Synthroid Drug Information

Adverse reactions associated with SYNTHROID therapy are primarily those of hyperthyroidism due to therapeutic overdosage . They include the following: General: fatigue, increased appetite, weight loss, heat intolerance, fever, excessive sweating Central nervous system: headache, hyperactivity, nervousness, anxiety, irritability, emotional lability, insomnia Musculoskeletal: tremors, muscle weakness, muscle spasm Cardiovascular: palpitations, tachycardia, arrhythmias, increased pulse and blood pressure, heart failure, angina, myocardial infarction, cardiac arrest Respiratory: dyspnea Gastrointestinal: diarrhea, vomiting, abdominal cramps, elevations in liver function tests Dermatologic: hair loss, flushing, rash Endocrine: decreased bone mineral density Reproductive: menstrual irregularities, impaired fertility Seizures have been reported rarely with the institution of levothyroxine therapy. Adverse Reactions in Pediatric Patients Pseudotumor cerebri and slipped capital femoral epiphysis have been reported in pediatric patients receiving levothyroxine therapy. Overtreatment may result in craniosynostosis in infants who have not undergone complete closure of the fontanelles, and in premature closure of the epiphyses in pediatric patients still experiencing growth with resultant compromised adult height.

Hypersensitivity Reactions Hypersensitivity reactions to inactive ingredients have occurred in patients treated with thyroid hormone products. These include urticaria, pruritus, skin rash, flushing, angioedema, various gastrointestinal symptoms (abdominal pain, nausea, vomiting and diarrhea), fever, arthralgia, serum sickness, and wheezing. Hypersensitivity to levothyroxine itself is not known to occur.

Adverse reactions associated with SYNTHROID therapy are primarily those of hyperthyroidism due to therapeutic overdosage: arrhythmias, myocardial infarction, dyspnea, muscle spasm, headache, nervousness, irritability, insomnia, tremors, muscle weakness, increased appetite, weight loss, diarrhea, heat intolerance, menstrual irregularities, and skin rash. To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc. at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Drugs Known to Affect Thyroid Hormone Pharmacokinetics Many drugs can exert effects

on 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 ( Tables 5 to 8 ). Table 5. Drugs That May Decrease T4 Absorption (Hypothyroidism) Potential impact: Concurrent use may reduce the efficacy of SYNTHROID by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Drug or Drug Class Effect Phosphate Binders (e.g., calcium carbonate, ferrous sulfate, sevelamer, lanthanum) Phosphate binders may bind to levothyroxine. Administer SYNTHROID at least 4 hours apart from these agents.

Orlistat Monitor patients treated concomitantly with orlistat and SYNTHROID for changes in thyroid function. Bile Acid Sequestrants (e.g., colesevelam, cholestyramine, colestipol) Ion Exchange Resins (e.g., Kayexalate) Bile acid sequestrants and ion exchange resins are known to decrease levothyroxine absorption. Administer SYNTHROID at least 4 hours prior to these drugs or monitor TSH levels.

Proton Pump Inhibitors Sucralfate Antacids (e.g., aluminum & magnesium hydroxides, simethicone) Gastric acidity is an essential requirement for adequate absorption of levothyroxine. Sucralfate, antacids and proton pump inhibitors may cause hypochlorhydria, affect intragastric pH, and reduce levothyroxine absorption. Monitor patients appropriately.

Table 6. Drugs That May Alter T4 and Triiodothyronine (T3) Serum Transport Without Affecting Free Thyroxine (FT4) Concentration (Euthyroidism) Drug or Drug Class Effect Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen These drugs may increase serum thyroxine-binding globulin (TBG) concentration. Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid These drugs may decrease serum TBG concentration. Potential impact (below): Administration of these agents with SYNTHROID results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations.

Salicylates (> 2 g/day) 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%. Other drugs: Carbamazepine Furosemide (> 80 mg IV) Heparin Hydantoins Non-Steroidal Anti-inflammatory Drugs - Fenamates These drugs may cause protein-binding site displacement. Furosemide has been shown to inhibit the protein binding of T4 to TBG and albumin, causing an increase free T4 fraction in serum.

Furosemide competes for T4-binding sites on TBG, prealbumin, and albumin, so that a single high dose can acutely lower the total T4 level. 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. Closely monitor thyroid hormone parameters.

Table 7. Drugs That May Alter Hepatic Metabolism of T4 (Hypothyroidism) Potential impact: Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased SYNTHROID requirements. Drug or Drug Class Effect Phenobarbital Rifampin Phenobarbital has been shown to reduce the response to thyroxine. Phenobarbital increases L-thyroxine metabolism by inducing uridine 5’-diphospho-glucuronosyltransferase (UGT) and leads to lower T4 serum levels.

Changes in thyroid status may occur if barbiturates are added or withdrawn from patients being treated for hypothyroidism. Rifampin has been shown to accelerate the metabolism of levothyroxine. Table 8. Drugs That May Decrease Conversion of T4 to T3 Potential impact: 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. Drug or Drug Class Effect Beta-adrenergic antagonists (e.g., Propranolol > 160 mg/day) In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change, TSH levels remain normal, and patients are clinically euthyroid. Actions of particular beta-adrenergic antagonists may be impaired when a hypothyroid patient is converted to the euthyroid state.

Glucocorticoids (e.g., Dexamethasone > 4 mg/day) 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). Other drugs: Amiodarone Amiodarone inhibits peripheral conversion of levothyroxine (T4) to triiodothyronine (T3) and may cause isolated biochemical changes (increase in serum free-T4, and decreased or normal free-T3) in clinically euthyroid patients.

Antidiabetic Therapy Addition of

SYNTHROID therapy in patients with diabetes mellitus may worsen glycemic control and result in increased antidiabetic agent or insulin requirements. Carefully monitor glycemic control, especially when thyroid therapy is started, changed, or discontinued .

Oral Anticoagulants

SYNTHROID 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 SYNTHROID dose is increased. Closely monitor coagulation tests to permit appropriate and timely dosage adjustments.

Digitalis Glycosides

SYNTHROID may reduce the therapeutic effects of digitalis glycosides. Serum digitalis glycoside levels may decrease when a hypothyroid patient becomes euthyroid, necessitating an increase in the dose of digitalis glycosides.

Antidepressant Therapy Concurrent use of tricyclic (e.g., amitriptyline) or tetracyclic (e.g., maprotiline)

antidepressants and SYNTHROID 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 central nervous system stimulation. SYNTHROID may accelerate the onset of action of tricyclics.

Administration of sertraline in patients stabilized on SYNTHROID may result in increased SYNTHROID requirements.

Ketamine Concurrent use of ketamine and

SYNTHROID may produce marked hypertension and tachycardia. Closely monitor blood pressure and heart rate in these patients.

Sympathomimetics Concurrent use of sympathomimetics and

SYNTHROID 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.

Tyrosine-Kinase Inhibitors Concurrent use of tyrosine-kinase inhibitors such as imatinib may cause

hypothyroidism. Closely monitor TSH levels in such patients.

Drug-Food Interactions Consumption of certain foods may affect

SYNTHROID absorption thereby necessitating adjustments in dosing . Soybean flour, cottonseed meal, walnuts, and dietary fiber may bind and decrease the absorption of SYNTHROID from the gastrointestinal tract. Grapefruit juice may delay the absorption of levothyroxine and reduce its bioavailability. 7.10 Drug-Laboratory Test Interactions Thyroxine-binding Globulin (TBG) Consider changes in TBG concentration when interpreting T4 and T3 values. Measure and evaluate unbound (free) hormone and/or determine the free-T4 index (FT4I) in this circumstance.

Pregnancy, infectious hepatitis, estrogens, estrogen-containing oral contraceptives, and acute intermittent porphyria increase TBG concentration. Nephrosis, severe hypoproteinemia, severe liver disease, acromegaly, androgens, and corticosteroids decrease TBG concentration. Familial hyper- or hypo-thyroxine binding globulinemias have been described, with the incidence of TBG deficiency approximating 1 in 9000. Biotin Biotin supplementation is known to interfere with thyroid hormone immunoassays that are based on a biotin and streptavidin interaction, which may result in erroneous thyroid hormone test results.

Stop biotin and biotin-containing supplements for at least 2 days prior to thyroid testing.

Pregnancy Risk Summary The clinical experience, including data from postmarketing studies, in pregnant women treated with oral levothyroxine to maintain euthyroid state have not reported increased rates of major birth defects, miscarriages, or other adverse maternal or fetal outcomes. There are risks to the mother and fetus associated with untreated hypothyroidism in pregnancy. Since TSH levels may increase during pregnancy, TSH should be monitored and SYNTHROID dosage adjusted during pregnancy (see Clinical Considerations). Animal reproductive studies have not been conducted with levothyroxine sodium.

SYNTHROID should not be discontinued during pregnancy and hypothyroidism diagnosed during pregnancy should be promptly treated. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Maternal hypothyroidism during pregnancy is associated with a higher rate of complications, including spontaneous abortion, gestational hypertension, pre-eclampsia, stillbirth, and premature delivery. Untreated maternal hypothyroidism may have an adverse effect on fetal neurocognitive development.

Dose Adjustments During Pregnancy and the Postpartum Period Pregnancy may increase SYNTHROID requirements. Serum TSH levels should be monitored and the SYNTHROID dosage adjusted during pregnancy. Since postpartum TSH levels are similar to preconception values, the SYNTHROID dosage should return to the pre-pregnancy dose immediately after delivery.

Pediatric Use SYNTHROID is indicated in patients from birth to less than 17 years of age: As a replacement therapy in primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) congenital or acquired hypothyroidism. As an adjunct to surgery and radioiodine therapy in the management of thyrotropin-dependent well-differentiated thyroid cancer. Rapid restoration of normal serum T4 concentrations is essential for preventing the adverse effects of congenital hypothyroidism on cognitive development as well as on overall physical growth and maturation.

Therefore, initiate SYNTHROID therapy immediately upon diagnosis. Levothyroxine is generally continued for life in these patients . Closely monitor infants during the first 2 weeks of SYNTHROID therapy for cardiac overload and arrhythmias.

is contraindicated in patients with uncorrected adrenal insufficiency . Uncorrected adrenal insufficiency.

The signs and symptoms of overdosage are those of hyperthyroidism . In addition, confusion and disorientation may occur. Cerebral embolism, shock, coma, and death have been reported. Seizures occurred in a 3-year-old child ingesting 3.6 mg of levothyroxine.

Symptoms may not necessarily be evident or may not appear until several days after ingestion of levothyroxine sodium. Reduce the SYNTHROID dosage or discontinue temporarily if signs or symptoms of overdosage occur. Initiate appropriate supportive treatment as dictated by the patient’s medical status.

For current information on the management of poisoning or overdosage, contact the National Poison Control Center at 1-800-222-1222 or www.poison.org.