Levolet

What is Levolet and how is it used?

Levolet is a prescription medicine used to treat the symptoms ofHypothyroidism(lowthyroid hormone). Levolet may be used alone or with other medications.

Levolet belongs to a class of drugs calledThyroidProducts.

It is not known if Levolet is safe and effective in children younger than 1 month of age.

What are the possible side effects of Levolet?

Levolet may cause serious side effects including:

• hives,
• difficulty breathing,
• swelling of your face, lips, tongue, or throat,
• fast or irregular heartbeats,
• chest pain,
• pain spreading to your jaw orshoulder,
• shortness of breath,
• fever,
• hot flashes,
• sweating,
• tremors,
• feeling unusually cold,
• weakness,
• tiredness,
• sleep problems (insomnia),
• memory problems,
• depression,
• irritableness,
• headache,
• leg cramps,
• muscle aches,
• nervousness,
• dryness of your skin or hair,
• hair loss,
• irregular menstrual periods,
• vomiting,
• diarrhea,
• appetite changes, and
• weight changes

Get medical help right away, if you have any of the symptoms listed above.

The most common side effects of Levolet include:

• chest pain,
• irregular heartbeats,
• shortness of breath,
• headache,
• leg cramps,
• muscle pain or weakness,
• tremors,
• nervousness,
• irritableness,
• difficulty sleeping,
• increased appetite,
• feeling hot,
• weight loss,
• changes in your menstrual periods,
• diarrhea,
• skin rash, and
• partial hair loss

Tell the doctor if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of Levolet. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

DESCRIPTION

LEVOLET (levothyroxinesodium tablets, USP) contain synthetic crystalline L-3,3',5,5'tetraiodothyronine sodium salt [levothyroxine (T4) sodium]. Synthetic T4 is chemically identical to that produced in the humanthyroid gland. Levothyroxine (T4) sodium has an empirical formula of C₁₅H₁₀I₄N NaO₄• H₂O,分子量为798.86(无水),和structural formula as shown:

LEVOLET tablets for oral administration are supplied in the following strengths: 25 mcg, 50 mcg, 75 mcg, 88 mcg, 100 mcg, 112 mcg, 125 mcg, 137 mcg, 150 mcg, 175 mcg, 200 mcg, and 300 mcg. Each LEVOLET tablet contains the inactive ingredients butylhydroxyanisole, hydroxypropyl methylcellulose, magnesium stearate, mannitol, microcrystalline cellulose, and talc. Table 6 provides a listing of the color additives by tablet strength:

Table 6: LEVOLET Tablets Color Additives

INDICATIONS

Hypothyroidism

LEVOLET is indicated as a replacement therapy in primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) congenital or acquired hypothyroidism.

Pituitary Thyrotropin (Thyroid-Stimulating Hormone, TSH) Suppression

LEVOLET is indicated as an adjunct to surgery and radioiodine therapy in the management of thyrotropin-dependent well-differentiated thyroid cancer.

Limitations Of Use

• LEVOLET 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 LEVOLET may induce hyperthyroidism [seeWARNINGS AND PRECAUTIONS].
• LEVOLET is not indicated for treatment of hypothyroidism during the recovery phase of subacute thyroiditis.

DOSAGE AND ADMINISTRATION

General Administration Information

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

Administer LEVOLET at least 4 hours before or after drugs known to interfere with LEVOLET absorption [seeDRUG INTERACTIONS].

边条时评估剂量调整的必要性rly administering within one hour of certain foods that may affect LEVOLET absorption [seeDRUG INTERACTIONSandCLINICAL PHARMACOLOGY].

Administer LEVOLET 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. Ensure the patient ingests the full amount of the suspension. Do not store the suspension. Do not administer in foods that decrease absorption of LEVOLET, such as soybean-based infant formula [seeDRUG INTERACTIONS].

General Principles Of Dosing

The dose of LEVOLET 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 [seeDOSAGE AND ADMINISTRATION,WARNINGS AND PRECAUTIONS, andDRUG INTERACTIONS]. 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 [seeDOSAGE AND ADMINISTRATION].

The peak therapeutic effect of a given dose of LEVOLET may not be attained for 4 to 6 weeks.

Dosing In Specific Patient Populations

Primary Hypothyroidism In Adults And In Adolescents In Whom Growth And Puberty Are Complete

Start LEVOLET 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 LEVOLET 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 LEVOLET 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 LEVOLET 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 LEVOLET 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 LEVOLET 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 LEVOLET in pediatric patients with hypothyroidism is based on body weight and changes with age as described in Table 1. Start LEVOLET 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 [seeDOSAGE AND ADMINISTRATION].

Table 1: LEVOLET Dosing Guidelines for Pediatric Hypothyroidism

Pediatric Patients From Birth To 3 Months Of Age At Risk For Cardiac Failure

Start at a lower starting dose and 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, 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

在怀孕的LEVOLET剂量的需求可能增加nancy. Measure serum TSH and free-T4 as soon as pregnancy is confirmed and, at a 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 LEVOLET by 12.5 to 25 mcg/day and measure TSH every 4 weeks until a stable LEVOLET dose is reached and serum TSH is within the normal trimester-specific range. Reduce LEVOLET dosage to pre-pregnancy levels immediately after delivery and measure serum TSH levels 4 to 8 weeks postpartum to ensure LEVOLET 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 LEVOLET 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 LEVOLET at 1.0 mcg per kg body weight per day. Evaluate serum TSH every 4 weeks and adjust LEVOLET dosage until a serum TSH is within the normal trimester specific range [seeUse In Specific Populations].

TSH Suppression In Well-differentiated Thyroid Cancer

一般来说,TSH抑制低于0.1 IU / liter, and this usually requires a LEVOLET 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.

Monitoring TSH And/Or Thyroxine (T4) Levels

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 LEVOLET 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

先天性甲状腺功能减退,患者的评估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 LEVOLET therapy and/or of the serum TSH to decrease below 20 IU per liter within 4 weeks may indicate the patient is not receiving adequate therapy. Assess compliance, dose of medication administered, and method of administration prior to increasing the dose of LEVOLET [seeWARNINGS AND PRECAUTIONSandUse In Specific Populations].

Secondary And Tertiary Hypothyroidism

Monitor serum free-T4 levels and maintain in the upper half of the normal range in these patients.

HOW SUPPLIED

Dosage Forms And Strengths

LEVOLET tablets are available as follows:

Storage And Handling

LEVOLET(levothyroxine sodium, USP) tablets are supplied as follows:

Storage Conditions

商店在25°C(77°F);远足允许15°to 30° C (59° to 86° F) [seeUSP Controlled Room Temperature]. LEVOLET tablets should be protected from light and moisture.

Manufactured by: Genus Lifesciences Inc. Allentown, PA 18102. Revised: Dec 2021

SIDE EFFECTS

Adverse reactions associated with LEVOLET therapy are primarily those of hyperthyroidism due to therapeutic overdosage [seeWARNINGS AND PRECAUTIONS,OVERDOSAGE]. They include the following:

• General:fatigue, increased appetite, weight loss, heat intolerance, fever, excessive sweating
• Central nervous system:headache,hyperactivity, nervousness, anxiety, irritability, emotionallability, insomnia
• Musculoskeletal:tremors, muscle weakness,muscle spasm
• Cardiovascular:palpitations,tachycardia, arrhythmias, increasedpulseand blood pressure,heart failure,angina,myocardial infarction, cardiac arrest
• Respiratory:dyspnea
• Gastrointestinal:diarrhea, vomiting, abdominal cramps, elevations in liver function tests
• Dermatologic:hair loss, flushing, rash
• Endocrine:decreasedbone mineral density
• Reproductive:menstrual irregularities, impaired fertility

Seizures have been reported rarely with the institution of levothyroxine therapy.

Adverse Reactions In Pediatric Patients

Pseudotumor cerebriand slipped capitalfemoralepiphysishave been reported in pediatric patients receiving levothyroxine therapy. Overtreatment may result incraniosynostosisin infants and premature closure of the epiphyses in pediatric patients still experiencing growth with resultant compromised adult height.

Hypersensitivity Reactions

Hypersensitivity reactions to inactive ingredients have occurred in patients treated with thyroid hormone products. These includeurticaria,pruritus, skin rash, flushing,angioedema, variousgastrointestinalsymptoms (abdominal pain, nausea, vomiting and diarrhea), fever,arthralgia, serum sickness, andwheezing. Hypersensitivity to levothyroxine itself is not known to occur.

DRUG INTERACTIONS

Drugs Known To Affect Thyroid Hormone Pharmacokinetics

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

表2:药物可能降低T4吸收(沪元pothyroidism)
Potential impact: Concurrent use may reduce the efficacy of LEVOLET by binding and delaying or preventing absorption, potentially resulting in hypothyroidism.

Table 3: Drugs That May Alter T4 and Triiodothyronine (T3) Serum Transport Without Affecting Free Thyroxine (FT4) Concentration (Euthyroidism)

Table 4: Drugs That May Alter Hepatic Metabolism of T4 (Hypothyroidism)

Table 5: Drugs That May Decrease Conversion of T4 to T3

Antidiabetic Therapy

Addition of LEVOLET therapy in patients withdiabetes mellitusmay worsen glycemic control and result in increasedantidiabetic agentorinsulinrequirements. Carefully monitor glycemic control, especially when thyroid therapy is started, changed, or discontinued [seeWARNINGS AND PRECAUTIONS].

Oral Anticoagulants

LEVOLET increases the response to oralanticoagulanttherapy. Therefore, a decrease in the dose of anticoagulant may be warranted with correction of the hypothyroid state or when the LEVOLET dose is increased. Closely monitorcoagulationtests to permit appropriate and timely dosage adjustments.

Digitalis Glycosides

LEVOLET may reduce the therapeutic effects of digitalis glycosides. Serum digitalis glycoside levels may decrease when a hypothyroid patient becomeseuthyroid, necessitating an increase in the dose of digitalis glycosides.

Antidepressant Therapy

Concurrent use of tricyclic (e.g.,amitriptyline) or tetracyclic (e.g., maprotiline)antidepressants和LEVOLET可能会增加治疗和有毒effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias andcentral nervous systemstimulation. LEVOLET may accelerate the onset of action of tricyclics. Administration of sertraline in patients stabilized on LEVOLET may result in increased LEVOLET requirements.

Ketamine

Concurrent use of ketamine and LEVOLET may produce markedhypertensionand tachycardia. Closely monitor blood pressure and heart rate in these patients.

Sympathomimetics

Concurrent use of sympathomimetics and LEVOLET may increase the effects of sympathomimetics or thyroid hormone.Thyroid hormonesmay increase the risk ofcoronary insufficiencywhen sympathomimetic agents are administered to patients withcoronary artery disease.

Tyrosine-Kinase Inhibitors

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

Drug-Food Interactions

Consumption of certain foods may affect LEVOLET absorption thereby necessitating adjustments in dosing [seeDOSAGE AND ADMINISTRATION]. Soybean flour, cottonseed meal, walnuts, and dietaryfibermay bind and decrease the absorption of LEVOLET from thegastrointestinal tract. Grapefruit juice may delay the absorption of levothyroxine and reduce its bioavailability.

Drug-Laboratory Test Interactions

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 intermittentporphyriaincrease TBG concentration.Nephrosis, severe hypoproteinemia, severeliver disease,acromegaly, androgens, and corticosteroids decrease TBG concentration.Familialhyper-or hypo-thyroxinebinding globulinemias have been described, with the incidence of TBG deficiency approximating 1 in 9000.

WARNINGS

Included as part of thePRECAUTIONSsection.

PRECAUTIONS

Cardiac Adverse Reactions In The Elderly and In Patients With Underlying Cardiovascular Disease

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 withcardiovascular diseaseand in elderly patients. Initiate LEVOLET therapy in this population at lower doses than those recommended in younger individuals or in patients without cardiac disease [seeDOSAGE AND ADMINISTRATION,Use In Specific Populations].

Monitor for cardiac arrhythmias during surgical procedures in patients with coronary artery disease receiving suppressive LEVOLET therapy. Monitor patients receiving concomitant LEVOLET and sympathomimetic agents for signs and symptoms of coronary insufficiency.

If cardiac symptoms develop or worsen, reduce the LEVOLET dose or withhold for one week and restart at a lower dose.

Myxedema Coma

Myxedema comais a life-threatening emergency characterized bypoor circulationand 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.

Acute Adrenal Crisis In Patients With Concomitant Adrenal Insufficiency

Thyroid hormone increases metabolic clearance of glucocorticoids. Initiation of thyroidhormone therapyprior to initiatingglucocorticoidtherapy may precipitate an acute adrenal crisis in patients with adrenal insufficiency. Treat patients with adrenal insufficiency with replacement glucocorticoids prior to initiating treatment with LEVOLET [seeCONTRAINDICATIONS].

Prevention Of Hyperthyroidism Or Incomplete Treatment Of Hypothyroidism

LEVOLET has a narrow therapeutic index. Over or undertreatment with LEVOLET may have negative effects on growth and development,cardiovascularfunction, bone metabolism, reproductive function,cognitivefunction, emotional state, gastrointestinal function, and glucose andlipidmetabolism. Titrate the dose of LEVOLET carefully and monitor response to titration to avoid these effects [seeDOSAGE AND ADMINISTRATION]. Monitor for the presence of drug or food interactions when using LEVOLET and adjust the dose as necessary [seeDRUG INTERACTIONSandCLINICAL PHARMACOLOGY].

Worsening Of Diabetic Control

Addition of levothyroxine therapy in patients withdiabetesmellitus may worsen glycemic control and result in increased antidiabetic agent or insulin requirements. Carefully monitor glycemic control after starting, changing, or discontinuing LEVOLET [seeDRUG INTERACTIONS].

Decreased Bone Mineral Density Associated With Thyroid Hormone Over-Replacement

Increased boneresorptionand decreased bone mineral density may occur as a result of levothyroxine over-replacement, particularly inpost-menopausalwomen. 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 serumparathyroid hormone的水平。管理的最低做se of LEVOLET that achieves the desired clinical andbiochemicalresponse to mitigate this risk.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Long-term carcinogenicity studies in animals to evaluate thecarcinogenicpotential of levothyroxine have not been performed. Studies to evaluate mutagenic potential and animal fertility have not been performed.

Use In Specific Populations

Pregnancy

Risk Summary

The clinical experience, including data from post-marketing studies, in pregnant women treated with oral levothyroxine to maintain a euthyroid state have not reported increased rates of major birth defects, miscarriages, or other adverse maternal or fetal outcomes. 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 LEVOLET dosage adjusted during pregnancy (seeClinical Considerations). Animal reproduction studies have not been conducted with levothyroxine sodium. LEVOLET should not be discontinued during pregnancy and hypothyroidism diagnosed during pregnancy should be promptly treated.

The estimated background risk of major birth defects andmiscarriagefor the indicated population is unknown. All pregnancies have a background risk ofbirth defect, loss, or other adverse outcomes. 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, includingspontaneous abortion,gestational hypertension,pre-eclampsia, stillbirth, and premature delivery. Untreated maternal hypothyroidism may have anadverse effecton fetal neurocognitive development.

Dose Adjustments During Pregnancy And The Postpartum Period

Pregnancy may increase LEVOLET requirements. Serum TSH levels should be monitored and the LEVOLET dosage adjusted during pregnancy. SincepostpartumTSH levels are similar to preconception values, the LEVOLET dosage should return to the pre-pregnancy dose immediately after delivery [seeDOSAGE AND ADMINISTRATION].

Lactation

Risk Summary

左旋甲状腺素是以前发表的研究报告sent in human milk following the administration of oral levothyroxine. No adverse effects on the breastfed infant have been reported and there is no information on the effects of levothyroxine on milk production. Adequate levothyroxine treatment during lactation may normalize milk production in hypothyroid lactating mothers with low milk supply. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for LEVOLET and any potential adverse effects on the breastfed infant from LEVOLET or from the underlying maternal condition.

Pediatric Use

The initial dose of LEVOLET varies with age and body weight.

Dosing adjustments are based on an assessment of the individual patient's clinical and laboratory parameters [seeDOSAGE AND ADMINISTRATION].

In children in whom a diagnosis of permanent hypothyroidism has not been established, discontinue

LEVOLET 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.

Congenital Hypothyroidism[SeeDOSAGE AND ADMINISTRATION]

Rapid restoration of normal serum T4 concentrations isessentialfor preventing the adverse effects ofcongenitalhypothyroidism on intellectual development as well as on overallphysical growthand maturation. Therefore, initiate LEVOLET therapy immediately upon diagnosis. Levothyroxine is generally continued for life in these patients.

Closely monitor infants during the first 2 weeks of LEVOLET therapy for cardiac overload, arrhythmias, andaspirationfrom 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.

Geriatric Use

Because of the increasedprevalenceof cardiovascular disease among the elderly, initiate LEVOLET at less than the full replacement dose [seeWARNINGS AND PRECAUTIONSandDOSAGE AND ADMINISTRATION].Atrial arrhythmiascan occur in elderly patients.Atrial fibrillationis the most common of the arrhythmias observed with levothyroxine overtreatment in the elderly.

OVERDOSE

The signs and symptoms of overdosage are those of hyperthyroidism [seeWARNINGS AND PRECAUTIONSandADVERSE REACTIONS]. In addition, confusion and disorientation may occur. Cerebralembolism,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 LEVOLET dose or discontinue temporarily if signs or symptoms of overdosage occur. Initiate appropriate supportive treatment as dictated by the patient’s medical status.

For current information on the management ofpoisoningor overdosage, contact the National Poison Control Center at 1-800-222-1222 or www.poison.org.

CONTRAINDICATIONS

LEVOLET is contraindicated in patients with uncorrected adrenal insufficiency [seeWARNINGS AND PRECAUTIONS].

CLINICAL PHARMACOLOGY

Mechanism Of Action

Thyroid hormones exert theirphysiologicactions through control of DNAtranscriptionand protein synthesis.Triiodothyronine(T3) and L-thyroxine (T4) diffuse into the cellnucleusand bind to thyroid receptor proteins attached to DNA. This hormone nuclear receptor complex activates gene transcription and synthesis ofmessenger RNAand 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.

Pharmacodynamics

Oral levothyroxine sodium is a synthetic T4 hormone that exerts the same physiologic effect asendogenousT4, thereby maintaining normal T4 levels when a deficiency is present.

Pharmacokinetics

Absorption

Absorption of orally administered T4 from the gastrointestinal tract ranges from 40% to 80%. The majority of the LEVOLET dose is absorbed from thejejunumand upperileum. The relative bioavailability of LEVOLET tablets, compared to an equal nominal dose of oral levothyroxine sodium solution, is approximately 93%. T4 absorption is increased by fasting and decreased inmalabsorptionsyndromes and by certain foods such as soybeans. Dietary fiber decreases bioavailability of T4. Absorption mayalsodecrease withage.Inaddition, many drugsandfoods affect T4 absorption [seeDRUG INTERACTIONS].

Distribution

Circulating thyroid hormones are greater than 99% bound to plasma proteins, including thyroxine-binding globulin (TBG), thyroxine-bindingprealbumin(TBPA), andalbumin(TBA), whose capacities and affinities vary for each hormone. The higheraffinityof 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 [seeDRUG INTERACTIONS]. Thyroid hormones do not readily cross the placental barrier [seeUse In Specific Populations].

Elimination

Metabolism

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 thebileand gut where they undergo enterohepatic recirculation.

Excretion

Thyroid hormones are primarily eliminated by the kidneys. A portion of the conjugated hormone reaches thecolonunchanged and is eliminated in the feces. Approximately 20% of T4 is eliminated in thestool. Urinary excretion of T4 decreases with age.

Table 7: Pharmacokinetic Parameters of Thyroid Hormones in Euthyroid Patients

PATIENT INFORMATION

Inform the patient of the following information to aid in the safe and effective use of LEVOLET:

Dosing And Administration

• Instruct patients to take LEVOLET only as directed by their healthcare provider.
• Instruct patients to take LEVOLET 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 LEVOLET 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 LEVOLET.

Important Information

• Inform patients that it may take several weeks before they notice an improvement in symptoms.
• Inform patients that the levothyroxine in LEVOLET is intended to replace a hormone that is normally produced by the thyroidgland. Generally, replacement therapy is to be taken for life.
• Inform patients that LEVOLET 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, particularlyheart disease, diabetes, clotting disorders, and adrenal orpituitary glandproblems, as the dose of medications used to control these other conditions may need to be adjusted while they are taking LEVOLET. 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 LEVOLET 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 LEVOLET therapy, but this is usually temporary.