Levothyroxine

The dosage of levothyroxine is highly individualized and is based on several factors, including the patient's age, body weight, cardiovascular status, and the underlying cause of the hypothyroidism. For a healthy adult with no cardiovascular disease, the typical full replacement dose is approximately 1.6 micrograms (mcg) per kilogram of body weight per day (e.g., roughly 100-125 mcg/day for a 70 kg adult).

In cases of mild or subclinical hypothyroidism, healthcare providers may start with a lower dose, such as 25-50 mcg once daily. Doses are typically adjusted in increments of 12.5 to 25 mcg every 4 to 6 weeks until the patient's TSH levels are within the target reference range. For TSH suppression in thyroid cancer, higher doses may be required to drive TSH levels below 0.1 mIU/L.

Levothyroxine is approved for use in children and is critical for preventing neurodevelopmental delays in infants with congenital hypothyroidism. Dosing in children is generally higher per kilogram of body weight than in adults because of their rapid growth and development.

• Newborns (0-3 months): 10-15 mcg/kg/day.
• Infants (3-6 months): 8-10 mcg/kg/day.
• Children (1-5 years): 5-6 mcg/kg/day.
• Children (6-12 years): 4-5 mcg/kg/day.
• Adolescents (>12 years): 2-3 mcg/kg/day until growth is complete.

Healthcare providers monitor pediatric patients closely to ensure that the dose supports normal linear growth and bone maturation without causing premature closure of the epiphyses (growth plates).

Renal Impairment

No specific dose adjustments are generally required for patients with kidney disease. However, since thyroid hormones affect renal blood flow and filtration, your doctor will monitor your kidney function and TSH levels closely.

Hepatic Impairment

While the liver is the primary site of T4 to T3 conversion, standard dosing is usually maintained in patients with liver disease. However, severe hepatic impairment may alter the protein binding of the hormone, necessitating more frequent monitoring.

Elderly Patients

In patients over the age of 65 or those with known heart disease, the starting dose is significantly lower—often 12.5 to 25 mcg per day. The 'start low and go slow' approach is used to prevent putting excessive strain on the heart, which could lead to arrhythmias or angina (chest pain).

To ensure consistent absorption, levothyroxine must be taken under strict conditions:

• Timing: Take the medication once daily on an empty stomach, preferably 30 to 60 minutes before breakfast. Alternatively, it can be taken at bedtime, at least 3 to 4 hours after the last meal.
• Consistency: Stick to the same brand or generic version. Small differences in manufacturing can affect how much drug you absorb. If your pharmacy changes your brand, inform your doctor, as you may need a TSH test in 6 weeks.
• Water: Swallow the tablet or capsule whole with a full glass of water. Do not use coffee, juice, or milk, as these can interfere with absorption.
• Storage: Store at room temperature (68°F to 77°F), away from moisture, heat, and light. Do not store in a bathroom cabinet where humidity is high.

If you miss a dose, take it as soon as you remember. However, if it is almost time for your next dose, skip the missed dose and return to your regular schedule. Do not take two doses at once to make up for a missed one. Because of the drug's long half-life, a single missed dose is unlikely to cause immediate symptoms, but chronic inconsistency will lead to unstable TSH levels.

An overdose of levothyroxine can cause a state of 'thyrotoxicosis' (excessive thyroid hormone). Symptoms include a rapid or irregular heartbeat, chest pain, tremors, extreme nervousness, confusion, and heat stroke. In severe cases, it can lead to seizures or heart failure. If an overdose is suspected, contact a poison control center or seek emergency medical care immediately.

> Important: Follow your healthcare provider's dosing instructions exactly. Do not adjust your dose or stop taking the medication without explicit medical guidance, as this can lead to a recurrence of symptoms or serious health complications.

Most side effects of levothyroxine are actually symptoms of 'iatrogenic hyperthyroidism'—meaning they occur because the dose is slightly too high for the body's needs. When the dose is perfectly calibrated, side effects are rare. Common symptoms of excessive replacement include:

• Increased Appetite and Weight Loss: You may feel hungrier than usual, yet still lose weight because your metabolism is running too fast.
• Heat Intolerance: Feeling excessively hot when others are comfortable, often accompanied by increased sweating.
• Nervousness and Anxiety: A feeling of 'jitteriness,' inner restlessness, or irritability.
• Insomnia: Difficulty falling or staying asleep due to a heightened metabolic state.
• Tremors: Fine shaking, most noticeable in the hands.

These effects may occur as the body adjusts to the medication or if the dose is moderately high:

• Palpitations: The sensation of a racing, fluttering, or skipping heartbeat.
• Diarrhea: Increased frequency of bowel movements or loose stools as the digestive tract speeds up.
• Menstrual Irregularities: Changes in the timing or flow of menstrual periods.
• Muscle Weakness: Particularly in the upper arms and thighs.
• Headache: Often described as a tension-type headache that may persist until the dose is adjusted.

• Hair Loss: Partial hair loss may occur during the first few months of therapy, particularly in children. This is usually temporary as the body equilibrates.
• Pseudotumor Cerebri: A rare condition of increased pressure within the skull, reported primarily in children.
• Craniosynostosis: Premature fusion of the skull bones in infants, associated with excessive dosing.

> Warning: Stop taking Levothyroxine and call your doctor immediately if you experience any of these serious cardiovascular or allergic symptoms.

1. 1Chest Pain (Angina): This may indicate that the heart is being overworked by the increased metabolic demand.
2. 2Shortness of Breath: Especially when lying down or during mild exertion.
3. 3Fainting or Severe Dizziness: Could be a sign of an underlying heart rhythm disturbance.
4. 4Rapid or Irregular Pulse (Atrial Fibrillation): A common complication of over-replacement, especially in older adults.
5. 5Signs of an Allergic Reaction: While rare, some patients are allergic to the dyes or fillers in the tablets. Symptoms include hives, swelling of the face, lips, or throat, and difficulty breathing.

Prolonged use of levothyroxine at doses that suppress TSH below normal levels can lead to two significant long-term health issues:

• Bone Mineral Density Loss: Excessive thyroid hormone increases bone turnover, where bone is broken down faster than it can be replaced. This increases the risk of osteoporosis and fractures, particularly in postmenopausal women.
• Cardiac Hypertrophy: The heart muscle may thicken or weaken over time if forced to pump at an accelerated rate for years, increasing the risk of heart failure.

FDA Black Box Warning: Not for Obesity or Weight Loss

Thyroid hormones, including levothyroxine, either alone or with other therapeutic agents, should not be used for the treatment of obesity or for weight loss. In euthyroid patients (those with normal thyroid function), doses within the range of daily hormonal requirements are ineffective for weight reduction. Larger doses may produce serious or even life-threatening manifestations of toxicity, particularly when given in association with sympathomimetic amines such as those used for their anorectic (appetite suppressant) effects.

Report any unusual symptoms or changes in your health to your healthcare provider immediately to ensure your dose remains in the safe therapeutic window.

Levothyroxine is a lifelong medication for most patients. It has a narrow therapeutic index, meaning that even small changes in the amount of drug in your system can lead to significant health consequences. Patients must be aware that this is not a 'cure' for hypothyroidism but a replacement for a hormone the body can no longer produce. Consistency in how and when you take the medication is the cornerstone of safe therapy.

The FDA has issued a Black Box Warning stating that levothyroxine should never be used as a tool for weight loss or to treat obesity. In individuals with normal thyroid function, taking levothyroxine will not result in weight loss and can lead to dangerous cardiac events, especially if combined with diet pills or stimulants.

• Cardiovascular Disorders: Levothyroxine increases the heart rate and the force of heart contractions. In patients with coronary artery disease, arrhythmias, or hypertension, this can trigger angina or a myocardial infarction (heart attack). If you have heart disease, your doctor will start you on a very low dose.
• Adrenal Insufficiency: Before starting levothyroxine, patients must be screened for adrenal insufficiency. If a patient has an underactive adrenal gland, starting thyroid hormone first can trigger an 'adrenal crisis,' a life-threatening condition. Adrenal issues must be treated with glucocorticoids before thyroid therapy begins.
• Diabetes Mellitus: Thyroid hormone affects glucose metabolism. Adding levothyroxine may increase your blood sugar levels, potentially requiring an adjustment in your insulin or oral diabetes medications.
• Bone Mineral Density: As mentioned in the side effects section, long-term over-replacement can lead to bone thinning. Patients at risk for osteoporosis should have their TSH monitored closely to avoid over-suppression.

Regular laboratory testing is the only way to ensure the safety of levothyroxine therapy.

• TSH (Thyroid Stimulating Hormone): This is the primary marker. For most patients, the goal is a TSH within the standard reference range (typically 0.4 to 4.0 mIU/L).
• Free T4: Sometimes measured alongside TSH to get a clearer picture of hormone levels.
• Frequency: Tests are usually performed 6 to 8 weeks after any dose change or brand change. Once a stable dose is reached, testing is typically performed once or twice a year.

Levothyroxine generally does not interfere with the ability to drive or operate machinery. However, if you are experiencing tremors, nervousness, or dizziness due to a dose that is too high, you should exercise caution until your levels are stabilized.

There is no direct interaction between alcohol and levothyroxine. However, excessive alcohol consumption can affect liver function, which may indirectly influence how your body converts T4 to T3. Moderation is advised.

Do not stop taking levothyroxine abruptly. Because it is a replacement for a vital hormone, stopping it will cause your hypothyroid symptoms to return, often more severely. There is no 'withdrawal syndrome' in the traditional sense, but your metabolism will crash, leading to extreme fatigue, depression, and potentially myxedema. If discontinuation is necessary (e.g., for certain medical tests), it must be done under strict medical supervision.

> Important: Discuss all your medical conditions, especially heart problems, diabetes, or adrenal issues, with your healthcare provider before starting Levothyroxine.

While few drugs are strictly contraindicated, the use of levothyroxine with uncompensated adrenal insufficiency is a clinical contraindication. Additionally, using it alongside high-dose sympathomimetics (like certain weight loss drugs) is dangerous due to the risk of cardiac arrest.

• Warfarin and Anticoagulants: Levothyroxine increases the catabolism (breakdown) of vitamin K-dependent clotting factors. This can significantly increase the blood-thinning effect of warfarin, raising the risk of bleeding. Your doctor will likely need to decrease your warfarin dose when starting thyroid hormone.
• Insulin and Oral Diabetes Drugs: Thyroid hormones can decrease the effectiveness of insulin and other diabetes medications. Blood glucose should be monitored closely when starting, stopping, or changing the dose of levothyroxine.
• Digoxin: Levothyroxine can decrease the effectiveness of digoxin. As a patient moves from a hypothyroid to a euthyroid state, the dose of digoxin may need to be increased.

• Tricyclic Antidepressants (TCAs): Using levothyroxine with TCAs (like amitriptyline) may increase the therapeutic and toxic effects of both drugs, potentially leading to heart rhythm issues.
• Amiodarone: This heart medication contains high levels of iodine and can cause either hypothyroidism or hyperthyroidism, complicating levothyroxine therapy.

Food is the most common 'interactor' with levothyroxine.

• Calcium and Dairy: Calcium carbonate and dairy products can bind to levothyroxine in the gut, preventing its absorption. Wait at least 4 hours between taking levothyroxine and consuming calcium-rich foods or supplements.
• Soy and Walnuts: High-fiber foods, soybean flour (infant formula), and walnuts have been shown to decrease absorption.
• Coffee: Caffeine can significantly reduce the absorption of levothyroxine tablets. Wait at least 60 minutes after taking your pill before drinking coffee.

• Iron (Ferrous Sulfate): Like calcium, iron binds to levothyroxine. These must be separated by at least 4 hours.
• Biotin (Vitamin B7): Biotin does not change the level of thyroid hormone in your body, but it interferes with the lab tests used to measure it. It can cause falsely high T4 and falsely low TSH levels, leading to a wrong diagnosis. Stop biotin supplements at least 3-5 days before a thyroid blood test.
• Magnesium and Aluminum Antacids: These can interfere with absorption and should be separated by 4 hours.

Certain drugs can change the levels of thyroxine-binding globulin (TBG), which affects the 'Total T4' measurement but not necessarily the 'Free T4.' These include estrogens (including birth control pills), which increase TBG, and androgens or anabolic steroids, which decrease TBG. Always tell your doctor if you start or stop hormonal therapy.

> Important: Tell your doctor about ALL medications, supplements, and herbal products you are taking, as many common items can prevent this medication from working correctly.

There are three primary conditions where levothyroxine must not be used:

1. 1Acute Myocardial Infarction (Heart Attack): In the acute phase of a heart attack, the heart muscle is damaged and vulnerable. Increasing the metabolic demand and heart rate with levothyroxine can worsen the damage or cause fatal arrhythmias.
2. 2Uncorrected Adrenal Insufficiency: Thyroid hormone increases the metabolic clearance of glucocorticoids. In a patient with adrenal insufficiency, this can precipitate an acute adrenal crisis, characterized by low blood pressure, shock, and death.
3. 3Untreated Thyrotoxicosis: If a patient already has too much thyroid hormone (hyperthyroidism), adding synthetic T4 will worsen the condition and potentially lead to a 'thyroid storm.'

These are conditions where the drug should be used with extreme caution:

• Angina Pectoris or Severe Cardiovascular Disease: The risk of triggering chest pain or a heart attack must be balanced against the need for thyroid hormone.
• Osteoporosis: In postmenopausal women with low bone density, the dose must be kept at the lowest effective level to prevent further bone loss.
• Malabsorption Syndromes: Conditions like Celiac disease or bariatric surgery may make oral tablets ineffective, requiring a switch to liquid or gel-cap formulations.

Patients with known hypersensitivity to any of the inactive ingredients in the specific brand of levothyroxine (such as lactose, corn starch, or specific color dyes like Tartrazine/FD&C Yellow No. 5) should use an alternative formulation. Gel capsules (Tirosint) are often used for patients with multiple sensitivities as they contain the fewest excipients.

> Important: Your healthcare provider will evaluate your complete medical history, including heart health and adrenal function, before prescribing Levothyroxine.

Levothyroxine is considered safe and essential during pregnancy (FDA Category A). Thyroid hormone is critical for the neurological development of the fetus, especially in the first trimester before the baby's own thyroid begins to function.

• Increased Demand: Pregnancy increases the body's requirement for thyroid hormone. Most women with hypothyroidism will need to increase their dose by 25-50% shortly after conception.
• Monitoring: TSH levels should be checked every 4 weeks during the first half of pregnancy to ensure levels remain within pregnancy-specific ranges.
• Risks of Untreated Hypothyroidism: Failure to treat hypothyroidism during pregnancy increases the risk of miscarriage, preeclampsia, and lower IQ in the child.

Small amounts of thyroid hormone are excreted into breast milk. However, this is not known to cause any adverse effects on the nursing infant. Levothyroxine is considered compatible with breastfeeding. Maintaining normal thyroid levels in the mother is also important for maintaining an adequate milk supply.

Levothyroxine is the standard of care for congenital and acquired hypothyroidism in children. The goal is to rapidly restore normal TSH and T4 levels to ensure normal physical and mental development.

• Monitoring: Children require more frequent monitoring than adults to track growth and bone age.
• Caution: Over-treatment in infants can lead to craniosynostosis (early skull fusion), and in older children, it can lead to accelerated bone age and reduced adult height.

Patients over 65 are more sensitive to the effects of thyroid hormone, particularly on the heart and bones.

• Start Low: A common starting dose for the elderly is 12.5 to 25 mcg.
• Cardiac Risk: There is a higher risk of atrial fibrillation and silent myocardial ischemia.
• Polypharmacy: Older adults are more likely to be taking medications that interact with levothyroxine, such as calcium supplements or blood thinners.

While no specific dose reduction is mandated for renal impairment, the clearance of many drugs is altered in kidney disease. Patients on dialysis may have fluctuating thyroid hormone levels and require more frequent TSH monitoring.

In patients with cirrhosis or hepatitis, the liver's ability to produce thyroxine-binding globulin (TBG) and convert T4 to T3 may be impaired. While the dose of levothyroxine usually stays the same, the 'Total T4' lab result may be misleadingly low, making 'Free T4' and TSH the more reliable markers for these patients.

> Important: Special populations, particularly pregnant women and the elderly, require individualized medical assessment and frequent lab monitoring.

Levothyroxine is a synthetic L-isomer of thyroxine (T4). Its primary mechanism is the activation of nuclear thyroid hormone receptors. Once T4 is converted to T3 (the active form) by 5'-deiodinase enzymes, T3 enters the cell and the nucleus. It binds to thyroid hormone receptors (TR) which are attached to thyroid response elements (TRE) on the DNA. This binding acts as a 'switch' for gene transcription. It increases the expression of genes responsible for the production of Na+/K+ ATPase (the sodium-potassium pump), beta-adrenergic receptors, and various metabolic enzymes. This results in an increase in the basal metabolic rate and heat production (thermogenesis).

• Onset of Action: For oral therapy, the therapeutic effects are not immediate. It may take 3 to 5 days to begin seeing a change in metabolic markers, and 4 to 6 weeks to reach a 'steady state' where the full effect of a specific dose can be measured by a TSH test.
• Duration: Due to its long half-life and high protein binding, the effects of a single dose persist for several days to a week after discontinuation.

| Parameter | Value |

|---|---|

| Bioavailability | 64% to 80% (Fasting) |

| Protein Binding | >99% (TBG, TTR, Albumin) |

| Half-life | 6 to 7 days (Euthyroid) |

| Tmax | 2 to 4 hours |

| Metabolism | Liver (Deiodination, Glucuronidation) |

| Excretion | Renal (approx. 80%), Fecal (approx. 20%) |

• Molecular Formula: C15H10I4NNaO4 (as sodium salt)
• Molecular Weight: 798.85 g/mol
• Solubility: Very slightly soluble in water; soluble in solutions of alkali hydroxides.
• Structure: It is a phenolic compound containing four iodine atoms, which are essential for its biological activity.

Levothyroxine is the cornerstone of the l-Thyroxine [EPC] class. It is categorized as a thyroid hormone replacement. Unlike liothyronine (synthetic T3), which has a short half-life and causes rapid peaks in hormone levels, levothyroxine provides a stable, long-acting reservoir that the body can convert into T3 as needed, making it the preferred physiological choice for long-term therapy.