Administer UNITHROID tablets orally as a single daily dose, on an empty stomach, one-half to one hour before breakfast.

Administer UNITHROID at least 4 hours before or after drugs that are known to interfere with UNITHROID absorption [see Drug Interactions (7.1)].

Evaluate the need for dose adjustments when regularly administering within one hour of certain foods that may affect UNITHROID absorption [see Drug Interactions (7.9), Clinical Pharmacology (12.3)].

Administer UNITHROID to infants and children who cannot swallow intact tablets by crushing the tablet, suspending the freshly crushed tablet in a small amount (5 mL to 10 mL or 1 teaspoon 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 UNITHROID, such as soybean-based infant formula [see Drug Interactions (7.9)].

The dose of UNITHROID 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), 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 UNITHROID may not be attained for 4 to 6 weeks.

Primary Hypothyroidism in Adults and in Adolescents in Whom Growth and Puberty Are Complete

Start UNITHROID 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 UNITHROID is approximately 1.6 mcg per kg per day (for example: 100 mcg per day to 125 mcg per day for a 70 kg adult).

Adjust the dose by 12.5 mcg 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 mcg 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 UNITHROID 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 mcg to 25 mcg per day. Adjust the dose in 12.5 mcg 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 UNITHROID 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 UNITHROID 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 UNITHROID 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 UNITHROID in pediatric patients with hypothyroidism is based on body weight and changes with age as described in Table 1. Start UNITHROID at the full daily dose in most pediatric patients. Start at a lower starting dose in newborns (0 to 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: UNITHROID Dosing Guidelines for Pediatric Hypothyroidism

Age	Daily Dose Per Kg Body Weight a
0 to 3 months	10 mcg/kg daily to 15 mcg/kg daily
3 to 6 months	8 mcg/kg daily to 10 mcg/kg daily
6 to 12 months	6 mcg/kg daily to 8 mcg/kg daily
1 to 5 years	5 mcg/kg to 6 mcg/kg daily
6 to 12 years	4 mcg/kg to 5 mcg/kg daily
Greater than 12 years but growth and puberty incomplete	2 mcg/kg to 3 mcg/kg daily
Growth and puberty complete	1.6 mcg/kg daily

a - The dose should be adjusted based on clinical response and laboratory parameters [see Warnings and Precautions (5.4), Drug Interactions (7.10), and Use In Specific Populations (8.4)].

Newborns (0 to 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.

Pediatric Patients at Risk for Hyperactivity:

To minimize the risk of hyperactivity in pediatric patients, 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: UNITHROID 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 UNITHROID by 12.5 mcg daily to 25 mcg daily and measure TSH every 4 weeks until a stable UNITHROID dose is reached and serum TSH is within the normal trimester-specific range. Reduce UNITHROID dosage to pre-pregnancy levels immediately after delivery and measure serum TSH levels 4 to 8 weeks postpartum to ensure UNITHROID 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 UNITHROID at the full replacement dose (1.6 mcg per kg body weight per day). In patients with mild hypothyroidism (TSH less than 10 mIU per liter) start UNITHROID at 1 mcg per kg body weight per day. Evaluate serum TSH every 4 weeks and adjust UNITHROID 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

The dose of UNITHROID should target TSH levels within the desired therapeutic range. This may require a UNITHROID dose of greater than 2 mcg per kg per day, depending on the target level for TSH suppression.

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 UNITHROID may be evidence of inadequate absorption, poor compliance, drug interactions, or a combination of these factors.

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-T. 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 UNITHROID therapy and/or of the serum TSH to decrease below 20 mIU 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 UNITHROID [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.

Overtreatment 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 UNITHROID 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 UNITHROID therapy. Monitor patients receiving concomitant UNITHROID and sympathomimetic agents for signs and symptoms of coronary insufficiency. If cardiovascular symptoms develop or worsen, reduce or withhold the UNITHROID dose for one week and restart at a lower dose. 

Myxedema coma is a life-threatening emergency characterized by poor circulation and hypometabolism, and may result in unpredictable absorption of levothyroxine sodium from the gastrointestinal tract. Use of oral thyroid hormone drug products is not recommended to treat myxedema coma. Administer thyroid hormone products formulated for intravenous administration to treat myxedema coma.

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 UNITHROID [see Contraindications (4)].

UNITHROID has a narrow therapeutic index. Over- or under-treatment with UNITHROID may have negative effects on growth and development, cardiovascular function, bone metabolism, reproductive function, cognitive function, emotional state, gastrointestinal function, and on glucose and lipid metabolism. Titrate the dose of UNITHROID 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 UNITHROID and adjust the dose as necessary [see Drug Interactions (7), 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 UNITHROID [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 UNITHROID that achieves the desired clinical and biochemical response to mitigate against this risk.

Many drugs can exert effects on thyroid hormone pharmacokinetics (e.g. absorption, synthesis, secretion, catabolism, protein binding, and target tissue response) and may alter the therapeutic response to UNITHROID (see Tables 2 – 5).

Table 2: Drugs That May Decrease T4 Absorption (Hypothyroidism)

Potential impact: Concurrent use may reduce the efficacy of UNITHROID by binding and delaying or preventing absorption, potentially resulting in hypothyroidism.
Drug or Drug Class	Effect
Calcium Carbonate Ferrous Sulfate	Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer UNITHROID at least 4 hours apart from these agents.
Orlistat	Monitor patients treated concomitantly with orlistat and UNITHROID for changes in thyroid function.
Bile Acid Sequestrants -Colesevelam -Cholestyramine -Colestipol Ion Exchange Resins -Kayexalate -Sevelamer	Bile acid sequestrants and ion exchange resins are known to decrease levothyroxine absorption. Administer UNITHROID at least 4 hours prior to these drugs or monitor thyrotropin-stimulating hormone (TSH) levels.
Other drugs: Proton Pump Inhibitors Sucralfate Antacids - Aluminum & Magnesium Hydroxides - Simethicone	Gastric acidity is an essential requirement for adequate absorption of levothyroxine. Sucralfate, antacids and proton pump inhibitors may cause hypochlorhydria, affect intragastric pH, and reduce levothyroxine absorption. Monitor patients appropriately.

Table 3: Drugs That May Alter T 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 UNITHROID 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 increased 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 FT4 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 UNITHROID 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 slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the 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: 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.

Addition of UNITHROID 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 UNITHROID is started, changed, or discontinued [see Warnings and Precautions (5.5)].

UNITHROID 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 UNITHROID dose is increased. Closely monitor coagulation tests to permit appropriate and timely dosage adjustments.

UNITHROID may reduce the therapeutic effects of digitalis glycosides. Serum digitalis glycoside levels may be decreased 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 UNITHROID 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. UNITHROID may accelerate the onset of action of tricyclics. Administration of sertraline in patients stabilized on UNITHROID may result in increased UNITHROID requirements.

Concurrent use of ketamine and UNITHROID may produce marked hypertension and tachycardia. Closely monitor blood pressure and heart rate in these patients.

Concurrent use of sympathomimetics and UNITHROID 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.

Concurrent use of tyrosine-kinase inhibitors such as imatinib may cause hypothyroidism. Closely monitor TSH levels in such patients.

Consumption of certain foods may affect UNITHROID absorption thereby necessitating adjustments in dosing [see Dosage and Administration (2.1)]. Soybean flour (infant formula), cotton seed meal, walnuts, and dietary fiber may bind and decrease the absorption of UNITHROID from the GI 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 concentrations. 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.

Risk Summary

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 thyroid-stimulating hormone (TSH) levels may increase during pregnancy, TSH should be monitored and UNITHROID dosage adjusted during pregnancy (see Clinical Considerations). There are no animal studies conducted with levothyroxine during pregnancy. UNITHROID should not be discontinued during pregnancy and hypothyroidism diagnosed during pregnancy should be promptly treated.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk

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.

Dose Adjustments During Pregnancy and the Postpartum Period

Pregnancy may increase UNITHROID requirements. Serum TSH level should be monitored and the UNITHROID dosage adjusted during pregnancy. Since postpartum TSH levels are similar to preconception values, the UNITHROID dosage should return to the pre-pregnancy dose immediately after delivery   [see  Dosage and Administration  (2.3)]. 

Data

Human Data

Levothyroxine is approved for use as a replacement therapy for hypothyroidism. There is a long experience of levothyroxine use in pregnant women, including data from post-marketing studies that have not reported increased rates of fetal malformations, miscarriages or other adverse maternal or fetal outcomes associated with levothyroxine use in pregnant women.

Risk Summary

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 UNITHROID and any potential adverse effects on the breastfed infant from UNITHROID or from the underlying maternal condition.

The initial dose of UNITHROID 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 UNITHROID 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 assessments to guide diagnosis and treatment, if warranted.

Congenital Hypothyroidism [see Dosage and Administration (2.3, 2.4)]

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 UNITHROID therapy immediately upon diagnosis. Levothyroxine is generally continued for life in these patients. 

Closely monitor infants during the first 2 weeks of UNITHROID therapy for cardiac overload, arrhythmias, and aspiration from avid suckling.

Closely monitor patients to avoid undertreatment or overtreatment. Undertreatment may have deleterious effects on intellectual development and linear growth. Overtreatment is associated with craniosynostosis in infants, may adversely affect the tempo of brain maturation, and may accelerate the bone age and result in premature epiphyseal closure and compromised adult stature.

Acquired Hypothyroidism in Pediatric Patients

Closely monitor patients to avoid undertreatment and overtreatment. Undertreatment may result in poor school performance due to impaired concentration and slowed mentation and in reduced adult height. Overtreatment may accelerate the bone age and result in premature epiphyseal closure and compromised adult stature. 

Treated children may manifest a period of catch-up growth, which may be adequate in some cases to normalize adult height. In children with severe or prolonged hypothyroidism, catch-up growth may not be adequate to normalize adult height.

Because of the increased prevalence of cardiovascular disease among the elderly, initiate UNITHROID at less than the full replacement dose [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)]. Atrial arrhythmias can occur in elderly patients. Atrial fibrillation is the most common of the arrhythmias observed with levothyroxine overtreatment in the elderly. 

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.

The physiological actions of thyroid hormones are produced predominantly by T3, the majority of which (approximately 80%) is derived from T4 by deiodination in peripheral tissues.

Oral levothyroxine sodium is a synthetic T4 hormone that exerts the same physiologic effect as endogenous T4, thereby maintaining normal T4 levels when a deficiency is present.

Animal studies have not been performed to evaluate the carcinogenic potential, mutagenic potential or effects on fertility of levothyroxine sodium.