This information is intended for U.S. residents only.
`SYNTHROID®
`(levothyroxine sodium, USP)
`SYNTHROID Tablets — for oral administration
`SYNTHROID Injection — for parenteral administration
`
`-q only
`
`• DESCRIPTION
`• CLINICAL PHARMACOLOGY
`• PHARMACOKINETICS
`• INDICATIONS AND USAGE
`• CONTRAINDICATIONS
`• WARNINGS
`• PRECAUTIONS
`• ADVERSE REACTIONS
`• OVERDOSAGE
`• DOSAGE AND ADMINISTRATION
`• HOW SUPPLIED
`• DIRECTIONS FOR RECONSTITUTION
`
`DESCRIPTION: SYNTHROID (levothyroxine sodium, USP) Tablets and injection contain synthetic crystalline L-3, 3', 5, 5'-
`tetraiodothyronine sodium salt [levothyroxine (T4) sodium]. Synthetic T4 is identical to that produced in the human thyroid gland.
`Levothyroxine (T4) Sodium has an empirical formula of CE5H1014NNa04xH20, molecular weight of 798.86 (anhydrous), and
`structural formula as shown:
`
`HO
`
`CH2-- C COONa-XH2O
`
`NH2
`
`LEVOTHYROXINE SODIUM
`
`Inactive Ingredients (SYNTHROID Tablets): acacia, confectioner's sugar (contains corn starch), lactose, magnesium stearate,
`povidone, talc. The following are the color additives by tablet strength:
`Strength
`(mcg) Color Additive(s)
`25 (cid:9)
`FD&C Yellow No. 6
`50 None
`FD&C Red. No. 40, FD&C Blue No. 2
`75 (cid:9)
`FD&C Blue No. 1, FD&C Yellow No. 6, D&C Yellow No. 10
`88 (cid:9)
`100 (cid:9) D&C Yellow No. 10, FD&C Yellow No. 6
`112 D&C Red No. 27 & 30
`FD&C Yellow No. 6, FD&C. Red No. 40, FD&C Blue No. 1
`125 (cid:9)
`150 FD&C Blue No. 2
`FD&C Blue No. 1, D&C Red No. 27 & 30
`175 (cid:9)
`200 FD&C Red No. 40
`300 (cid:9) D&C Yellow No. 10, FD&C Yellow No. 6, FD&C Blue No. 1
`
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`Inactive Ingredients (SYNTHROID Injection): 10 mg mannitol, USP, 0.7 mg tribasic sodium phosphate, anhydrous (200 mcg/vial),
`1.75 mg tribasic sodium phosphate, anhydrous (500 meg/vial.), sodium hydroxide, Q.S. for pH adjustment.
`Levothyroxine sodium powder for reconstitution for injection is a sterile preparation.
`
`CLINICAL PHARMACOLOGY: The synthesis and secretion of the major thyroid hormones, L-thyroxine (T4) and L-triiodothyronine
`(TA from the normally functioning thyroid gland are regulated by complex feedback mechanisms of the hypothalamic-pituitary-thyroid
`axis. The thyroid gland is stimulated to secrete thyroid hormones by the action of thyrotropin (thyroid stimulating hormone, TSH), which
`is produced in the anterior pituitary gland. TSH secretion is in turn controlled by thyrotropin-releasing hormone (TRH) produced in the
`hypothalamus, circulating thyroid hormones, and possibly other mechanisms. Thyroid hormones circulating in the blood act as feedback
`inhibitors of both TSH and TRH secretion. Thus, when serum concentrations of T3 and T4 are increased, secretion of TSH and TRH
`decreases. Conversely, when serum thyroid hormone concentrations are decreased, secretion of TSH and TRH is increased. Administration
`of exogenous thyroid hormones to euthyroid individuals results in suppression of endogenous thyroid hormone secretion.
`The mechanisms by which thyroid hormones exert their physiologic actions have not been completely elucidated. T4 and T3
`are transported into cells by passive and active mechanisms. T3 in cell cytoplasm and T3 generated from T4 within the cell diffuse
`into the nucleus and bind to thyroid receptor proteins, which appear to be primarily attached to DNA. Receptor binding leads to
`activation or repression of DNA transcription, thereby altering the amounts of mRNA and resultant proteins. Changes in protein
`concentrations are responsible for the metabolic changes observed in organs and tissues.
`Thyroid hormones enhance oxygen consumption of most body tissues and increase the basal metabolic rate and metabolism of
`carbohydrates, lipids, and proteins. Thus, they exert a profound influence on every organ system and are of particular importance
`in the development of the central nervous system. Thyroid hormones also appear to have direct effects on tissues, such as increased
`myocardial contractility and decreased systemic vascular resistance.
`The physiologic effects of thyroid hormones are produced primarily by T3, a large portion of which is derived from the deiodi-
`nation of T4 in peripheral tissues. About 70 to 90 percent of peripheral T3 is produced by monodeiodination of T4 at the 5' position
`(outer ring). Peripheral monodeiodination of T4 at the 5 position (inner ring) results in the formation of reverse triiodothyronine
`(rT3), which is calorigenically inactive.
`
`• PHARMACOKINETICS: Few clinical studies have evaluated the kinetics of orally administered thyroid hormone. In animals, the most
`active sites of absorption appear to be the proximal and mid-jejunum. T4 is not absorbed from the stomach and little, if any, drug is absorbed
`from the duodenum. There seems to be no absorption of T4 from the distal colon in animals. A number of human studies have confirmed
`the importance of an intact jejunum and ileum for T4 absorption and have shown some absorption from the duodenum. Studies involving
`radioiodinated T4 fecal tracer excretion methods, equilibration, and AUC methods have shown that absorption varies from 48 to 80 percent
`of the administered dose. The extent of absorption is increased in the fasting state and decreased in malabsorption syndromes, such as
`spare. Absorption may also decrease with age. The degree of T4 absorption is dependent on the product formulation as well as on the
`character of the intestinal contents, including plasma protein and soluble dietary factors, which bind thyroid hormone making it unavailable
`for diffusion. Decreased absorption may result from administration of infant soybean formula, ferrous sulfate, sodium polystyrene
`sulfonate, aluminum hydroxide, sucralfate, or bile acid sequestrants. T4 absorption following intramuscular administration is variable.
`Distribution of thyroid hormones in human body tissues and fluids has not been fully elucidated. More than 99 percent of circulating
`hormones is bound to serum proteins, including thyroxine-binding globulin (TBG), thyroxine-binding prealbumin (TBPA), and albumin
`(TBA). T4 is more extensively and firmly bound to serum proteins than is T3. Only unbound thyroid hormone is metabolically active. The
`higher affinity of TBG and TBPA for T4 partly explains the higher serum levels, slower metabolic clearance, and longer serum elimina-
`tion half-life of this hormone.
`Certain drugs and physiologic conditions can alter the binding of thyroid hormones to serum proteins and/or the concen-
`trations of the serum proteins available for thyroid hormone binding. These effects must be considered when interpreting the
`results of thyroid function tests. (See Drug Interactions and Laboratory Test Interactions.)
`T4 is eliminated slowly from the body, with a half-life of 6 to 7 days. T3 has a half-life of 1 to 2 days. The liver is the major site of degra-
`dation for both hormones. T4 and T3 are conjugated with glucuronic and sulfuric acids and excreted in the bile. There is an enterohepatic
`circulation of thyroid hormones, as they are liberated by hydrolysis in the intestine and reabsorbed. A portion of the conjugated material
`reaches the colon unchanged, is hydrolyzed there, and is eliminated as free compounds in the feces. In man, approximately 20 to 40 per-
`cent of T4 is eliminated in the stool. About 70 percent of the T4 secreted daily is deiodinated to yield equal amounts of T3 and rT3. Subse-
`quent deiodination of T3 and rT3 yields multiple forms of diiodothyronine. A number of other minor T4 metabolites have also been
`identified. Although some of these metabolites have biologic activity, their overall contribution to the therapeutic effect of T4 is minimal.
`
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`- INDICATIONS AND USAGE: SYNTHROID is indicated:
`1. As replacement or supplemental therapy in patients of any age or state (including pregnancy) with hypothyroidism of any etiol-
`ogy except transient hypothyroidism during the recovery phase of subacute thyroiditis: primary hypothyroidism resulting from thyroid
`dysfunction, primary atrophy, or partial or total absence of the thyroid gland, or from the effects of surgery, radiation or drugs, with or
`without the presence of goiter, including subclinical hypothyroidism; secondary (pituitary) hypothyroidism; and tertiary (hypothala-
`mic) hypothyroidism (see CONTRAINDICATIONS and PRECAUTIONS). SYNTHROID Injection can be used intravenously
`when rapid repletion is required, and either intravenously or intramuscularly when the oral route is precluded.
`2. As a pituitary TSH suppressant in the treatment or prevention of various types of euthyroid goiters, including thyroid nodules,
`subacute or chronic lymphocytic thyroiditis (Hashimoto's), multinodular goiter, and in conjunction with surgery and radioactive
`iodine therapy in the management of thyrotropin-dependent well-differentiated papillary or follicular carcinoma of the thyroid.
`
`CONTRAINDICATIONS: SYNTHROID is contraindicated in patients with untreated thyrotoxicosis of any etiology or an
`apparent hypersensitivity to thyroid hormones or any of the inactive product constituents. (The 50 mcg tablet is formulated
`without color additives for patients who are sensitive to dyes.) There is no well-documented evidence of true allergic or idio-
`syncratic reactions to thyroid hormone. SYNTHROID is also contraindicated in the patients with uncorrected adrenal insuffi-
`ciency, as thyroid hormones increase tissue demands for adrenocortical hormones and may thereby precipitate acute adrenal
`crisis (see PRECAUTIONS).
`
`WARNINGS: Thyroid hormones, either alone or together with other therapeutic agents, should not be used for the treatment
`of obesity. In euthyroid patients, doses within the range of daily hormonal requirements are ineffective for weight reduction.
`Larger doses may produce serious or even life threatening manifestations of toxicity, particularly when given in association
`with sympathomimetic amines such as those used for their anorectic effects.
`
`The use of SYNTHROID in the treatment of obesity, either alone or in combination with other drugs, is unjustified. The use of
`SYNTHROID is also unjustified in the treatment of male or female infertility unless this condition is associated with hypothyroidism.
`
`PRECAUTIONS: General: SYNTHROID should be used with caution in patients with cardiovascular disorders, including
`angina, coronary artery disease, and hypertension, and in the elderly who have a greater likelihood of occult cardiac disease.
`Concomitant administration of thyroid hormone and sympathomimetic agents to patients with coronary artery disease may
`increase the risk of coronary insufficiency.
`Use of SYNTHROID in patients with concomitant diabetes mellitus, diabetes insipidus or adrenal cortical insufficiency may
`aggravate the intensity of their symptoms. Appropriate adjustments of the various therapeutic measures directed at these concomi-
`tant endocrine diseases may therefore be required. Treatment of myxedema coma may require simultaneous administration of glu-
`cocorticoids (see DOSAGE AND ADMINISTRATION).
`T4 enhances the response to anticoagulant therapy. Prothrotnbin time should be closely monitored in patients taking both
`SYNTHROID and oral anticoagulants, and the dosage of anticoagulant adjusted accordingly.
`Seizures have been reported rarely in association with the initiation of levothyroxine sodium therapy, and may be related to
`the effect of thyroid hormone on seizure threshold.
`Lithium blocks the TSH-mediated release of T4 and T3. Thyroid function should therefore be carefully monitored during lithium
`initiation, stabilization, and maintenance. If hypothyroidism occurs during lithium treatment, a higher than usual SYNTHROID
`dose may be required.
`Information for the Patient:
`I. SYNTHROID is intended to replace a hormone that is normally produced by your thyroid gland. It is generally taken for
`life, except in cases of temporary hypothyroidism associated with an inflammation of the thyroid gland.
`2. Before or at any time while using SYNTHROID you should tell your doctor if you are allergic to any foods or medicines,
`are pregnant or intend to become pregnant, are breast-feeding, are taking or start taking any other prescription or nonprescription
`(OTC) medications, or have any other medical problems (especially hardening of the arteries, heart disease, high blood pressure,
`or history of thyroid, adrenal or pituitary gland problems).
`3. Use SYNTHROID only as prescribed by your doctor. Do not discontinue SYNTHROID or change the amount you take
`or how often you take it, except as directed by your doctor.
`4. SYNTHROID, like all medicines obtained from your doctor, must be used only by you and for the condition determined
`appropriate by your doctor.
`5. It may lake a few weeks for SYNTHROID to begin working. Until it begins working, you may not notice any change in your symptoms.
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`6. You should notify your doctor if you experience any of the following symptoms, or if you experience any other unusual medical
`event: chest pain, shortness of breath, hives or skin rash, rapid or irregular heartbeat, headache, irritability, nervousness, sleeplessness,
`diarrhea, excessive sweating, heat intolerance, changes in appetite, vomiting, weight gain or loss, changes in menstrual periods, fever,
`hand tremors, leg cramps.
`7. You should inform your doctor or dentist that you are taking SYNTHROID before having any kind of surgery.
`8. You should notify your doctor if you become pregnant while taking SYNTHROID. Your dose of this medicine will likely
`have to be increased while you are pregnant.
`9. If you have diabetes, your dose of insulin or oral antidiabetic agent may need to be changed after starting SYNTHROID. You
`should monitor your blood or urinary glucose levels as directed by your doctor and report any changes to your doctor immediately.
`10. If you are taking an oral anticoagulant drug such as warfarin, your dose may need to be changed after starting
`SYNTHROID. Your coagulation status should be checked often to determine if a change in dose is required.
`11. Partial hair loss may occur rarely during the first few months of SYNTHROID therapy, but it is usually temporary.
`12. SYNTHROID is the trade name for tablets containing the thyroid hormone levothyroxine, manufactured by Abbott Laboratories.
`Other manufacturers also make tablets containing levothyroxine. You should not change to another manufacturer's product without dis-
`cussing that change with your doctor first. Repeat blood tests and a change in the amount of levothyroxine you take may be required.
`13. Keep SYNTHROID out of the reach of children. Store SYNTHROID away from heat and moisture.
`Laboratory Tests: Treatment of patients with SYNTHROID requires periodic assessment of adequacy of titration by appropriate
`laboratory tests and clinical evaluation. Selection of appropriate tests for the diagnosis and management of thyroid disorders
`depends on patient variables such as presenting signs and symptoms, pregnancy, and concomitant medications. A combination of
`sensitive TSH assay and free T4 estimate (free T4, free T4 index) are recommended to confirm a diagnosis of thyroid disease.
`Normal ranges for these parameters are age-specific in newborns and younger children.
`TSH alone or initially may be useful for thyroid disease screening and for monitoring therapy for primary hypothyroidism as a linear
`inverse correlation exists between serum TSH and free T4. Measurement of total serum T4 and T3, resin T3 uptake, and free T3 concen-
`trations may also be useful. Antithyroid microsomal antibodies are an indicator of autoimrnune thyroid disease. The presence of positive
`microsomal antibodies in an euthyroid patient is a major risk factor for the future development of hypothyroidism. An elevated serum TSH
`in the presence of a normal T4 may indicate subclinical hypothyroidism. Intracellular resistance to thyroid honnone is quite rare, and is
`suggested by clinical signs and symptoms of hypothyroidism in the presence of high serum T4 levels. Adequacy of SYNTHROID ther-
`apy for hypothyroidism of pituitary or hypothalamic origin should be assessed by measuring free T4, which should be maintained in the
`upper half of the normal range. Measurement of TSH is not a reliable indicator of response to therapy for this condition. Adequacy of
`SYNTHROID therapy for congenital and acquired pediatric hypothyroidism should be assessed by measuring serum total T4 or free T4,
`which should be maintained in the upper half of the normal range. In congenital hypothyroidism, normalization of serum TSH levels may
`lag behind normalization of serum T4 levels by 2 to 3 months or longer. In rare patients serum TSH remains relatively elevated despite
`clinical euthyroidism and age-specific normal levels of T4 or free T4.
`Drug Interactions: The magnitude and relative clinical importance of the effects noted below are likely to be patient-specific and
`may vary by such factors as age, gender, race, intercurrent illnesses, dose of either agent, additional concomitant medications, and
`timing of drug administration. Any agent that alters thyroid hormone synthesis, secretion, distribution, effect on target tissues,
`metabolism, or elimination may alter the optimal therapeutic dose of SYNTHROID.
`Levothyroxine sodium absorption—The following agents may bind and decrease absorption of levothyroxine sodium from the
`gastrointestinal tract: aluminum hydroxide, cholestyramine resin, colestipol hydrochloride, ferrous sulfate, sodium polystyrene
`sulfonate, soybean flour (e.g., infant formula), sucralfate.
`Binding to serum proteins—The following agents may either inhibit levothyroxine sodium binding to serum proteins or alter the con-
`centrations of serum binding proteins: androgens and related anabolic hormones, asparaginase, clofibrate, estrogens and estrogen-
`containing compounds, 5-fluorouracil, furosemide, glucocorticoids, meclofenamic acid, mefenamic acid, methadone, perphenazine,
`phenylbutazone, phenytoin, salicylates, tamoxifen.
`Thyroid physiology—The following agents may alter thyroid hormone or TSH levels, generally by effects on thyroid honnone
`synthesis, secretion, distribution, metabolism, hormone action, or elimination, or altered TSH secretion: aminoglutethimide,
`p-aminosalicylic acid, amiodarone, androgens and related anabolic hormones, complex anions (thiocyanate, perchlorate, pertech-
`netate), antithyroid drugs, P-adrenergic blocking agents, carbamazepine, chloral hydrate, diazepam, dopamine and dopamine ago-
`nists, ethionamide, glucocorticoids, heparin, hepatic enzyme inducers, insulin, iodinated cholestographic agents, iodine-containing
`compounds, levodopa, lovastatin, lithium, 6-mercaptopurine, metoclopramide, mitotane, nitroprusside, phenobarbital, phenytoin,
`resorcinol, rifampin, somatostatin analogs, sulfonamides, sulfonylureas, thiazide diuretics.
`Adrenocorticoids—Metabolic clearance of adrenocorticoids is decreased in hypothyroid patients and increased in hyperthyroid
`patients, and may therefore change with changing thyroid status.
`Atniodartme—Amiodarone therapy alone can cause hypothyroidism or hyperthyroidism.
`
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`Anticoagulants (oral)—The hypoprothrombinemic effect of anticoagulants may be potentiated, apparently by increased
`catabolism of vitamin K-dependent clotting factors.
`Antidiabetic agents (insulin, sulfonylureas)—Requirements for insulin or oral antidiabetic agents may be reduced in hypothyroid
`patients with diabetes mellitus, and may subsequently increase with the initiation of thyroid hormone replacement therapy.
`[3-adrenergic blocking agents—Actions of some beta-blocking agents may be impaired when hypothyroid patients become euthyroid.
`Cytokines (interferon, interleukin)—Cytokines have been reported to induce both hyperthyroidism and hypothyroidism.
`Digitalis glycosides—Therapeutic effects of digitalis glycosides may be reduced. Serum digitalis levels may be decreased in hyper-
`thyroidism or when a hypothyroid patient becomes euthyroid.
`Ketamine—Marked hypertension and tachycardia have been reported in association with concomitant administration of
`levothyroxine sodium and ketamine.
`Maprotiline—Risk of cardiac arrhythmias may increase.
`Sodium iodide 0 231 and 1311), sodium pertechnetate Tc99m—Uptake of radiolabeled ions may be decreased.
`Somatremiromatmpin—Excessive concurrent use of thyroid hormone may accelerate epiphyseal closure. Untreated hypothyroidism
`may interfere with the growth response to somatrem or somatropin.
`Theophylline—Theophylline clearance may decrease in hypothyroid patients and return toward normal when a euthyroid
`state is achieved.
`Tricyclic antidepressants—Concurrent use may increase the therapeutic and toxic effects of both drugs, possibly due to
`increased catecholamine sensitivity. Onset of action of tricyclics may be accelerated.
`Sympathontimetic agents—Possible increased risk of coronary insufficiency in patients with coronary artery disease.
`Laboratory Test Interactions: A number of drugs or moieties are known to alter serum levels of TSH, T4 and T3 and may
`thereby influence the interpretation of laboratory tests of thyroid function (see Drug Interactions).
`1. Changes in TBG concentration should be taken into consideration when interpreting T4 and T3 values. Drugs such as estrogens
`and estrogen-containing oral contraceptives increase TBG concentrations. TBG concentrations may also be increased dining preg-
`nancy and in infectious hepatitis. Decreases in TBG concentrations are observed in nephrosis, acromegaly, and after androgen or cor-
`ticosteroid therapy. Familial hyper- or hypo-thyroxine-binding-globulinemias have been described. The incidence of TBG deficiency
`is approximately 1 in 9000. Certain drugs such as salicylates inhibit the protein-binding of T4. In such cases, the unbound (free) hor-
`mone should be measured. Alternatively, an indirect measure of free thyroxine, such as the FT4I may be used.
`2. Medicinal or dietary iodine interferes with in vivo tests of radioiodine uptake, producing low uptakes which may not indicate
`a true decrease in hormone synthesis.
`3. Persistent clinical and laboratory evidence of hypothyroidism despite an adequate replacement dose suggests either poor
`patient compliance, impaired absorption, drug interactions, or decreased potency of the preparation due to improper storage.
`Carcinogenesis, Mutagenesis, and Impairment of Fertility: Although animal studies to determine the mutagenic or carcinogenic
`potential of thyroid hormones have not been performed, synthetic T4 is identical to that produced by the human thyroid gland. A
`reported association between prolonged thyroid hormone therapy and breast cancer has not been confirmed and patients receiving
`levothyroxine sodium for established indications should not discontinue therapy.
`Pregnancy: Pregnancy Category A. Studies in pregnant women have not shown that levothyroxine sodium increases the risk of
`fetal abnormalities if administered during pregnancy. If levothyroxine sodium is used during pregnancy, the possibility of fetal harm
`appears remote. Because studies cannot rule out the possibility of harm levothyroxine sodium should be used during pregnancy
`only if clearly needed.
`Thyroid hormones cross the placental barrier to some extent. T4 levels in the cord blood of athyroid fetuses have been shown
`to be about one-third of maternal levels. Nevertheless, maternal-fetal transfer of T4 may not prevent in utero hypothyroidism.
`Hypothyroidism during pregnancy is associated with a higher rate of complications, including spontaneous abortion and
`preeclampsia, and has been reported to have an adverse effect on fetal and childhood development. On the basis of current
`knowledge, SYNTHROID® (levothyroxine sodium, USP) should therefore not be discontinued during pregnancy, and hypothy-
`roidism diagnosed during pregnancy should be treated. Studies have shown that during pregnancy T4 concentrations may
`decrease and TSH concentrations may increase to values outside normal ranges. Postpartum values are similar to preconcep-
`tion values. Elevations in TSH may occur as early as 4 weeks gestation.
`Pregnant women who are maintained on SYNTHROID should have their TSH measured periodically. An elevated TSH should
`be corrected by an increase in SYNTHROID dose. After pregnancy, the dose can be decreased to the optimal preconception dose.
`Nursing Mothers: Minimal amounts of thyroid hormones are excreted in human milk. Thyroid hormones are not associated
`with serious adverse reactions and do not have known tumorigenic potential. While caution should be exercised when
`SYNTHROID is administered to a nursing woman, adequate replacement doses of levothyroxine sodium are generally needed
`to maintain normal lactation.
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`Pediatric Use: Congenital hypothyroidism: Rapid restoration of normal serum T4 concentrations is essential for preventing
`the deleterious effects of neonatal thyroid hormone deficiency on intelligence, as well as on overall growth and development.
`SYNTHROID should be initiated immediately upon diagnosis, and is generally continued for life. The goal of therapy is to
`maintain the serum total T4 or FT4 in the upper half of the normal range and serum TSH in the normal range.
`An initial starting dose of 10 to 15 mcg/kg/day (ages 0-3 months) will generally increase serum T4 concentrations to the upper
`half of the normal range in less than 3 weeks. Clinical assessment of growth and development and thyroid status should be mon-
`itored frequently. In most cases, the dose of SYNTHROID per body weight will decrease gradually as the patient grows through
`infancy and childhood (see Table). Prolonged use of large closes in infants may be associated with later behavior problems.
`Thyroid function tests (serum total T4 or FT4, and TSH) should be monitored closely and used to determine the adequacy of
`SYNTHROID therapy. Normalization of serum T4 levels is usually followed by a rapid decline of TSH levels. Nevertheless, nor-
`malization of TSH may lag behind normalization of T4 levels by 2 to 3 months or longer. The relative elevation of serum TSH
`is more marked during the early months of therapy, but can persist to some degree throughout life. In rare patients TSH remains
`relatively elevated despite clinical euthyroidism and age-specific normal levels of total T4 or FT4, Increasing the SYNTHROID
`dosage to suppress TSH into the normal range may result in overtreatment, with an elevated serum T4 level and clinical features
`of hyperthyroidism, including irritability, increased appetite with diarrhea, and sleeplessness. Another risk of prolonged
`overlreatment in infants is premature cranial synostosis.
`Assessment of permanence of hypothyroidism may be done when transient hypothyroidism is suspected. Levothyroxine
`therapy may be interrupted for 30 days after 3 years of age and serum measurement of T4 and TSH levels obtained. If T4 is
`low and the TSH level is elevated, permanent hypothyroidism is confirmed and therapy should be re-instituted. If T4 and TSH
`remain in the normal range, a presumptive diagnosis of transient hypothyroidism can be made. In this instance, continued clin-
`ical monitoring and periodic reevaluation of thyroid function may be warranted.
`Acquired hypothyroidism. The initial dose of SYNTHROID varies with age and body weight, and should be adjusted to main-
`tain serum total T4 or free T4 levels in the upper half of the normal range. In general, in the absence of overriding clinical con-
`cerns, children should be started on a full replacement dose. Children with underlying heart disease should be started at lower
`doses, with careful upward titration. Children with severe, long-standing hypothyroidism may also be started on a lower initial
`dose with upward titration in an attempt to avoid premature closure of epiphyses. The recommended dose per body weight
`decreases with age (see Table).
`Treated children may resume growth at a rate greater than normal (period of transient catch-up growth). In some cases catch-
`up growth may be adequate to normalize growth; however, in children with severe and prolonged hypothyroidism, adult height
`may be reduced. Excessive thyroxine replacement may initiate accelerated bone maturation resulting in disproportionate
`advancement in skeletal age and shortened adult stature.
`Assessment of permanence of hypothyroidism may be done when transient hypothyroidism is suspected. Levothyroxine
`therapy may be interrupted for 30 days and serum measurement of T4 and TSH levels obtained. If T4 is low and the TSH level
`is elevated, permanent hypothyroidism is confirmed and therapy should be re-instituted. If T4 and TSH remain in the normal
`range, a presumptive diagnosis of transient hypothyroidism can be made. In this instance, continued clinical monitoring and
`periodic reevaluation of thyroid function may be warranted.
`
`ADVERSE REACTIONS: Adverse reactions other than those indicative of thyrotoxicosis as a result of therapeutic
`overdosage, either initially or during the maintenance periods, are rare (see OVERDOSAGE). Craniosynostosis has been
`associated with iatrogenic hyperthyroidism in infants receiving thyroid hormone replacement therapy. Inadequate doses of
`SYNTHROID may produce or fail to resolve symptoms of hypothyroidism. Hypersensitivity reactions to the product
`excipients, such as rash and urticaria, may occur. Partial hair loss may occur during the initial months of therapy, but is
`generally transient. The incidence of continued hair loss is unknown. Pseudotumor cerebri has been reported in pediatric
`patients receiving thyroid hormone replacement therapy.
`
`OVERDOSAGE: Signs and Symptoms: Excessive doses of SYNTHROID result in a hypermetabolic state
`indistinguishable from thyrotoxicosis of endogenous origin. Signs and symptoms of thyrotoxicosis include weight loss,
`increased appetite, palpitations, nervousness, diarrhea, abdominal cramps, sweating, tachycardia, increased pulse and blood
`pressure, cardiac arrhythmias, tremors, insomnia, heat intolerance, fever, and menstrual irregularities. Symptoms are not
`always evident or may not appear until several days after ingestion.
`Treatment of Overdosage: SYNTHROID should be reduced in dose or temporarily discontinued if signs and symptoms of
`overdosage appear.
`In the treatment of acute massive SYNTHROID overdosage, symptomatic and supportive therapy should be instituted immediately.
`Treatment is aimed at reducing gastrointestinal absorption and counteracting central and peripheral effects, mainly those of increased
`sympathetic activity. The stomach should be emptied immediately by emesis or gastric lavage if not otherwise contraindicated (e.g., by
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`coma, convulsions or loss of gag reflex). Cholestyramine and activated charcoal have also been used to decrease levothyroxine sodium
`absorption. Oxygen should be administered and ventilation maintained as necessary. f3-receptor antagonists, particularly propranolol, are
`useful in counteracting many of the effects of increased sympathetic activity. Propranolol may be administered intravenously at a dosage
`of 1 to 3 mg over a 10 minute period or orally, 80 to 160 mg/day, especially when no contraindications exist for its use. Cardiac glyco-
`sides may be administered if congestive heart failure develops. Measures to control fever, hypoglycemia, or fluid loss should be initiated
`as necessary. Glucocorticoids may be administered to inhibit the conversion of T4 to T3.
`Since T4 is extensively protein bound, very little drug will be removed by dialysis.
`
`DOSAGE AND ADMINISTRATION: The dosage and rate of administration of SYNTHROID is determined by the indica-
`tion, and must in every case be individualized according to patient response and laboratory findings.
`Hypothyroidism: The goal of therapy for primary hypothyroidism is to achieve and maintain a clinical and biochemical euthy-
`roid state with consequent resolution of hypothyroid signs and symptoms. The starting dose of SYNTHROID, the frequency of
`dose titration, and the optimal full replacement dose must be individualized for every patient, and will be influenced by such
`factors as age, weight, cardiovascular status, presence of other illness, and the severity and duration of hypothyroid symptoms.
`The usual full replacement dose of SYNTHROID for younger, healthy adults is approximately 1.6 mcg/kg/clay administered
`once dail