Primary Hypothyroidism in Adults and in Adolescents in Whom Growth and Puberty are Complete
Start levothyroxine sodium tablets at the full replacement dose in otherwise healthy, non-elderly individuals who have been hypothyroid for only a short time (such as a few months). The average full replacement dose of levothyroxine sodium tablets is approximately 1.6 mcg per kg per day (for example: 100 to 125 mcg per day for a 70 kg adult).
Adjust the dose by 12.5 to 25 mcg increments every 4 to 6 weeks until the patient is clinically euthyroid and the serum TSH returns to normal. Doses greater than 200 mcg per day are seldom required. An inadequate response to daily doses of greater than 300 mcg per day is rare and may indicate poor compliance, malabsorption, drug interactions or a combination of these factors.
For elderly patients or patients with underlying cardiac disease, start with a dose of 12.5 to 25 mcg per day. Increase the dose every 6 to 8 weeks, as needed until the patient is clinically euthyroid and the serum TSH returns to normal. The full replacement dose of levothyroxine sodium tablets may be less than 1 mcg per kg per day in elderly patients.
In patients with severe longstanding hypothyroidism, start with a dose of 12.5 to 25 mcg per day. Adjust the dose in 12.5 to 25 mcg increments every 2 to 4 weeks until the patient is clinically euthyroid and the serum TSH level is normalized.
Secondary or Tertiary Hypothyroidism
Start levothyroxine sodium tablets at the full replacement dose in otherwise healthy, non-elderly individuals. Start with a lower dose in elderly patients, patients with underlying cardiovascular disease or patients with severe longstanding hypothyroidism as described above. Serum TSH is not a reliable measure of levothyroxine sodium tablets dose adequacy in patients with secondary or tertiary hypothyroidism and should not be used to monitor therapy. Use the serum free-T4 level to monitor adequacy of therapy in this patient population. Titrate levothyroxine sodium tablets dosing per above instructions until the patient is clinically euthyroid and the serum free-T4 level is restored to the upper half of the normal range.
Pediatric Dosage - Congenital or Acquired Hypothyroidism
The recommended daily dose of levothyroxine sodium tablets in pediatric patients with hypothyroidism is based on body weight and changes with age as described in
Table 1. Start levothyroxine sodium tablets at the full daily dose in most pediatric patients. Start at a lower starting dose in newborns (0-3 months) at risk for cardiac failure and in children at risk for hyperactivity (see below). Monitor for clinical and laboratory response
[see Dosage and Administration (2.4)].
Table 1. Levothyroxine Sodium Tablets Dosing Guidelines for Pediatric Hypothyroidism
| AGE | Daily Dose Per Kg Body Weight
a |
| 0-3 months | 10-15 mcg/kg/day |
| 3-6 months | 8-10 mcg/kg/day |
| 6-12 months | 6-8 mcg/kg/day |
| 1-5 years | 5-6 mcg/kg/day |
| 6-12 years | 4-5 mcg/kg/day |
| Greater than 12 years but growth and puberty incomplete | 2-3 mcg/kg/day |
| Growth and puberty complete | 1.6 mcg/kg/day |
| a. The dose should be adjusted based on clinical response and laboratory parameters
[see Dosage and Administration (2.4) and Use in Specific Populations (8.4)]. |
Newborns (0-3 months) at risk for cardiac failure: Consider a lower starting dose in newborns at risk for cardiac failure. Increase the dose every 4 to 6 weeks as needed based on clinical and laboratory response.
Children at risk for hyperactivity: To minimize the risk of hyperactivity in children, start at one- fourth the recommended full replacement dose, and increase on a weekly basis by one-fourth the full recommended replacement dose until the full recommended replacement dose is reached.
Pregnancy
Pre-existing Hypothyroidism: Levothyroxine sodium tablets dose requirements may increase during pregnancy. Measure serum TSH and free-T4 as soon as pregnancy is confirmed and, at minimum, during each trimester of pregnancy. In patients with primary hypothyroidism, maintain serum TSH in the trimester-specific reference range. For patients with serum TSH above the normal trimester-specific range, increase the dose of levothyroxine sodium tablets by 12.5 to 25 mcg/day and measure TSH every 4 weeks until a stable levothyroxine sodium tablets dose is reached and serum TSH is within the normal trimester-specific range. Reduce levothyroxine sodium tablets dosage to pre-pregnancy levels immediately after delivery and measure serum TSH levels 4 to 8 weeks postpartum to ensure levothyroxine sodium tablets dose is appropriate.
New Onset Hypothyroidism: Normalize thyroid function as rapidly as possible. In patients with moderate to severe signs and symptoms of hypothyroidism, start levothyroxine sodium tablets at the full replacement dose (1.6 mcg per kg body weight per day). In patients with mild hypothyroidism (TSH <10 IU per liter) start levothyroxine sodium tablets at 1.0 mcg per kg body weight per day. Evaluate serum TSH every 4 weeks and adjust levothyroxine sodium tablets dosage until a serum TSH is within the normal trimester specific range
[see Use in Specific Populations (8.1)].
TSH Suppression in Well-differentiated Thyroid Cancer
Generally, TSH is suppressed to below 0.1 IU per liter, and this usually requires a levothyroxine sodium tablets dose of greater than 2 mcg per kg per day. However, in patients with high-risk tumors, the target level for TSH suppression may be lower.
Adults
In adult patients with primary hypothyroidism, monitor serum TSH levels after an interval of 6 to 8 weeks after any change in dose. In patients on a stable and appropriate replacement dose, evaluate clinical and biochemical response every 6 to 12 months and whenever there is a change in the patient’s clinical status.
Pediatrics
In patients with congenital hypothyroidism, assess the adequacy of replacement therapy by measuring both serum TSH and total or free-T4. Monitor TSH and total or free-T4 in children as follows: 2 and 4 weeks after the initiation of treatment, 2 weeks after any change in dosage, and then every 3 to 12 months thereafter following dose stabilization until growth is completed. Poor compliance or abnormal values may necessitate more frequent monitoring. Perform routine clinical examination, including assessment of development, mental and physical growth and bone maturation, at regular intervals.
While the general aim of therapy is to normalize the serum TSH level, TSH may not normalize in some patients due to in utero hypothyroidism causing a resetting of pituitary-thyroid feedback. Failure of the serum T4 to increase into the upper half of the normal range within 2 weeks of initiation of levothyroxine sodium tablets therapy and/or of the serum TSH to decrease below 20 IU per liter within 4 weeks may indicate the child is not receiving adequate therapy. Assess compliance, dose of medication administered and method of administration prior to increasing the dose of levothyroxine sodium tablets
[see Warnings and Precautions (5.1) and Use in Specific Populations (8.4)].
Secondary and Tertiary Hypothyroidism
Monitor serum free-T4 levels and maintain in the upper half of the normal range in these patients.
Adverse Reactions in Children
Pseudotumor cerebri and slipped capital femoral epiphysis have been reported in children receiving levothyroxine therapy. Overtreatment may result in craniosynostosis in infants and premature closure of the epiphyses in children with resultant compromised adult height.
Hypersensitivity Reactions
Hypersensitivity reactions to inactive ingredients have occurred in patients treated with thyroid hormone products. These include urticaria, pruritus, skin rash, flushing, angioedema, various gastrointestinal symptoms (abdominal pain, nausea, vomiting and diarrhea), fever, arthralgia, serum sickness and wheezing. Hypersensitivity to levothyroxine itself is not known to occur.
Table 3. Drugs That May Alter T4 and Triiodothyronine (T3) Serum Transport Without Affecting Free Thyroxine (FT4) Concentration (Euthyroidism)
| Drug or Drug Class | Effect |
Clofibrate
Estrogen-containing oral contraceptives Estrogens (oral)
Heroin / Methadone 5-Fluorouracil
Mitotane Tamoxifen | These drugs may increase serum thyroxine-binding globulin (TBG) concentration. |
Androgens / Anabolic Steroids Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
| These drugs may decrease serum TBG concentration. |
| Potential impact (below): Administration of these agents with levothyroxine sodium tablets results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations. |
| Salicylates (>2 g/day) | Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total T4 levels may decrease by as much as 30%. |
Other drugs: Carbamazepine Furosemide (>80 mg IV) Heparin
Hydantoins
Non-Steroidal Anti-inflammatory Drugs
-Fenamates
| These drugs may cause protein-binding site displacement. Furosemide has been shown to inhibit the protein binding of T4 to TBG and albumin, causing an increase free T4 fraction in serum. Furosemide competes for T4-binding sites on TBG, prealbumin and albumin, so that a single high dose can acutely lower the total T4 level. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total and free T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. Closely monitor thyroid hormone parameters. |
Table 4. Drugs That May Alter Hepatic Metabolism of T4 (Hypothyroidism)
| Potential impact: Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine sodium tablets requirements. |
| Drug or Drug Class | Effect |
| Phenobarbital Rifampin | Phenobarbital has been shown to reduce the response to thyroxine. Phenobarbital increases L-thyroxine metabolism by inducing uridine 5’-diphospho-glucuronosyltransferase (UGT) and leads to a lower T4 serum levels. Changes in thyroid status may occur if barbiturates are added or withdrawn from patients being treated for hypothyroidism. Rifampin has been shown to accelerate the metabolism of levothyroxine. |
Table 5. Drugs That May Decrease Conversion of T4 to T3
| Potential impact: Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. |
| Drug or Drug Class | Effect |
| Beta-adrenergic antagonists (e.g., Propranolol >160 mg/day) | In patients treated with large doses of propranolol (>160 mg/day), T3 and T4 levels change, TSH levels remain normal and patients are clinically euthyroid. Actions of particular beta-adrenergic antagonists may be impaired when a hypothyroid patient is converted to the euthyroid state. |
Glucocorticoids
(e.g., Dexamethasone ≥4 mg/day)
| Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (See above). |
| Other drugs: Amiodarone | Amiodarone inhibits peripheral conversion of levothyroxine (T4) to triiodothyronine (T3) and may cause isolated biochemical changes (increase in serum free-T4 and decreased or normal free-T3) in clinically euthyroid patients. |
Dosing and Administration
• Instruct patients that levothyroxine sodium tablets should be taken with a full glass of water since the tablet may rapidly disintegrate.
• Instruct patients to take levothyroxine sodium tablets only as directed by their healthcare provider.
• Instruct patients to take levothyroxine sodium tablets as a single dose, preferably on an empty stomach, one-half to one hour before breakfast.
• Inform patients that agents such as iron and calcium supplements and antacids can decrease the absorption of levothyroxine. Instruct patients not to take levothyroxine sodium tablets within 4 hours of these agents.
• Instruct patients to notify their healthcare provider if they are pregnant or breastfeeding or are thinking of becoming pregnant while taking levothyroxine sodium tablets.
Important Information
• Inform patients that it may take several weeks before they notice an improvement in symptoms.
• Inform patients that the levothyroxine in levothyroxine sodium tablets is intended to replace a hormone that is normally produced by the thyroid gland. Generally, replacement therapy is to be taken for life.
• Inform patients that levothyroxine sodium tablets should not be used as a primary or adjunctive therapy in a weight control program.
• Instruct patients to notify their healthcare provider if they are taking any other medications, including prescription and over-the-counter preparations.
• Instruct patients to notify their physician of any other medical conditions they may have, particularly heart disease, diabetes, clotting disorders and adrenal or pituitary gland problems, as the dose of medications used to control these other conditions may need to be adjusted while they are taking levothyroxine sodium tablets. If they have diabetes, instruct patients to monitor their blood and/or urinary glucose levels as directed by their physician and immediately report any changes to their physician. If patients are taking anticoagulants, their clotting status should be checked frequently.
• Instruct patients to notify their physician or dentist that they are taking levothyroxine sodium tablets prior to any surgery.
Adverse Reactions
• Instruct patients to notify their healthcare provider if they experience any of the following symptoms: rapid or irregular heartbeat, chest pain, shortness of breath, leg cramps, headache, nervousness, irritability, sleeplessness, tremors, change in appetite, weight gain or loss, vomiting, diarrhea, excessive sweating, heat intolerance, fever, changes in menstrual periods, hives or skin rash or any other unusual medical event.
• Inform patients that partial hair loss may occur rarely during the first few months of levothyroxine sodium tablets therapy, but this is usually temporary.
