypothyroidism. Gold standard treatment.
Overview
Levothyroxine sodium is the synthetic form of thyroxine (T4), the predominant thyroid hormone produced by the thyroid gland. It is the most prescribed medication in the United States and the gold standard treatment for hypothyroidism worldwide. T4 is a prodrug that is converted to the active hormone triiodothyronine (T3) by tissue deiodinases (DIO1, DIO2, DIO3). Approximately 80% of circulating T3 is derived from peripheral T4-to-T3 conversion. Levothyroxine has a long half-life of approximately 6-7 days, providing stable hormone levels with once-daily dosing. Full replacement doses are approximately 1.6 mcg/kg/day, though individual requirements vary based on age, weight, pregnancy status, malabsorption, and residual thyroid function. Multiple brand and generic formulations exist (Synthroid, Levoxyl, Tirosint, Unithroid), with the FDA requiring bioequivalence within narrow limits. However, some patients report differences between brands, and the ATA recommends maintaining consistent formulation. Levothyroxine absorption is affected by food, coffee, calcium, iron, PPIs, and other medications — consistent timing relative to meals is essential. Overreplacement (suppressed TSH) increases risks of atrial fibrillation and osteoporosis, particularly in elderly patients.
Indications
- FDA-approved: Hypothyroidism (primary, secondary, tertiary)
- FDA-approved: TSH suppression in thyroid cancer management
- FDA-approved: Myxedema coma (IV, in conjunction with T3)
- Off-label: Subclinical hypothyroidism (TSH 5-10 mIU/L, symptomatic)
Mechanism of Action
Levothyroxine is absorbed in the jejunum and ileum with approximately 40-80% bioavailability, highly dependent on fasting state and GI conditions
Dosing
| Compound | Dose | Frequency | Notes |
|---|---|---|---|
| Levothyroxine | 25-50 mcg | Once daily (empty stomach) | Starting dose for elderly or cardiac patients |
| Levothyroxine | 1.6 mcg/kg/day | Once daily (empty stomach) | Full replacement dose estimate for healthy adults |
| Levothyroxine gel cap | Individualized | Once daily | Gel capsule — better absorption in malabsorption or PPI use |
Evidence Grade
GRADE A
Safety & Contraindications
- Narrow therapeutic index — dose adjustments in 12.5-25 mcg increments
- Overreplacement risk: atrial fibrillation, osteoporosis, anxiety, insomnia
- Underreplacement: persistent hypothyroid symptoms, weight gain, fatigue
- Absorption affected by food, coffee, calcium, iron, PPIs — take on empty stomach
- Cardiac risk in elderly: start at low dose (25-50 mcg) and titrate slowly
- Drug interactions: warfarin (increased effect), diabetes medications (increased requirements)
- Pregnancy: requirements increase 30-50% — monitor TSH frequently