What are the common side effects of levothyroxine (T4) therapy?

Levothyroxine Side Effects

Primary Side Effects from Therapeutic Overdose

The adverse effects of levothyroxine are primarily manifestations of iatrogenic hyperthyroidism due to excessive dosing, which occurs in approximately 25% of patients who are unintentionally maintained on doses high enough to suppress TSH completely 1, 2.

Cardiovascular Effects

• Palpitations, tachycardia, arrhythmias, increased pulse and blood pressure are common cardiovascular manifestations of levothyroxine overdose 2
• Heart failure, angina, myocardial infarction, and cardiac arrest can occur in severe cases, particularly in patients with pre-existing coronary artery disease 2
• Atrial fibrillation risk increases significantly with TSH suppression, especially in elderly patients 1, 3
• Left ventricular hypertrophy and abnormal cardiac output may develop with prolonged TSH suppression 1, 4
• Shortened systolic time intervals typical of hyperthyroidism occur even in patients considered "euthyroid" on replacement doses 5

Musculoskeletal and Bone Effects

• Decreased bone mineral density and increased bone resorption occur with levothyroxine over-replacement, particularly in post-menopausal women 2
• Osteoporotic fractures are a significant risk even with slight overdose, especially in elderly and postmenopausal women 1, 3
• Tremors, muscle weakness, and muscle spasm are common manifestations 2
• Increased serum calcium and phosphorous levels with elevated bone alkaline phosphatase and suppressed parathyroid hormone occur with over-replacement 2

Neurological and Psychiatric Effects

• Headache, hyperactivity, nervousness, anxiety, irritability, emotional lability, and insomnia are central nervous system manifestations 2
• Seizures have been reported rarely with institution of levothyroxine therapy 2

Metabolic and General Effects

• Fatigue, increased appetite, weight loss, heat intolerance, fever, and excessive sweating are general manifestations of overdose 2
• Worsening of glycemic control in patients with diabetes mellitus may occur, requiring increased antidiabetic agent or insulin requirements 2

Gastrointestinal Effects

• Diarrhea, vomiting, abdominal cramps, and elevations in liver function tests can occur 2

Dermatologic Effects

• Hair loss, flushing, and rash are reported dermatologic manifestations 2

Reproductive Effects

• Menstrual irregularities and impaired fertility may occur 2

Critical Warnings and Special Situations

Acute Adrenal Crisis Risk

• Thyroid hormone increases metabolic clearance of glucocorticoids, and initiating levothyroxine before glucocorticoid therapy can precipitate acute adrenal crisis in patients with adrenal insufficiency 2
• Patients with adrenal insufficiency must receive replacement glucocorticoids prior to starting levothyroxine 6, 1, 2

Cardiac Monitoring Requirements

• Monitor for cardiac arrhythmias during surgical procedures in patients with coronary artery disease receiving suppressive levothyroxine therapy 2
• If cardiac symptoms develop or worsen, reduce the levothyroxine dose or withhold for one week and restart at a lower dose 2

Pediatric-Specific Adverse Effects

• Pseudotumor cerebri and slipped capital femoral epiphysis have been reported in pediatric patients 2
• Craniosynostosis in infants who have not undergone complete closure of fontanelles can occur with overtreatment 2
• Premature closure of epiphyses in pediatric patients still experiencing growth results in compromised adult height 2

Hypersensitivity Reactions to Inactive Ingredients

• Urticaria, pruritus, skin rash, flushing, and angioedema can occur as reactions to inactive ingredients 2
• Gastrointestinal symptoms (abdominal pain, nausea, vomiting, diarrhea), fever, arthralgia, serum sickness, and wheezing have been reported 2
• This product contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions including bronchial asthma in susceptible persons, particularly those with aspirin hypersensitivity 2
• Hypersensitivity to levothyroxine itself is not known to occur 2

Common Pitfalls Leading to Adverse Effects

Overtreatment

• About 25% of patients on levothyroxine are unintentionally maintained on doses sufficient to fully suppress TSH, increasing risks for osteoporosis, fractures, and cardiac complications 1, 7
• Overtreatment occurs in 14-21% of treated patients and increases risk for atrial fibrillation, osteoporosis, and fractures 1

Drug Interactions Affecting Absorption

• Phosphate binders (calcium carbonate, ferrous sulfate), bile acid sequestrants, proton pump inhibitors, sucralfate, and antacids can reduce levothyroxine absorption 2
• Administer levothyroxine at least 4 hours apart from these agents 2

Monitoring Failures

• Adjusting doses too frequently before reaching steady state (should wait 6-8 weeks between adjustments) leads to inappropriate dosing 1
• Failure to monitor TSH regularly (every 6-8 weeks during titration, then every 6-12 months) contributes to over- or under-treatment 1