DRUG INTERACTIONS
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 LEVOTHROID® . 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.
Table 2: Drug-Thyroidal Axis Interactions
| Drugs that may reduce TSH secretion -the reduction is not sustained; therefore, hypothyroidism does not occur |
| Drug or Drug Class |
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Dopamine / Dopamine Agonists
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Glucocorticoids
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Octreotide
|
| Effect - Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (>/=1 µg/kg/min); Glucocorticoids (hydrocortisone >/=100 mg/day or equivalent); Octreotide (>100 µg/day).
|
| Drugs that alter thyroid hormone secretion |
| Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism |
| Drug or Drug Class |
|
Aminoglutethimide
|
Iodide
|
Methimazole
|
|
Amiodarone
|
(including iodine-containing
Radiographic contrast agents)
Lithium
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Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
|
| Effect - 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 |
| Drug or Drug Class |
|
Amiodarone
|
|
Iodide (including iodine-containing Radiographic contrast agents)
|
| Effect - Iodide and drugs that contain pharmacological 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.
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| Drugs that may decrease T4 absorption, which may result in hypothyroidism |
| Drug or Drug Class |
|
Antacids
|
Bile Acid Sequestrants
|
Cation Exchange Resins
|
|
- Aluminum & Magnesium
|
- Cholestyramine
|
- Kayexalate
|
|
Hydroxides
|
- Colestipol
|
Ferrous Sulfate
|
|
- Simethicone
|
Calcium Carbonate
|
Sucralfate
|
| Effect - 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.
|
| 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 |
|
Clofibrate
|
Estrogens (oral)
|
Mitotane
|
|
Estrogen-containing
|
Heroin/Methadone
|
Tamoxifen
|
|
oral contraceptives
|
5-Flourouracil
|
| Drugs that may decrease serum TBG concentration |
|
Androgens / Anabolic Steroids
|
Glucocorticoids
|
|
Asparaginase
|
Slow-Release Nicotinic Acid
|
| Drugs that may cause protein-binding site displacement |
| Drug or Drug Class |
|
Furosemide (> 80 mg IV)
|
Non Steroidal Anti-Inflammatory Drugs
|
|
Heparin
|
- Fenamates
|
|
Hydantoins
|
- Phenylbutazone
|
|
Salicylates (>2 g/day)
|
| Effect - 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 |
| Drug or Drug Class |
|
Carbamazepine Hydantoins Phenobarbital Rifampin
|
| Effect - 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 |
| Drug or Drug Class |
|
Amiodarone
|
Glucocorticoids
|
|
Beta-adrenergic antagonists
|
- (e.g., Dexamethasone >/=4 mg/day)
|
|
- (e.g., Propranolol > 160 mg/day)
|
- Propylthiouracil (PTU)
|
| Effect - 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).
|
| Miscellaneous |
| Drug or Drug Class |
|
Anticoagulants (oral)
|
|
- Coumarin Derivatives
|
- Indandione Derivatives
|
| Effect - 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.
|
| Drug or Drug Class |
|
Antidepressants
|
|
- Tricyclics (e.g., Amitriptyline)
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- Selective Serotonin Reuptake Inhibitors
|
|
- Tetracyclics (e.g., Maprotiline)
|
(SSRIs; e.g., Sertraline)
|
| Effect - 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.
|
| Drug or Drug Class |
|
Antidiabetic Agents
|
- Meglitinides
|
- Sulfonylureas
|
|
- Biguanides
|
- Thiazolidinediones
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- Insulin
|
| Effect - 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.
|
| Drug or Drug Class |
|
Cardiac Glycosides
|
| Effect - 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.
|
| Drug or Drug Class |
|
Cytokines
|
- Interferon-(alpha)
|
- Interleukin-2
|
| Effect - Therapy with interferon-(alpha) 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-(beta) and -(gamma) have not been reported to cause thyroid dysfunction.
|
| Drug or Drug Class |
|
Growth Hormones
|
- Somatrem
|
- Somatropin
|
| Effect - Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
|
| Drug or Drug Class |
|
Ketamine
|
| Effect - Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
|
| Drug or Drug Class |
|
Methylxanthine Bronchodilators
|
- (e.g., Theophylline)
|
| Effect - Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
|
| Drug or Drug Class |
|
Radiographic Agents
|
| Effect - Thyroid hormones may reduce the uptake of123 I,131 I, and99m Tc.
|
| Drug or Drug Class |
|
Sympathomimetics
|
| Effect - 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.
|
| Drug or Drug Class |
|
Chloral Hydrate
|
Metoclopramide
|
Perphenazine
|
|
Diazepam
|
6-Mercaptopurine
|
Resorcinol
|
|
Ethionamide
|
Nitroprusside
|
(excessive topical use)
|
|
Lovastatin
|
Para-aminosalicylate sodium
|
Thiazide Diuretics
|
| Effect - These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.
|
|
Oral anticoagulants
- Levothyroxine 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 LEVOTHROID® dose is increased. Prothrombin time should be closely monitored to permit appropriate and timely dosage adjustments (see Table 2).
Digitalis glycosides
- The therapeutic effects of digitalis glycosides may be reduced by levothyroxine. Serum digitalis glycoside levels may be decreased when a hypothyroid patient becomes euthyroid, necessitating an increase in the dose of digitalis glycosides (see Table 2).
Drug-Food Interactions - Consumption of certain foods may affect levothyroxine absorption thereby necessitating adjustments in dosing. Soybean flour (infant formula), cotton seed meal, walnuts, and dietary fiber may bind and decrease the absorption of levothyroxine sodium from the GI tract.
Drug-Laboratory Test Interactions - Changes in TBG concentration must be considered when interpreting T4 and T3 values, which necessitates measurement and evaluation of unbound (free) hormone and/or determination of the free-T4 index (FT4 I). Pregnancy, infectious hepatitis, estrogens, estrogen-containing oral contraceptives, and acute intermittent porphyria increase TBG concentrations. Decreases in TBG concentrations are observed in nephrosis, severe hypoproteinemia, severe liver disease, acromegaly, and after androgen or corticosteroid therapy (see also Table 2). Familial hyper- or hypo-thyroxine binding globulinemias have been described, with the incidence of TBG deficiency approximating 1 in 9000. Carcinogenesis, Mutagenesis, and Impairment of Fertility - Animal studies have not been performed to evaluate the carcinogenic potential, mutagenic potential or effects on fertility of levothyroxine. The synthetic T4 in LEVOTHROID® is identical to that produced naturally by the human thyroid gland. Although there has been a reported association between prolonged thyroid hormone therapy and breast cancer, this has not been confirmed. Patients receiving LEVOTHROID® for appropriate clinical indications should be titrated to the lowest effective replacement dose.
Pregnancy - Category A - Studies in women taking levothyroxine sodium during pregnancy have not shown an increased risk of congenital abnormalities. Therefore, the possibility of fetal harm appears remote. LEVOTHROID® should not be discontinued during pregnancy and hypothyroidism diagnosed during pregnancy should be promptly treated.
Hypothyroidism during pregnancy is associated with a higher rate of complications, including spontaneous abortion, pre-eclampsia, stillbirth and premature delivery. Maternal hypothyroidism may have an adverse effect on fetal and childhood growth and development. During pregnancy, serum T4 levels may decrease and serum TSH levels increase to values outside the normal range. Since elevations in serum TSH may occur as early as 4 weeks gestation, pregnant women taking LEVOTHROID® should have their TSH measured during each trimester. An elevated serum TSH level should be corrected by an increase in the dose of LEVOTHROID® . Since postpartum TSH levels are similar to preconception values, the LEVOTHROID® dosage should return to the pre-pregnancy dose immediately after delivery. A serum TSH level should be obtained 6-8 weeks postpartum.
Thyroid hormones cross the placental barrier to some extent as evidenced by levels in cord blood of athyreotic fetuses being approximately one-third maternal levels. Transfer of thyroid hormone from the mother to the fetus, however, may not be adequate to prevent in utero hypothyroidism.
Nursing Mothers - Although thyroid hormones are excreted only minimally in human milk, caution should be exercised when LEVOTHROID® is administered to a nursing woman. However, adequate replacement doses of levothyroxine are generally needed to maintain normal lactation.
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OVERDOSAGE
The signs and symptoms of overdosage are those of hyperthyroidism (see PRECAUTIONS and ADVERSE REACTIONS). In addition, confusion and disorientation may occur. Cerebral embolism, shock, coma, and death have been reported. Seizures have occurred in a child ingesting 18 mg of levothyroxine. Symptoms may not necessarily be evident or may not appear until several days after ingestion of levothyroxine sodium.
TREATMENT OF OVERDOSAGE
Levothyroxine sodium should be reduced in dose or temporarily discontinued if signs or symptoms of overdosage occur. Acute Massive Overdosage - This may be a life-threatening emergency, therefore, symptomatic and supportive therapy should be instituted immediately. If not contraindicated (e.g., by seizures, coma, or loss of the gag reflex), the stomach should be emptied by emesis or gastric lavage to decrease gastrointestinal absorption. Activated charcoal or cholestyramine may also be used to decrease absorption. Central and peripheral increased sympathetic activity may be treated by administering (beta)-receptor antagonists, e.g., propranolol, provided there are no medical contraindications to their use. Provide respiratory support as needed; control congestive heart failure and arrhythmia; control fever, hypoglycemia, and fluid loss as necessary. Large doses of antithyroid drugs (e.g., methimazole or propylthiouracil) followed in one to two hours by large doses of iodine may be given to inhibit synthesis and release of thyroid hormones. Glucocorticoids may be given to inhibit the conversion of T4 to T3. Plasmapheresis, charcoal hemoperfusion and exchange transfusion have been reserved for cases in which continued clinical deterioration occurs despite conventional therapy. Because T4 is highly protein bound, very little drug will be removed by dialysis.
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