Levoxyl (Levothyroxine Sodium) - Drug Interactions, Contraindications, Overdosage

DRUG INTERACTIONS

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 LEVOXYL^®. In addition, thyroid hormones and thyroid status have varied effects on the pharmacokinetics and action 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

Drug or Drug Class	Effect
Drugs that may reduce TSH secretion -the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine / Dopamine Agonists Glucocorticoids Octreotide	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
Aminoglutethimide Amiodarone Iodide (including iodine- Containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	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
Amiodarone Iodide (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 - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Sucralfate	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 decrease serum TBG concentration	Drugs that may increase serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non 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
Carbamazepine Hydantoins Phenobarbital Rifampin	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
Amiodarone Beta-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).
Miscellaneous
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    - Thiazolidediones    - 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	Thereapy wih 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 123I, 131I, and 99mTc
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 Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	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 LEVOXYL^® dose is increased. Prothrombin time should be closely monitored to permit appropriate and timely dosage adjustments (see Table 2).

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 approximately 20 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 B-receptor antagonists, e.g., propranolol (1 to 3 mg intravenously over a 10-minute period, or orally, 80 to 160 mg/day). Provide respiratory support as needed; control congestive heart failure; control fever, hypoglycemia, and fluid loss as necessary. Glucocorticoids may be given to inhibit the conversion of T₄ to T₃. Because T₄ is highly proteinbound, very little drug will be removed by dialysis.

CONTRAINDICATIONS

Levothyroxine is contraindicated in patients with untreated subclinical (suppressed serum TSH level with normal T₃ and T₄ levels) or overt thyrotoxicosis of any etiology and in patients with acute myocardial infarction. Levothyroxine is contraindicated in patients with uncorrected adrenal insufficiency since thyroid hormones may precipitate an acute adrenal crisis by increasing the metabolic clearance of glucocorticoids (see PRECAUTIONS). LEVOXYL^® is contraindicated in patients with hypersensitivity to any of the inactive ingredients in LEVOXYL^® tablets (see DESCRIPTION, Inactive Ingredients).

Levothyroxine sodium should not be used in the treatment of male or female infertility unless this condition is associated with hypothyroidism.

In patients with nontoxic diffuse goiter or nodular thyroid disease, particularly the elderly or those with underlying cardiovascular disease, levothyroxine sodium therapy is contraindicated if the serum TSH level is already suppressed due to the risk of precipitating overt thyrotoxicosis (see CONTRAINDICATIONS). If the serum TSH level is not suppressed, LEVOXYL^® should be used with caution in conjunction with careful monitoring of thyroid function for evidence of hyperthyroidism and clinical monitoring for potential associated adverse cardiovascular signs and symptoms of hyperthyroidism.