Tirosint (Levothyroxine Sodium) - Drug Interactions, Contraindications, Overdosage, etc

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 TIROSINT. 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

Drug or Drug Class	Effect
Drugs that may reduce TSH secretion -the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists	Use of these agents may result in a transient reduction in TSH secretion when
Glucocorticoids	administered at the following doses: Dopamine (> 1 mcg/kg/min);
Octreotide	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	Long-term lithium therapy can result in goiter in up to 50% of patients, and either
Amiodarone	subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus,
Iodide (including iodine-containing	neonate, elderly and euthyroid patients with underlying thyroid disease (e.g.,
radiographic contrast agents)	Hashimoto's thyroiditis or with Grave's disease previously treated with
Lithium	radioiodine or surgery) are among those individuals who are particularly
Methimazole	susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and
Propylthiouracil (PTU)	amiodarone are slowly excreted, producing more prolonged hypothyroidism than
Sulfonamides	parenterally administered iodinated contrast agents. Long-term
Tolbutamide	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 and drugs that contain pharmacologic amounts of iodide may cause
Iodide (including iodine-containing radiographic contrast agents)		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 T 4 absorption, which may result in hypothyroidism
Antacids		Concurrent use may reduce the efficacy of levothyroxine by binding and delaying
- Aluminum & Magnesium		or preventing absorption, potentially resulting in hypothyroidism. Calcium
Hydroxides		carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate
- Simethicone		likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4
Bile Acid Sequestrants		hours apart from these agents.
-Cholestyramine
-Colestipol
Calcium Carbonate
Cation Exchange Resins-Kayexalate
Ferrous Sulfate
Sucralfate
Drugs that may alter T 4 and T 3 serum transport - but FT 4 concentration remains normal; and therefore, the
patient remains euthyroid
Drugs that may increase serum TBG concentration			Drugs that may decrease serum TBG concentration
Clofibrate			Androgens / Anabolic Steroids
Estrogen-containing oral contraceptives			Asparaginase
Estrogens (oral)			Glucocorticoids
Heroin / Methadone			Slow-Release Nicotinic Acid
5-Fluorouracil
Mitotane
Tamoxifen
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV)		Administration of these agents with levothyroxine results in an initial transient
Heparin		increase in FT4. Continued administration results in a decrease in serum T4 and
Hydantoins		normal FT4 and TSH concentrations and, therefore, patients are clinically
Non Steroidal Anti-Inflammatory		euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An
Drugs		initial increase in serum FT4 is followed by return of FT4 to normal levels with
- Fenamates		sustained therapeutic serum salicylate concentrations, although total-T4 levels
- Phenylbutazone		may decrease by as much as 30%.
Salicylates (> 2 g/day)
Drugs that may alter T 4 and T 3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine		Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause
Hydantoins		increased hepatic degradation of levothyroxine, resulting in increased
Phenobarbital Rifampin		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 T 4 5’-deiodinase activity
Amiodarone		Administration of these enzyme inhibitors decreases the peripheral conversion of
Beta-adrenergic antagonists		T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually
-(e.g., Propranolol > 160 mg/day)		normal but may occasionally be slightly increased. In patients treated with large
Glucocorticoids-(e.g., Dexamethasone > 4 mg/day)		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
Propylthiouracil (PTU)		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)		Thyroid hormones appear to increase the catabolism of vitamin K-dependent
- Coumarin Derivatives		clotting factors, thereby increasing the anticoagulant activity of oral
- Indandione Derivatives		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		Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase
-Tricyclics (e.g., Amitriptyline)		the therapeutic and toxic effects of both drugs, possibly due to increased receptor
-Tetracyclics (e.g., Maprotiline)		sensitivity to catecholamines. Toxic effects may include increased risk of cardiac
-Selective Serotonin Reuptake		arrhythmias and CNS stimulation; onset of action of tricyclics may be
Inhibitors (SSRIs; e.g., Sertraline)		accelerated. Administration of sertraline in patients stabilized on levothyroxine
		may result in increased levothyroxine requirements.
Antidiabetic Agents		Addition of levothyroxine to antidiabetic or insulin therapy may result in
-Biguanides		increased antidiabetic agent or insulin requirements. Careful monitoring of
-Meglitinides		diabetic control is recommended, especially when thyroid therapy is started,
-Sulfonylureas		changed, or discontinued.
-Thiazolidinediones
-Insulin
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		Therapy with interferon-α has been associated with the development of
-Interferon-α		antithyroid microsomal antibodies in 20% of patients and some have transient
-Interleukin-2		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		Excessive use of thyroid hormones with growth hormones may accelerate
- Somatrem		epiphyseal closure. However, untreated hypothyroidism may interfere with
- Somatropin		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		Decreased theophylline clearance may occur in hypothyroid patients; clearance
- (e.g., Theophylline)		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		These agents have been associated with thyroid hormone
Diazepam		and/or TSH level alterations by various mechanisms.
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics

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 TIROSINT 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).

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 P-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 toT₃. 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.

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). TIROSINT is contraindicated in patients with hypersensitivity to any of the inactive ingredients in TIROSINT capsules (See DESCRIPTION, Inactive Ingredients).

TIROSINT is also contraindicated for anyone who may be unable to swallow a capsule (e.g., infants, small children).