Levothyroxine

Levothyroxine is synthetic thyroxine (T4) and the treatment of choice for hypothyroidism in all age groups. A long half-life allows once-daily dosing, and conversion to triiodothyronine (T3) in tissues provides physiological T3. Weight-based dosing, absorption on an empty stomach and spacing from interacting drugs are the main prescribing points. It is not an agent for obesity or weight loss, and large doses are toxic.

Classification. Thyroid hormone, T4. Tablets in strengths of 12.5 to 300 micrograms (strengths vary by market); oral solution; soft capsules; intravenous powder or solution (100 and 500 micrograms) for myxoedema coma.

Mechanism. Converted by deiodinases (type 1 and type 2) to T3, which binds nuclear thyroid hormone receptors and regulates gene transcription for metabolic rate, cardiac output, growth and brain development.

Pharmacodynamics. Raises basal metabolic rate, heart rate and cardiac output, lowers TSH through negative feedback, and corrects hypothyroid symptoms over 6 to 12 weeks. Full steady state needs about 6 weeks.

Pharmacokinetics. Oral absorption 40 to 80% (about 70% fasting) in the jejunum and ileum, falling with food, calcium, iron, antacids and some gut disease. Over 99.9% protein bound. Half-life about 6 to 7 days. Metabolised by deiodination in liver, kidney and tissues; excreted in urine and faeces.

Hypothyroidism, adults (first line).

• Full replacement about 1.6 micrograms/kg/day orally once daily, usually 75 to 150 micrograms. Use lean body weight in obesity.
• Young and healthy adults: start at about 1.6 micrograms/kg/day, or 50 to 100 micrograms daily.
• Older adults (over 65 to 70 years), and anyone with coronary disease or arrhythmia: start 12.5 to 25 micrograms daily and increase by 12.5 to 25 micrograms every 6 to 8 weeks.
• Adjust the dose by 12.5 to 25 micrograms every 6 to 8 weeks to a TSH in the reference range (usually 0.4 to 4 mIU/L, with 0.5 to 2.5 mIU/L as a common target in younger adults). In people over 70 years a TSH up to 6 mIU/L can be acceptable.
• Maximum usual dose about 2 micrograms/kg/day; needs over this suggest non-adherence, poor absorption or interacting drugs.

Subclinical hypothyroidism.

• Treat if TSH is over 10 mIU/L on repeated testing, or if TSH is 4 to 10 mIU/L with symptoms, positive thyroid peroxidase antibodies, goitre, pregnancy or planned pregnancy, or high cardiovascular risk. Start 25 to 50 micrograms daily; use lower doses in older adults. Avoid treating a mildly raised TSH in people over 70 years without symptoms.

Central hypothyroidism.

• Start the corticosteroid first when adrenal insufficiency is possible. Adjust the levothyroxine dose to free T4 in the upper half of the reference range, since TSH is unreliable.

Pregnancy.

• In pre-existing hypothyroidism, increase the dose by about 25 to 30% (two extra tablets weekly) as soon as pregnancy is confirmed. Check TSH every 4 weeks up to 20 weeks and at least once at 26 to 32 weeks, targeting a TSH in the lower half of the trimester-specific range (or under 2.5 mIU/L). Return to the pre-pregnancy dose after delivery and check TSH at 6 weeks.

Congenital and childhood hypothyroidism.

• Newborns: 10 to 15 micrograms/kg/day, started as soon as possible after diagnosis. Ages 1 to 5 years: 5 to 6 micrograms/kg/day; 6 to 12 years: 4 to 5 micrograms/kg/day; over 12 years with growth incomplete: 2 to 3 micrograms/kg/day; growth complete: 1.6 micrograms/kg/day. Directed by a paediatric endocrinologist, with frequent TSH and free T4 checks.

Thyroid cancer, TSH suppression (specialist).

• 2 to 2.5 micrograms/kg/day to a TSH target set by risk (under 0.1 mIU/L in high-risk disease, 0.1 to 0.5 mIU/L in intermediate risk).

Myxoedema coma (emergency).

• Levothyroxine 200 to 400 micrograms intravenously as a loading dose (use the lower end in older adults and coronary disease), then 1.6 micrograms/kg/day, as 75% of the oral dose when given intravenously (about 50 to 100 micrograms daily), until oral dosing is possible.
• Give hydrocortisone 100 mg intravenously every 8 hours before or with the first levothyroxine dose until adrenal insufficiency is excluded. Treat in critical care with warming, ventilatory support and fluid and sodium correction. Some centres add liothyronine.

Adjustments.

• Kidney: no change.
• Liver: no change; check albumin and binding protein effects.
• Older adults: start 12.5 to 25 micrograms daily and raise slowly.
• Weight: dose by lean weight; weight-based in children.

Major warning. Not for obesity or weight loss. In euthyroid patients doses within the replacement range do not reduce weight, and larger doses can cause serious or fatal toxicity, especially with sympathomimetic drugs.

Contraindications. Uncorrected adrenal insufficiency (give hydrocortisone first); thyrotoxicosis; acute myocardial infarction (unless hypothyroid state is treated cautiously); hypersensitivity to an excipient.

Serious adverse effects.

• Over-replacement: atrial fibrillation, tachycardia, angina, heart failure, tremor, insomnia, weight loss, anxiety.
• Bone loss and osteoporosis with long-term suppressive doses, particularly after the menopause.
• Under-replacement: persistent hypothyroid symptoms, raised cholesterol and TSH.
• Precipitation of adrenal crisis when started before cortisol replacement in unrecognised adrenal insufficiency.

Major interactions.

• Reduced absorption: calcium, iron, magnesium and aluminium preparations, sucralfate, bile acid sequestrants (colestyramine), phosphate binders (sevelamer, lanthanum), proton pump inhibitors, orlistat. Separate these from levothyroxine by at least 4 hours.
• Increased clearance and higher dose need: rifampicin, phenytoin, carbamazepine, phenobarbital, tyrosine kinase inhibitors (imatinib, sunitinib), and oestrogens (higher binding globulin).
• Amiodarone and lithium cause thyroid dysfunction; check thyroid function regularly.
• Warfarin: effect rises as hypothyroidism is corrected; monitor INR.
• Digoxin levels fall as hypothyroidism is corrected.
• Biotin supplements interfere with some TSH and free T4 assays; stop biotin for 2 days before tests.
• Diabetes: insulin and oral agent requirements may rise as the metabolic rate normalises.

Special groups.

• Pregnancy: essential and safe; raise the dose by about 25 to 30% as soon as pregnancy is confirmed. Untreated hypothyroidism harms foetal neurodevelopment.
• Breastfeeding: compatible; continue.
• Children: weight-based dosing (newborns 10 to 15 micrograms/kg/day, falling to 1.6 micrograms/kg/day when growth is complete); crush tablets in water for infants.
• Older adults: start low; low bone density and arrhythmia make over-replacement hazardous.
• Kidney and liver impairment: no dose change.
• East Africa: iodine deficiency and goitre remain regional causes of hypothyroidism and goitre; levothyroxine is not an iodine substitute. Rifampicin during TB treatment increases dose need, and ferrous sulphate and calcium given for anaemia or pregnancy interfere with absorption, so spacing needs to be explained clearly. Check supply and the tablet strength, because brand switches change the effective dose.

Formulation and administration. Swallow tablets with water on an empty stomach, 30 to 60 minutes before breakfast, or at bedtime at least 3 hours after the evening meal. Take at the same time each day and keep the same product. Avoid coffee, soy, and high-fibre supplements around the dose. For infants, crush the tablet in a little water or breast milk and give immediately.

Intravenous preparation. For myxoedema coma, reconstitute a 500 microgram vial with 5 mL of 0.9% sodium chloride (100 micrograms/mL), use immediately, and give by slow intravenous injection over 1 to 5 minutes. Do not mix with other drugs. Discard unused solution.

Baseline. TSH, free T4, thyroid peroxidase antibodies, lipid profile, ECG in older adults and in cardiac disease, and morning cortisol when adrenal or pituitary disease is possible.

Monitoring.

• TSH 6 to 8 weeks after starting or changing dose, until stable; then every 6 to 12 months, and annually once stable.
• Free T4 together with TSH in central hypothyroidism, in the first weeks after a dose change, and in pregnancy.
• Heart rate, ECG and symptoms during titration in older adults.
• Bone density in long-term suppressive therapy.

Dose reduction and stopping. Reduce the dose by 12.5 to 25 micrograms when TSH is suppressed or when over-replacement symptoms occur. Stop only if the diagnosis is revised; some patients with a transient cause (post-viral or drug-induced) can be trialled off therapy with TSH checks at 6 to 8 weeks.

Referral and escalation. Admit suspected myxoedema coma (hypothermia, bradycardia, hypoventilation, reduced consciousness, hyponatraemia). Refer to endocrinology for central hypothyroidism, pregnancy planning, thyroid cancer suppression, a dose over 2 micrograms/kg/day, or a TSH that stays abnormal despite verified adherence.