The diagnosis of hypothyroidism is confirmed by measuring TSH levels using a sensitive assay (second generation assay sensitivity ≤ 0.1 mIU/L or third generation assay sensitivity ≤ 0.01 mIU/L) and measurement of free-T4 .
The adequacy of therapy is determined by periodic assessment of appropriate laboratory tests and clinical evaluation. The choice of laboratory tests depends on various factors including the etiology of the underlying thyroid disease, the presence of concomitant medical conditions, including pregnancy, and the use of concomitant medications (see PRECAUTIONS — Drug Interactions and Drug-Laboratory Test Interactions). 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 decreased T4 potency of the drug product.
In adult patients with primary (thyroidal) hypothyroidism, serum TSH levels (using a sensitive assay) alone may be used to monitor therapy. The frequency of TSH monitoring during levothyroxine dose titration depends on the clinical situation but it is generally recommended at 6-8 week intervals until normalization. For patients who have recently initiated levothyroxine therapy and whose serum TSH has normalized or in patients who have had their dosage or brand of levothyroxine changed, the serum TSH concentration should be measured after 8-12 weeks. When the optimum replacement dose has been attained, clinical (physical examination) and biochemical monitoring may be performed every 6-12 months, depending on the clinical situation, and whenever there is a change in the patient’s status. It is recommended that a physical examination and a serum TSH measurement be performed at least annually in patients receiving SYNTHROID (see WARNINGS, PRECAUTIONS, and DOSAGE AND ADMINISTRATION).
In patients with congenital hypothyroidism, the adequacy of replacement therapy should be assessed by measuring both serum TSH (using a sensitive assay) and total- or free- T4 . During the first three years of life, the serum total- or free- T4 should be maintained at all times in the upper half of the normal range. While the aim of therapy is to also normalize the serum TSH level, this is not always possible in a small percentage of patients, particularly in the first few months of therapy. TSH may not normalize due to a resetting of the pituitary-thyroid feedback threshold as a result of in utero hypothyroidism. 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 mU/L within 4 weeks should alert the physician to the possibility that the child is not receiving adequate therapy. Careful inquiry should then be made regarding compliance, dose of medication administered, and method of administration prior to raising the dose of SYNTHROID.
The recommended frequency of monitoring of TSH and total or free T4 in children is as follows: at 2 and 4 weeks after the initiation of treatment; every 1-2 months during the first year of life; every 2-3 months between 1 and 3 years of age; and every 3 to 12 months thereafter until growth is completed. More frequent intervals of monitoring may be necessary if poor compliance is suspected or abnormal values are obtained. It is recommended that TSH and T4 levels, and a physical examination, if indicated, be performed 2 weeks after any change in SYNTHROID dosage. Routine clinical examination, including assessment of mental and physical growth and development, and bone maturation, should be performed at regular intervals (see PRECAUTIONS — Pediatric Use and DOSAGE AND ADMINISTRATION).
Many drugs affect 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. In addition, thyroid hormones and thyroid status have varied effects on the pharmacokinetics and actions of other drugs. A listing of drug-thyroidal axis interactions is contained in Table 2.
The list of drug-thyroidal axis interactions in Table 2 may not be comprehensive due to the introduction of new drugs that interact with the thyroidal axis or the discovery of previously unknown interactions. The prescriber should be aware of this fact and should consult appropriate reference sources (e.g., package inserts of newly approved drugs, medical literature) for additional information if a drug-drug interaction with levothyroxine is suspected.
|Drug or Drug Class||Effect|
|Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur|
|Dopamine/Dopamine AgonistsGlucocorticoidsOctreotide||Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).|
|Drugs that alter thyroid hormone secretion|
|Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism|
|AminoglutethimideAmiodaroneIodide (including iodine-containing radiographic contrast agents)LithiumMethimazolePropylthiouracil (PTU)SulfonamidesTolbutamide||Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.|
|Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism|
|AmiodaroneIodide (including iodine-containing radiographic contrast agents)||Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.|
|Drugs that may decrease T4 absorption, which may result in hypothyroidism|
|Antacids- Aluminum & Magnesium Hydroxides- SimethiconeBile Acid Sequestrants- Cholestyramine- ColestipolCalcium CarbonateCation Exchange Resins- KayexalateFerrous Sulfate OrlistatSucralfate||Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.|
|Drugs that may alter T4 and T3 serum transport — but FT4 concentration remains normal; and therefore, the patient remains euthyroid|
|Drugs that may increase serum TBG concentration||Drugs that may decrease serum TBG concentration|
|ClofibrateEstrogen-containing oral contraceptivesEstrogens (oral)Heroin / Methadone5-FluorouracilMitotaneTamoxifen||Androgens / Anabolic SteroidsAsparaginaseGlucocorticoidsSlow-Release Nicotinic Acid|
|Drugs that may cause protein-binding site displacement|
|Furosemide (> 80 mg IV)HeparinHydantoinsNon Steroidal Anti-Inflammatory Drugs — Fenamates — Phenylbutazone Salicylates (> 2 g/day)||Administration of these agents with levothyroxine results in an initial transient increase in FT4 . Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. 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%.|
|Drugs that may alter T4 and T3 metabolism|
|Drugs that may increase hepatic metabolism, which may result in hypothyroidism|
|CarbamazepineHydantoinsPhenobarbitalRifampin||Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. 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.|
|Drugs that may decrease T4 5′-deiodinase activity|
|AmiodaroneBeta-adrenergic antagonists- (e.g., Propranolol > 160 mg/day)Glucocorticoids- (e.g., Dexamethasone ≥ 4 mg/day)Propylthiouracil (PTU)||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. 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. 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).|
|Anticoagulants (oral)- Coumarin Derivatives- Indandione Derivatives||Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.|
|Antidepressants- Tricyclics (e.g., Amitriptyline)- Tetracyclics (e.g., Maprotiline)- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)||Concurrent use of tri/tetracyclic antidepressants and levothyroxine 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 CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.|
|Antidiabetic Agents- Biguanides- Meglitinides- Sulfonylureas- Thiazolidinediones- Insulin||Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.|
|Cardiac Glycosides||Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.|
|Cytokines- Interferon-α- Interleukin-2||Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.|
|Growth Hormones- Somatrem- Somatropin||Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.|
|Ketamine||Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.|
|Methylxanthine Bronchodilators- (e.g., Theophylline)||Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.|
|Radiographic Agents||Thyroid hormones may reduce the uptake of 123 I, 131 I, and 99m Tc.|
|Sympathomimetics||Concurrent use 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.|
|Chloral HydrateDiazepamEthionamideLovastatinMetoclopramide6-MercaptopurineNitroprussidePara-aminosalicylate sodiumPerphenazineResorcinol (excessive topical use)Thiazide Diuretics||These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.|
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