Thyroid hormones, including Synthroid, either alone or with other therapeutic agents, should not be used for the treatment of obesity or for weight loss.
Synthroid is indicated as a replacement therapy in primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) congenital or acquired hypothyroidism.
Synthroid is not indicated for suppression of benign thyroid nodules and nontoxic diffuse goiter in iodine-sufficient patients as there are no clinical benefits and overtreatment with Synthroid may induce hyperthyroidism [see Warnings and Precautions(5.4)].
Administer Synthroid as a single daily dose, on an empty stomach, one-half to one hour before breakfast.
Administer Synthroid at least 4 hours before or after drugs known to interfere with Synthroid absorption [see Drug Interactions (7.1)].
Evaluate the need for dose adjustments when regularly administering within one hour of certain foods that may affect Synthroid absorption [see Drug Interactions (7.9) and Clinical Pharmacology (12.3)].
Administer Synthroid to infants and children who cannot swallow intact tablets by crushing the tablet, suspending the freshly crushed tablet in a small amount (5 to 10 mL or 1 to 2 teaspoons) of water and immediately administering the suspension by spoon or dropper. Do not store the suspension. Do not administer in foods that decrease absorption of Synthroid, such as soybean-based infant formula [see Drug Interactions (7.9)].
The dose of Synthroid for hypothyroidism or pituitary TSH suppression depends on a variety of factors including: the patient's age, body weight, cardiovascular status, concomitant medical conditions (including pregnancy), concomitant medications, co-administered food and the specific nature of the condition being treated [see Dosage and Administration (2.3), Warnings and Precautions (5), and Drug Interactions (7)]. Dosing must be individualized to account for these factors and dose adjustments made based on periodic assessment of the patient's clinical response and laboratory parameters [see Dosage and Administration (2.4)].
The peak therapeutic effect of a given dose of Synthroid may not be attained for 4 to 6 weeks.
Start Synthroid 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 Synthroid 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 Synthroid may be less than 1 mcg per kg per day in elderly patients.
Start Synthroid 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 Synthroid 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 Synthroid 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.
The recommended daily dose of Synthroid in pediatric patients with hypothyroidism is based on body weight and changes with age as described in Table 1. Start Synthroid 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)].
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.
Pre-existing Hypothyroidism: Synthroid 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 Synthroid by 12.5 to 25 mcg/day and measure TSH every 4 weeks until a stable Synthroid dose is reached and serum TSH is within the normal trimester-specific range. Reduce Synthroid dosage to pre-pregnancy levels immediately after delivery and measure serum TSH levels 4 to 8 weeks postpartum to ensure Synthroid 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 Synthroid 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 Synthroid at 1.0 mcg per kg body weight per day. Evaluate serum TSH every 4 weeks and adjust Synthroid dosage until a serum TSH is within the normal trimester specific range [see Use in Specific Populations (8.1)].
Generally, TSH is suppressed to below 0.1 IU per liter, and this usually requires a Synthroid 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.
Assess the adequacy of therapy by periodic assessment of laboratory tests and clinical evaluation. Persistent clinical and laboratory evidence of hypothyroidism despite an apparent adequate replacement dose of Synthroid may be evidence of inadequate absorption, poor compliance, drug interactions, or a combination of these factors.
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 Synthroid 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 Synthroid [see Warnings and Precautions (5.1) and Use in Specific Populations (8.4)].
Synthroid is contraindicated in patients with uncorrected adrenal insufficiency [see Warnings and Precautions (5.3)].
Over-treatment with levothyroxine may cause an increase in heart rate, cardiac wall thickness, and cardiac contractility and may precipitate angina or arrhythmias, particularly in patients with cardiovascular disease and in elderly patients. Initiate Synthroid therapy in this population at lower doses than those recommended in younger individuals or in patients without cardiac disease [see Dosage and Administration (2.3), Use in Specific Populations (8.5)].
Monitor for cardiac arrhythmias during surgical procedures in patients with coronary artery disease receiving suppressive Synthroid therapy. Monitor patients receiving concomitant Synthroid and sympathomimetic agents for signs and symptoms of coronary insufficiency.
If cardiac symptoms develop or worsen, reduce the Synthroid dose or withhold for one week and restart at a lower dose.
Thyroid hormone increases metabolic clearance of glucocorticoids. Initiation of thyroid hormone therapy prior to initiating glucocorticoid therapy may precipitate an acute adrenal crisis in patients with adrenal insufficiency. Treat patients with adrenal insufficiency with replacement glucocorticoids prior to initiating treatment with Synthroid [see Contraindications (4)].
Synthroid has a narrow therapeutic index. Over- or undertreatment with Synthroid may have negative effects on growth and development, cardiovascular function, bone metabolism, reproductive function, cognitive function, emotional state, gastrointestinal function, and glucose and lipid metabolism. Titrate the dose of Synthroid carefully and monitor response to titration to avoid these effects [see Dosage and Administration (2.4)]. Monitor for the presence of drug or food interactions when using Synthroid and adjust the dose as necessary [see Drug Interactions (7.9) and Clinical Pharmacology (12.3)].
Addition of levothyroxine therapy in patients with diabetes mellitus may worsen glycemic control and result in increased antidiabetic agent or insulin requirements. Carefully monitor glycemic control after starting, changing, or discontinuing Synthroid [see Drug Interactions (7.2)].
Increased bone resorption and decreased bone mineral density may occur as a result of levothyroxine over-replacement, particularly in post-menopausal women. The increased bone resorption may be associated with increased serum levels and urinary excretion of calcium and phosphorous, elevations in bone alkaline phosphatase, and suppressed serum parathyroid hormone levels. Administer the minimum dose of Synthroid that achieves the desired clinical and biochemical response to mitigate this risk.
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.
Many drugs can exert effects on thyroid hormone pharmacokinetics and metabolism (e.g., absorption, synthesis, secretion, catabolism, protein binding, and target tissue response) and may alter the therapeutic response to Synthroid (see Tables 2-5 below).
Ferrous Sulfate Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer Synthroid at least 4 hours apart from these agents.
Orlistat Monitor patients treated concomitantly with orlistat and Synthroid for changes in thyroid function.
- Sevelamer Bile acid sequestrants and ion exchange resins are known to decrease levothyroxine absorption. Administer Synthroid at least 4 hours prior to these drugs or monitor TSH levels.
- 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.
(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.
(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).
Addition of Synthroid therapy in patients with diabetes mellitus may worsen glycemic control and result in increased antidiabetic agent or insulin requirements. Carefully monitor glycemic control, especially when thyroid therapy is started, changed, or discontinued [see Warnings and Precautions (5.5)].
Synthroid increases the response to oral anticoagulant therapy. Therefore, a decrease in the dose of anticoagulant may be warranted with correction of the hypothyroid state or when the Synthroid dose is increased. Closely monitor coagulation tests to permit appropriate and timely dosage adjustments.
Synthroid may reduce the therapeutic effects of digitalis glycosides. Serum digitalis glycoside levels may decrease when a hypothyroid patient becomes euthyroid, necessitating an increase in the dose of digitalis glycosides.
Concurrent use of tricyclic (e.g., amitriptyline) or tetracyclic (e.g., maprotiline) antidepressants and Synthroid may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and central nervous system stimulation. Synthroid may accelerate the onset of action of tricyclics. Administration of sertraline in patients stabilized on Synthroid may result in increased Synthroid requirements.
Concurrent use of ketamine and Synthroid may produce marked hypertension and tachycardia. Closely monitor blood pressure and heart rate in these patients.
Concurrent use of sympathomimetics and Synthroid may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Consumption of certain foods may affect Synthroid absorption thereby necessitating adjustments in dosing [see Dosage and Administration (2.1)]. Soybean flour, cottonseed meal, walnuts, and dietary fiber may bind and decrease the absorption of Synthroid from the gastrointestinal tract. Grapefruit juice may delay the absorption of levothyroxine and reduce its bioavailability.
Consider changes in TBG concentration when interpreting T4 and T3 values. Measure and evaluate unbound (free) hormone and/or determine the free-T4 index (FT4I) in this circumstance. Pregnancy, infectious hepatitis, estrogens, estrogen-containing oral contraceptives, and acute intermittent porphyria increase TBG concentration. Nephrosis, severe hypoproteinemia, severe liver disease, acromegaly, androgens, and corticosteroids decrease TBG concentration. Familial hyper- or hypo-thyroxine binding globulinemias have been described, with the incidence of TBG deficiency approximating 1 in 9000.
Experience with levothyroxine use in pregnant women, including data from post-marketing studies, have not reported increased rates of major birth defects or miscarriages [see Data]. There are risks to the mother and fetus associated with untreated hypothyroidism in pregnancy. Since TSH levels may increase during pregnancy, TSH should be monitored and Synthroid dosage adjusted during pregnancy [see Clinical Considerations]. There are no animal studies conducted with levothyroxine during pregnancy. Synthroid should not be discontinued during pregnancy and hypothyroidism diagnosed during pregnancy should be promptly treated.
Maternal hypothyroidism during pregnancy is associated with a higher rate of complications, including spontaneous abortion, gestational hypertension, pre‑eclampsia, stillbirth, and premature delivery. Untreated maternal hypothyroidism may have an adverse effect on fetal neurocognitive development.
Pregnancy may increase Synthroid requirements. Serum TSH levels should be monitored and the Synthroid dosage adjusted during pregnancy. Since postpartum TSH levels are similar to preconception values, the Synthroid dosage should return to the pre-pregnancy dose immediately after delivery [see Dosage and Administration (2.3)].
Limited published studies report that levothyroxine is present in human milk. However, there is insufficient information to determine the effects of levothyroxine on the breastfed infant and no available information on the effects of levothyroxine on milk production. Adequate levothyroxine treatment during lactation may normalize milk production in hypothyroid lactating mothers. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Synthroid and any potential adverse effects on the breastfed infant from Synthroid or from the underlying maternal condition.
The initial dose of Synthroid varies with age and body weight. Dosing adjustments are based on an assessment of the individual patient's clinical and laboratory parameters [see Dosage and Administration (2.3, 2.4)].
In children in whom a diagnosis of permanent hypothyroidism has not been established, discontinue Synthroid administration for a trial period, but only after the child is at least 3 years of age. Obtain serum T4 and TSH levels at the end of the trial period, and use laboratory test results and clinical assessment to guide diagnosis and treatment, if warranted.
Rapid restoration of normal serum T4 concentrations is essential for preventing the adverse effects of congenital hypothyroidism on intellectual development as well as on overall physical growth and maturation. Therefore, initiate Synthroid therapy immediately upon diagnosis. Levothyroxine is generally continued for life in these patients.
Closely monitor infants during the first 2 weeks of Synthroid therapy for cardiac overload, arrhythmias, and aspiration from avid suckling.
Because of the increased prevalence of cardiovascular disease among the elderly, initiate Synthroid at less than the full replacement dose [see Warnings and Precautions (5.1) and Dosage and Administration (2.3)]. Atrial arrhythmias can occur in elderly patients. Atrial fibrillation is the most common of the arrhythmias observed with levothyroxine overtreatment in the elderly.
The signs and symptoms of overdosage are those of hyperthyroidism [see Warnings and Precautions (5) and Adverse Reactions (6)]. In addition, confusion and disorientation may occur. Cerebral embolism, shock, coma, and death have been reported. Seizures occurred in a 3-year-old child ingesting 3.6 mg of levothyroxine. Symptoms may not necessarily be evident or may not appear until several days after ingestion of levothyroxine sodium.
Reduce the Synthroid dose or discontinue temporarily if signs or symptoms of overdosage occur. Initiate appropriate supportive treatment as dictated by the patient's medical status.
Note – FD&C Yellow No. 6 is orange in color.
Thyroid hormones exert their physiologic actions through control of DNA transcription and protein synthesis. Triiodothyronine(T3) and L-thyroxine (T4) diffuse into the cell nucleus and bind to thyroid receptor proteins attached to DNA. This hormone nuclear receptor complex activates gene transcription and synthesis of messenger RNA and cytoplasmic proteins.
Absorption of orally administered T4 from the gastrointestinal tract ranges from 40% to 80%. The majority of the Synthroid dose is absorbed from the jejunum and upper ileum. The relative bioavailability of Synthroid tablets, compared to an equal nominal dose of oral levothyroxine sodium solution, is approximately 93%. T4 absorption is increased by fasting, and decreased in malabsorption syndromes and by certain foods such as soybeans. Dietary fiber decreases bioavailability of T4. Absorption may also decrease with age. In addition, many drugs and foods affect T4 absorption [see Drug Interactions (7)].
Circulating thyroid hormones are greater than 99% bound to plasma proteins, including thyroxine-binding globulin (TBG), thyroxine-binding prealbumin (TBPA), and albumin (TBA), whose capacities and affinities vary for each hormone. The higher affinity of both TBG and TBPA for T4 partially explains the higher serum levels, slower metabolic clearance, and longer half-life of T4 compared to T3. Protein-bound thyroid hormones exist in reverse equilibrium with small amounts of free hormone. Only unbound hormone is metabolically active. Many drugs and physiologic conditions affect the binding of thyroid hormones to serum proteins [see Drug Interactions (7)]. Thyroid hormones do not readily cross the placental barrier [see Use in Specific Populations (8.1)].
T4 is slowly eliminated (see Table 7). The major pathway of thyroid hormone metabolism is through sequential deiodination. Approximately 80% of circulating T3 is derived from peripheral T4 by monodeiodination. The liver is the major site of degradation for both T4 and T3, with T4 deiodination also occurring at a number of additional sites, including the kidney and other tissues. Approximately 80% of the daily dose of T4 is deiodinated to yield equal amounts of T3 and reverse T3 (rT3). T3 and rT3 are further deiodinated to diiodothyronine. Thyroid hormones are also metabolized via conjugation with glucuronides and sulfates and excreted directly into the bile and gut where they undergo enterohepatic recirculation.
Standard animal studies have not been performed to evaluate the carcinogenic potential, mutagenic potential or effects on fertility of levothyroxine.
[see USP Controlled Room Temperature]. Synthroid tablets should be protected from light and moisture.
Instruct patients to take Synthroid only as directed by their healthcare provider.
Instruct patients to take Synthroid 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 Synthroid 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 Synthroid.
Inform patients that the levothyroxine in Synthroid 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 Synthroid should not be used as a primary or adjunctive therapy in a weight control program.
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 Synthroid. 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 Synthroid prior to any surgery.
Inform patients that partial hair loss may occur rarely during the first few months of Synthroid therapy, but this is usually temporary.