Levothyroxine - Drug Monograph

Introduction

Levothyroxine is a synthetic form of the endogenous thyroid hormone thyroxine (T4). It is one of the most commonly prescribed medications worldwide and serves as the cornerstone of thyroid hormone replacement therapy. As a hormone medication, it requires precise dosing and careful monitoring to achieve optimal therapeutic outcomes while minimizing adverse effects.

Mechanism of Action

Levothyroxine is a prohormone that undergoes peripheral deiodination to the active form, triiodothyronine (T3). It binds to thyroid receptor proteins in the cell nucleus and exerts its effects by controlling DNA transcription and protein synthesis. The drug influences metabolic processes throughout the body, including:

• Regulation of carbohydrate, protein, and fat metabolism
• Stimulation of cellular oxygen consumption
• Regulation of growth and development
• Modulation of cardiovascular function
• Maintenance of thermogenesis

Indications

• Hypothyroidism (primary, secondary, and tertiary)
• TSH suppression in thyroid cancer management
• Thyrotropin-dependent goiter prevention and treatment
• Myxedema coma (as part of combination therapy)

• Subclinical hypothyroidism (controversial)
• Augmentation therapy in refractory depression

Dosage and Administration

• Initial dose: 1.6 mcg/kg/day (typically 25-50 mcg/day)
• Titration: Increase by 12.5-25 mcg every 4-6 weeks based on TSH levels
• Maintenance: Individualized based on clinical response and laboratory parameters

• Elderly: Start with 25-50 mcg/day due to increased cardiovascular risk
• Cardiac disease: Initiate at 12.5-25 mcg/day with careful titration
• Pregnancy: Requirements typically increase by 25-50%
• Pediatrics: Weight-based dosing (consult pediatric dosing guidelines)

• Take on empty stomach, 30-60 minutes before breakfast
• Consistent timing daily is crucial
• Avoid concurrent administration with calcium, iron, or aluminum-containing products

Pharmacokinetics

• Absorption: Variable (40-80%) from proximal small intestine; food decreases absorption by up to 40%
• Distribution: Highly protein-bound (>99%) to thyroxine-binding globulin, prealbumin, and albumin
• Metabolism: Hepatic deiodination to T3 and reverse T3; conjugation with glucuronide and sulfate
• Elimination: Primarily fecal excretion; half-life approximately 7 days in euthyroid patients
• Onset: Gradual; full therapeutic effect may take 3-6 weeks

Contraindications

• Uncorrected adrenal insufficiency
• Untreated thyrotoxicosis
• Acute myocardial infarction
• Hypersensitivity to levothyroxine or any component
• Obesity treatment in euthyroid patients

Warnings and Precautions

• Not indicated for weight loss
• Doses beyond replacement needs may cause serious life-threatening toxicity

• Cardiovascular risk: May exacerbate angina or precipitate arrhythmias
• Osteoporosis risk: Overtreatment may accelerate bone loss
• Adrenal insufficiency: May precipitate adrenal crisis in untreated patients
• Diabetes: May alter glycemic control requiring antidiabetic medication adjustment

Drug Interactions

• Antacids/Aluminum: ↓ Absorption (separate by ≥4 hours)
• Calcium carbonate: ↓ Absorption (separate by ≥4 hours)
• Cholestyramine/Colestipol: ↓ Absorption (separate by ≥4-5 hours)
• Estrogens: May increase thyroxine-binding globulin
• Iron supplements: ↓ Absorption (separate by ≥4 hours)
• Proton pump inhibitors: May decrease absorption
• Rifampin/Carbamazepine: ↑ Hepatic metabolism
• Warfarin: Potentiates anticoagulant effect

Adverse Effects

• Palpitations
• Tachycardia
• Tremors
• Headache
• Insomnia
• Increased appetite
• Weight loss
• Heat intolerance

• Cardiac arrhythmias
• Angina pectoris
• Myocardial infarction
• Heart failure
• Thyroid storm (with overdose)
• Osteoporosis (long-term overtreatment)

Monitoring Parameters

• TSH, free T4
• Cardiac evaluation in elderly or those with cardiac history
• Bone density assessment if long-term therapy anticipated

• TSH every 4-8 weeks until stable, then every 6-12 months
• Clinical assessment of euthyroid status
• Cardiac monitoring in at-risk patients
• Bone density monitoring with long-term supraphysiologic dosing

• Pregnancy: Monitor TSH every 4 weeks during first trimester
• Pediatrics: Monitor growth, development, and bone maturation

Patient Education

• Take medication consistently at the same time each day
• Administer on empty stomach with water only
• Do not stop taking without medical supervision
• Report symptoms of over- or under-treatment:

- Palpitations, chest pain, excessive sweating (overdose) - Fatigue, weight gain, cold intolerance (underdose)

• Inform all healthcare providers about thyroid medication
• Keep regular follow-up appointments for monitoring
• Be aware of potential drug interactions with common supplements

• Consistent iodine intake (avoid large fluctuations)
• Regular exercise to maintain bone health
• Balanced diet with adequate calcium and vitamin D

References

1. Jonklaas J, Bianco AC, Bauer AJ, 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. 2. Garber JR, Cobin RH, Gharib H, et al. 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. 3. FDA Prescribing Information: Levothyroxine Sodium Tablets. Revised 2022. 4. Alexander EK, Pearce EN, Brent GA, et al. 2017 Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and the Postpartum. Thyroid. 2017;27(3):315-389. 5. Wiersinga WM, Duntas L, Fadeyev V, et al. 2012 ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism. Eur Thyroid J. 2012;1(2):55-71.