What are the potential side effects of Synthroid (levothyroxine) in a patient with hypothyroidism?

Side Effects of Synthroid (Levothyroxine)

Primary Side Effects from Overtreatment

The adverse reactions associated with Synthroid (levothyroxine) are primarily those of hyperthyroidism due to therapeutic overdosage, and approximately 25% of patients are unintentionally maintained on doses sufficient to fully suppress TSH, leading to serious complications. 1, 2

Cardiovascular Effects

• Palpitations, tachycardia, arrhythmias, increased pulse and blood pressure are common cardiovascular manifestations of levothyroxine overtreatment 2
• Heart failure, angina, myocardial infarction, and cardiac arrest can occur with excessive dosing, particularly in patients with underlying coronary artery disease 2
• Atrial fibrillation risk increases 3-5 fold when TSH is suppressed below 0.1-0.4 mIU/L, especially in patients over 60 years of age 1
• Prolonged TSH suppression is associated with increased cardiovascular mortality 1

Bone and Metabolic Effects

• Decreased bone mineral density and increased bone resorption occur with levothyroxine over-replacement, particularly in postmenopausal women 2
• Increased risk of osteoporotic fractures, especially hip and spine fractures in women over 65 years with TSH ≤0.1 mIU/L 1
• The increased bone resorption is associated with elevated serum calcium and phosphorous levels, increased bone alkaline phosphatase, and suppressed parathyroid hormone 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 the institution of levothyroxine therapy 2
• Tremors are common musculoskeletal manifestations 2

General Metabolic Effects

• Fatigue, increased appetite, weight loss, heat intolerance, fever, and excessive sweating reflect the hypermetabolic state 2
• Paradoxically, fatigue can occur in elderly patients with excessive thyroid hormone, creating a hypermetabolic state 1

Gastrointestinal Effects

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

Respiratory Effects

• Dyspnea can develop with overtreatment 2

Dermatologic Effects

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

Reproductive Effects

• Menstrual irregularities and impaired fertility can occur with levothyroxine therapy 2

Pediatric-Specific Adverse Reactions

• Pseudotumor cerebri and slipped capital femoral epiphysis have been reported in pediatric patients receiving levothyroxine 2
• Craniosynostosis in infants who have not undergone complete closure of the fontanelles may result from overtreatment 2
• Premature closure of the epiphyses in pediatric patients still experiencing growth, resulting in compromised adult height 2

Hypersensitivity Reactions

• Urticaria, pruritus, skin rash, flushing, and angioedema are hypersensitivity reactions to inactive ingredients 2
• Gastrointestinal symptoms (abdominal pain, nausea, vomiting, diarrhea), fever, arthralgia, serum sickness, and wheezing may occur 2
• Allergic-type reactions including bronchial asthma may occur in susceptible persons due to FD&C Yellow No. 5 (tartrazine) content, particularly in patients with aspirin hypersensitivity 2
• Hypersensitivity to levothyroxine itself is not known to occur 2

Critical Safety Considerations

Cardiac Risks in Specific Populations

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

Adrenal Crisis Risk

• Thyroid hormone increases metabolic clearance of glucocorticoids, and initiation of thyroid hormone therapy prior to glucocorticoid therapy may precipitate an acute adrenal crisis in patients with adrenal insufficiency 2
• Treat patients with adrenal insufficiency with replacement glucocorticoids prior to initiating levothyroxine 1, 2

Diabetic Control

• Addition of levothyroxine therapy in patients with diabetes mellitus may worsen glycemic control and result in increased antidiabetic agent or insulin requirements 2
• Carefully monitor glycemic control after starting, changing, or discontinuing levothyroxine 2

Common Pitfalls Leading to Side Effects

• Approximately 25% of patients on levothyroxine are unintentionally maintained on doses sufficient to fully suppress TSH, increasing risks for atrial fibrillation, osteoporosis, fractures, abnormal cardiac output, and ventricular hypertrophy 1
• Overtreatment occurs in 14-21% of treated patients, increasing risk for atrial fibrillation, osteoporosis, fractures, and cardiac complications 1
• Adjusting doses too frequently before reaching steady state (should wait 6-8 weeks between adjustments) is a common pitfall 1, 3

Monitoring to Prevent Side Effects

• Monitor TSH every 6-8 weeks while titrating hormone replacement to achieve goal TSH within the reference range (0.5-4.5 mIU/L) 1, 3
• Once adequately treated, repeat testing every 6-12 months or if symptoms change 1
• Development of low TSH on therapy suggests overtreatment; dose should be reduced or discontinued with close follow-up 1