Levothyroxine (T4) is an oral and parenteral synthetically derived levorotatory isomer of thyroxine (T4), a hormone secreted by the thyroid gland. Levothyroxine products are preferred over naturally-derived thyroid hormones from animal glands; effects during dosage titration are more predictable due to the standardized hormonal content of levothyroxine products. Oral levothyroxine is used in the treatment of primary, secondary (pituitary), and tertiary (hypothalamic) hypothyroidism and is the preferred replacement thyroid hormone in patients of all ages; other thyroid replacement hormones offer no discernable safety and efficacy advantage over levothyroxine. Thyroid replacement therapy is not used in transient hypothyroidism during the recovery phase of subacute thyroiditis. Using levothyroxine (T4) alone is sufficient in most individuals with hypothyroidism, including pediatric and pregnant patients. Almost all patients receiving levothyroxine alone will become euthyroid; there are few individuals who need T3 supplementation in addition to T4 to treat symptoms or biochemical imbalance. Levothyroxine is also the preferred agent when used as a diagnostic agent in TSH suppression tests as an aid in detecting hyperthyroidism, and as an adjunct agent in the treatment of well-differentiated thyroid cancer. Intravenous levothyroxine is primarily used to treat myxedema coma, a medical emergency; oral replacement is not recommended until such patients are clinically stable. Levothyroxine has been used clinically since the 1950s; marketed products are governed by modern FDA approval processes for safety, efficacy, purity, potency, and bioequivalence.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
-Administer on an empty stomach, at least 30 to 60 minutes before breakfast.
-Administer at least 4 hours apart from medications or food known to decrease absorption, and 4 hours apart from enteral feedings; evaluate the need for dose adjustments when the patient is regularly administering their dose within 1 hour of certain foods that may affect absorption.
-Soybean flour (infant formula), cotton seed meal, walnuts, and dietary fiber decrease levothyroxine absorption.
-Bioavailability is best when administered in the fasting state.
Oral Solid Formulations
Capsules:
-Administer whole. Do not administer capsules to patients that cannot swallow the intact capsule. The patient must swallow the capsules whole. Do not cut, crush, or chew. The capsules cannot be dissolved in water.
-Administer the capsule with a full glass of water to ease swallowing.
Tablets:
-Instruct patients to take tablets with a full glass of water. Reports exist of choking, gagging, dysphagia, and tablets getting stuck in the throat. Levothyroxine tablets may rapidly disintegrate; reports exist of choking, gagging, dysphagia, and tablets being stuck in the throat. Taking with a full glass of water reduces the risk for this problem in most patients.
-Tablets may be crushed and suspended in a small amount (5 to 10 mL or 1 to 2 teaspoonfuls) of water, breast milk, or non-soy based infant formula, and administered by spoon or dropper for those unable to swallow whole tablets. Administer immediately after preparation; do not store.
-Tablets may be crushed and sprinkled over a small amount (5 to 10 mL) of food (e.g., cool apple sauce). Administer immediately after preparation.
-Do not mix crushed tablets with enteral feedings or soybean-based infant formulas; these reduce bioavailability.
Oral Liquid Formulations
Tirosint-SOL oral solution:
-May administer in water or directly into the mouth.
-To administer in water, squeeze the contents of 1 single unit-dose ampule into a glass or cup containing water and stir. Do NOT dilute with any liquid other than water.
-The preparation should be administered immediately and consumed in its entirety to ensure the entire dose is received. Rinse the glass or cup with additional water and drink the contents to ensure the entire dose is taken. Do NOT use any liquid other than water.
-To administer directly (without water), either squeeze it into the mouth or onto a spoon and immediately consume.
-Storage: Store unopened ampules in the original container (pouch) at 25 degrees C (77 degrees F ); excursions are permitted to 15 to 30 degrees C (59 to 86 degrees F). Discard any unused ampules 15 days after opening the pouch.
Thyquidity oral solution:
-Administer directly into the mouth. Do NOT add to water.
-Storage: Store at 68 to 77 degrees F (20 to 25 degrees C) and dispense in original bottle. Use within 8 weeks of opening the bottle.
Extemporaneous Compounding-Oral
Extemporaneous preparation of a 25 mcg/mL levothyroxine oral suspension:
-NOTE: Levothyroxine is not available as an FDA-approved oral suspension.
-With a mortar and pestle, grind twenty-five 0.1 mg levothyroxine tablets into a fine powder.
-In a separate container, measure 40 mL glycerol.
-Add a small amount of the glycerol to the fine powder and mix into a uniform paste. Add geometric amounts of the glycerol until the suspension is pourable.
-Transfer suspension to a calibrated 100 mL amber bottle. In approximately 10 mL portions, rinse the mortar with the remaining glycerol and transfer washings into the amber bottle trying to leave no levothyroxine in the mortar.
-Add water to the amber bottle to bring the total volume to 100 mL.
-Label the bottle appropriately, including 'Shake well before each use' and 'Refrigerate'. The suspension is stable for 8 days when stored at approximately 4 degrees C (39.2 degrees F).
Injectable Administration
-May be administered intravenously or by intramuscular injection. The intravenous route is preferred.
-Visually inspect parenteral products for particulate matter and discoloration before administration whenever solution and container permit.
Reconstitution:
-Reconstitute by aseptically adding 5 mL of preservative-free 0.9% Sodium Chloride Injection, USP to a vial of lyophilized levothyroxine sodium for injection. Do not use other solutions to reconstitute. Shake well to dissolve completely.
-The resultant solution will have a final concentration as follows:
--approximately 20 mcg/mL for the 100 mcg vial.
-approximately 40 mcg/mL for 200 mcg vial.
-approximately 100 mcg/mL for the 500 mcg vial.
-The reconstituted injection is preservative free and is stable for 4 hours; unused portions should be discarded.
Intravenous Administration
-After reconstitution as directed, do not add levothyroxine sodium for injection to other IV fluids or medications.
-Inject IV via Y-site or a 3-way stopcock at a rate not to exceed 100 mcg per minute.
-In younger patients, inject over 2 to 3 minutes.
Intramuscular Administration
-Inject deeply into a large muscle. Aspirate prior to injection to avoid injection into a blood vessel.
Monitor for signs and symptoms of hypothyroidism that could require an upward adjustment of the thyroid hormone (e.g., levothyroxine) dosage. Signs or symptoms of underdosage or hypothyroidism include constipation, cold intolerance, dry skin (xerosis) or hair, fatigue, impaired intellectual performance or other mental status changes (e.g., depression), deepening of the voice, lethargy, weight gain, tongue enlargement, and, eventually, myxedema coma.
Adverse reactions to levothyroxine are rare. Adverse reactions usually indicate an inappropriate dosage of the hormone.
Transient partial alopecia may rarely occur in hypothyroid patients in the first few months of levothyroxine treatment, but normal hair growth usually recovers. Alopecia may occur during continued treatment due to hyperthyroidism from therapeutic overdosage.
In normal replacement dosages, adverse reactions to levothyroxine replacement are few; most patients tolerate therapy well and find symptomatic complaints due to hypothyroidism resolve with a return to euthymia. Symptoms of adverse reactions may indicate over-replacement of the hormone. Many of the signs and symptoms of excess thyroid hormone are subtle and insidious. Manifestations of excessive dosage or hyperthyroidism include anorexia, hyperhidrosis (sweating), diarrhea, abdominal pain or cramps, dyspnea, elevated hepatic enzymes, emotional lability, fatigue, fever, flushing, headache, heat intolerance, hyperactivity, appetite stimulation/change in appetite, infertility, irritability, insomnia, menstrual irregularity (e.g., amenorrhea), muscle weakness, muscle cramps, muscle spasm, nausea, vomiting, nervousness or anxiety, tremor, and weight loss. The clinician should be alert to constellations of symptoms that gradually worsen over time. Thyrotoxicosis is rare but may result from massive overdosage producing symptoms that resemble thyroid storm, including symptoms of sympathomimetic excess. Reduce the levothyroxine dose or temporarily discontinue the hormone if signs and symptoms of overdosage appear. Treatment is primarily symptomatic and supportive. If appropriate, levothyroxine may be reinstituted at a lower dosage. In normal individuals, normal hypothalamic-pituitary-thyroid axis function is restored in 6 to 8 weeks after cessation of therapy.
Excess levothyroxine therapy, as well as overt hyperthyroidism, can indirectly increase the workload of the heart increasing heart rate, cardiac wall thickness, and cardiac contractility; these effects may precipitate angina, heart rate changes, or arrhythmia exacerbation. Excessive dosage can produce symptoms including palpitations, sinus tachycardia, atrial fibrillation, cardiac arrhythmias, hypertension, heart failure, angina, myocardial infarction, and cardiac arrest. Peripheral edema may also occur. The clinician should be alert to constellations of symptoms that gradually worsen over time. Low initial doses of levothyroxine are advised for patients where compromised integrity of the cardiovascular system, particularly the coronary arteries, is suspected or known such as patients with angina pectoris or the elderly. Also, reduce the dose in such patients if a euthyroid state can only be reached at the expense of an aggravation of cardiovascular disease. During the first 2 weeks of levothyroxine for congenital hypothyroidism, monitor infants carefully for cardiac overload, arrhythmias, and aspiration from avid suckling. Young infants or older patients at increased risk for cardiac failure should receive lower initial doses. All pediatric and adult patients with cardiac disease should be carefully monitored for changes in health status during thyroid hormone therapy, particularly in the initial weeks of treatment. If cardiac symptoms develop or worsen, reduce the levothyroxine dose or withhold for 1 week and restart at a lower dose. Cardiac symptoms usually resolve with correction of the excessive dosage.
In infants, excessive doses of thyroid hormone preparations such as levothyroxine may produce craniosynostosis. Also, undertreatment in pediatric patients may result in slowed reduced adult height, and excessive hormone may accelerate the bone age and result in premature epiphyseal closure and compromised adult stature (growth inhibition). Slipped capital femoral epiphysis has been reported in children receiving levothyroxine.
Pseudotumor cerebri (benign intracranial hypertension or increased intracranial pressure) has been reported in pediatric patients receiving thyroid hormone replacement therapy such as levothyroxine. Symptoms such as a headache, papilledema, and elevated opening pressures on lumbar puncture may occur within weeks of starting thyroid hormone replacement therapy and must be differentiated from brain metastases, if applicable.
Seizures have rarely been reported with the institution of levothyroxine therapy.
Administration of levothyroxine resulting in suppressed serum thyrotropin (TSH) concentrations has been associated with bone loss and a potential increased risk for osteopenia and the premature development of osteoporosis. Because estrogen plays a protective role against bone loss; this increased risk is thought to be particularly relevant in postmenopausal women receiving prolonged thyroid replacement therapy. The relevance and risk in other specific populations are not known. In a meta-analysis, which pooled study data on the effects of slight over treatment with levothyroxine on pre- and postmenopausal women, a significant reduction in bone mass was observed in the postmenopausal study groups. Pooled study data contained skeletal measurements of the distal forearm, femoral neck, and lumbar spines of postmenopausal women. For all postmenopausal women, a theoretical bone consisting of 11.3% distal forearm, 42% femoral neck, and 46.7% lumbar spine was constructed (n = 317 measurements). Data showed that a postmenopausal woman at an average age of 61.2 years and treated with levothyroxine for 9.93 years (leading to suppressed serum TSH) would have an excess loss of bone mass of 9.02%; corresponding to an excess annual loss of 0.91% after 9.93 years of levothyroxine treatment as compared to healthy postmenopausal women.
No well-documented evidence from the literature of true allergic or idiosyncratic reactions to thyroid hormone exists. 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. Levothyroxine injection and oral dosage forms are synthetically derived and may be used in patients allergic to desiccated thyroid or thyroid extract derived from pork or beef.
Levothyroxine is contraindicated in any patient with a known hypersensitivity to levothyroxine or any of its excipients; however, there is no well-documented evidence in the literature of true allergic or idiosyncratic reactions to thyroid hormone. Hypersensitivity reactions to inactive ingredients have occurred in patients treated with thyroid hormone products. Levothyroxine oral capsule and oral solution are contraindicated in any patient with a known (glycerol) glycerin hypersensitivity. Levothyroxine injection and tablets are synthetically derived and may be used in patients allergic to desiccated thyroid or thyroid extract derived from pork or beef.
Levothyroxine is contraindicated for use in patients with diagnosed but untreated adrenal insufficiency. Initiation of thyroid hormone therapy prior to initiating glucocorticoid therapy may precipitate an acute adrenal crisis in patients with adrenal insufficiency due to an increase in the body's demand for adrenal hormones. Treat patients with adrenal insufficiency with replacement glucocorticoids prior to initiating treatment with levothyroxine.
Serum TSH is not a reliable measure of levothyroxine dose adequacy in patients with secondary (hypopituitarism) hypothyroidism or tertiary (hypothalamic) hypothyroidism and should not be used to monitor therapy. An inappropriate TSH may be seen if hypothyroidism is caused by TSH deficiency (e.g., secondary hypothyroidism in patients with panhypopituitarism), and the TSH will not normalize with thyroid treatment. Use the serum free-T4 level to monitor for adequacy of therapy in this patient population.
Many authorities recommend lower initial dosages and slower titration of thyroid hormones in patients with cardiac disease and coronary artery disease (CAD). Thyroid hormones such as levothyroxine should be used with great caution in patients where the integrity of the cardiovascular system is suspect. All levothyroxine dosage formulations are cardiostimulatory and should be used with great caution in patients with angina pectoris, uncontrolled hypertension, cardiac arrhythmias, CAD, a previous history of acute myocardial infarction, or current acute myocardial infarction. If adverse cardiac symptoms develop or worsen during treatment, reduce or withhold levothyroxine and cautiously restart at a lower dose. Over-treatment with thyroid hormones may cause cardiac stimulation and lead to increased heart rate, cardiac wall thickening, and increased cardiac contractility, which may precipitate angina or cardiac arrhythmias. Concomitant administration of levothyroxine with vasopressors or sympathomimetic agents may precipitate coronary insufficiency and associated symptoms, particularly in myxedematous patients or those with CAD. Fluid therapy should be administered with great care to prevent cardiac decompensation. In patients with compromised cardiac function, use thyroid hormones in conjunction with careful cardiac monitoring. A lower starting dose is recommended in adult and pediatric patients at risk for heart failure or sensitive to thyroid stimulation. Careful monitoring is also recommended during surgery, as some anesthetic agents may induce changes in heart rate or blood pressure when administered with thyroid hormones.
Levothyroxine therapy can worsen glycemic control in patients with diabetes mellitus, and result in increased antidiabetic agent or insulin requirements. The effects seen are poorly understood and depend upon a variety of factors such as dose and type of thyroid preparations and endocrine status of the patient. Blood glucose should be monitored closely during concomitant therapy, particularly during initiation, dose adjustments, or discontinuation of therapy.
Levothyroxine should not be used for obesity treatment or weight loss. In euthyroid patients, thyroid hormone doses within the range of daily hormonal requirements are ineffective for weight reduction. Larger doses may produce serious manifestations of toxicity and hyperthyroidism, especially if used with anorexic agents such as the sympathomimetic amines.
Patients with myxedema coma require immediate and intensive treatment. Myxedema coma is a life-threatening emergency characterized by poor circulation and hypometabolism and may result in unpredictable absorption of oral thyroid hormone from the gastrointestinal tract. Initial thyroid hormone replacement for myxedema coma should be given intravenously. The use of oral thyroid hormone drug products is not recommended. Although patients with myxedema coma often suffer from hypothermia, artificial rewarming is contraindicated. Peripheral vasodilation produced by artificial external heat further decreases circulation to vital internal organs and may increase shock if present. Administration of levothyroxine may restore normal body temperature within 24 to 48 hours if heat loss is prevented by keeping the patient covered with blankets in a warm room. Patients with myxedema coma show increased sensitivity to thyroid agents; initiate therapy with low doses of intravenous levothyroxine and increase gradually. Simultaneous administration of glucocorticoids is required for these patients. Patients with pituitary myxedema should receive such adrenocortical hormone replacement therapy at or before the start of thyroid hormone treatment to prevent acute adrenocortical insufficiency and shock. Hyponatremia is frequently present in myxedema coma, but usually resolves without specific therapy as the metabolic status of the patient improves with thyroid treatment. Use great care with fluid therapy to prevent cardiac decompensation; some patients with myxedema have inappropriate secretion of ADH and are susceptible to water intoxication. In some patients, respiratory depression has been a significant factor in the development or persistence of the comatose state. Decreased oxygen saturation and elevated CO2 levels respond quickly to artificial respiration.
Long-term use of levothyroxine has been associated with decreased bone mineral density with increased bone resorption, particularly in postmenopausal females on greater than replacement doses or in women receiving suppressive doses. The increased bone resorption may be associated with increased serum levels and urinary excretion of calcium and phosphorous, elevations in bone alkaline phosphatase, and suppressed serum parathyroid hormone levels. Patients should be given the minimum dose necessary for desired clinical and biochemical response to limit risks for osteopenia.
Levothyroxine capsules (Tirosint and others) are contraindicated for use in anyone unable to swallow a capsule, generally including pediatric patients less than 6 years of age and those patients with dysphagia. Do not cut or crush the capsules. Use caution when administering the Levoxyl brand of levothyroxine tablets to patients with dysphasia or other conditions that compromise the ability to swallow. Choking, gagging, tablets getting stuck in the throat, and dysphagia have been reported, mainly when the intact tablets were not taken with water. Counsel patients to take the tablet with water.
Caution should be used in geriatric patients since they may be more sensitive to the cardiac effects of thyroid replacement. In general, lower initial dosages and slower titration are recommended in elderly patients. Overall, thyroid hormone requirements in the elderly are typically 25% lower than in younger adults; individualize dosage. Atrial arrhythmias can occur in elderly patients. Atrial fibrillation is the most common of the arrhythmias observed with levothyroxine overtreatment in the elderly. According to the Beers Criteria, levothyroxine is the preferred replacement hormone versus other thyroid replacement medications; guidelines state levothyroxine is the agent of choice for most patients for hypothyroidism. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs); assessment of thyroid function (e.g., TSH, serum T4 or T3) should occur before initiating thyroid medication and periodically thereafter; reassess thyroid function if new signs and symptoms of hypothyroidism or hyperthyroidism develop. Initiate thyroid supplementation at low doses and increase gradually to avoid precipitating cardiac failure or adrenal crisis. Because there are many clinically significant medication interactions, re-evaluation of medication doses should occur as clinically indicated.
Hypothyroidism that is diagnosed during pregnancy should be promptly treated. During pregnancy, thyroxine (T4) is thought to be crucial for fetal brain development, and guidelines recommend that levothyroxine be the preferred drug for the treatment of hypothyroidism in the pregnant patient. The clinical experience to date does not indicate any adverse fetal effect when thyroid hormones such as levothyroxine are administered during pregnancy. Thyroid replacement therapy to hypothyroid women should not be discontinued during pregnancy. Thyroid hormones undergo minimal placental transfer. Measure TSH and free-T4 as soon as pregnancy is confirmed and, at a minimum, during each trimester to gauge the adequacy of thyroid replacement dosage since during pregnancy as thyroid requirements may increase. For patients with serum TSH above the normal trimester-specific range, increase the dose of thyroid hormone and measure TSH every 4 weeks until a stable dose is reached and serum TSH is within the normal trimester-specific range. Immediately after obstetric delivery, the dosage should return to the pre-pregnancy dose, monitor thyroid function tests TSH at 4 to 8 weeks postpartum to assess for needed adjustments.
Levothyroxine is the preferential drug to treat hypothyroidism in most patients and is considered compatible with breast-feeding. Changes in thyroid status in the post-partum period may require careful monitoring and maternal dosage adjustment. In general, adequate thyroid status is needed to maintain normal lactation, and there is no reason maternal replacement should be halted due to lactation alone. Limited published studies report that levothyroxine is present in human milk. There is insufficient information to determine the effects of levothyroxine on the breastfed infant and no available information on the effects of levothyroxine on milk production. However, thyroid hormones do not have a known tumorigenic potential and are not associated with reports of serious adverse reactions in nursing infants.
Levothyroxine use is only justified for treatment of female or male infertility if such infertility is accompanied by hypothyroidism.
Guidelines recommend levothyroxine (T4) as the generally preferred treatment for hypothyroidism in adults, adolescents, children, infants, and neonates. However, there are case reports of patients whose TSH values could only be normalized with a combination of both T4 and T3 (liothyronine). Therefore, treatment must be individualized. Closely monitor all patients to avoid undertreatment or excessive treatment, which may produce hyperthyroidism or iatrogenic thyrotoxicosis. The management of hypothyroidism in pediatric patients is similar to adults, but there are unique differences based on the requirement of normal thyroid function for neurocognitive development as well as growth and development. There are increased weight-based requirements for thyroid hormone replacement in children and adolescents compared to adults. As the child advances through the pediatric age into adulthood, thyroid hormone replacement doses decrease, with a transition to the average adult dose once endocrine maturation is complete. Careful monitoring for growth, weight, epiphyseal closure and maturation, and clinical status are important in all pediatric patients. In patients with congenital hypothyroidism, closely monitor infants during the first 2 weeks of thyroid hormone therapy for cardiac overload, arrhythmias, and aspiration from avid suckling. Closely monitor all pediatric patients to avoid undertreatment or overtreatment. Undertreatment may have harmful effects on intellectual development and linear growth. Excessive treatment is associated with craniosynostosis in infants, may adversely affect the tempo of brain maturation, and may accelerate the bone age and result in premature epiphyseal closure and compromised adult stature. In children with acquired hypothyroidism, undertreatment may result in poor school performance due to impaired concentration and slowed mentation and in reduced adult height. Overtreatment may accelerate the bone age and result in premature epiphyseal closure and compromised adult stature. Treated children may manifest a period of catch-up growth, which may be adequate in some cases to normalize adult height. In children with severe or prolonged hypothyroidism, catch-up growth may not be adequate to normalize adult height.
Thyroid Products Equivalent Oral Dosages - Listings are estimates only; individualize all dosing
Preparation - dosage equivalents - (T4:T3 ratio)
Levothyroxine - 0.1 mg - (1:0)
Liothyronine - 25 mcg - (0:1)
Liotrix-1 (levothyroxine; liothyronine synthetic)- 50 to 60 mcg/12.5 to 15 mcg - (4:1)
Thyroid USP (levothyroxine; liothyronine, porcine)- 60 mg (1 grain) - (2 to 5:1)
General Information
-Levothyroxine (T4) monotherapy is preferred over other forms of thyroid replacement in most patients for treatment.
-Levothyroxine is not indicated for suppression of benign thyroid nodules and nontoxic diffuse goiter in iodine-sufficient patients.
-Levothyroxine is not indicated during the recovery phase of subacute thyroiditis.
-Dosages must be individualized based on clinical response and laboratory parameters. Peak therapeutic effect occurs in 4 to 6 weeks.
-If any switch between any branded or generic levothyroxine formulations occurs, reevaluation; repeat TSH and T4 testing is recommended in 2 to 4 weeks to allow for any necessary dose titration. The FDA has classified several levothyroxine formulations as bioequivalent; consult current FDA equivalence recommendations available in the Orange Book.
For the treatment of hypothyroidism of any etiology, except during the recovery phase of subacute thyroiditis; used as a replacement in primary (thyroidal), secondary (pituitary), tertiary (hypothalamic), congenital (cretinism), or acquired hypothyroidism:
Oral dosage (capsules and tablets):
Adults: IF OTHERWISE HEALTHY: May initiate at full replacement dosage of roughly 1.6 mcg/kg/day PO. Adjust the dose by 12.5 mcg to 25 mcg increments every 4 to 6 weeks until desired response. GERIATRIC PATIENTS OR IF CARDIAC DISEASE PRESENT: Initiate with 12.5 to 25 mcg PO once daily with gradual (12.5 to 25 mcg) increments at 6 to 8-week intervals as needed. The full replacement dose may be less than 1 mcg/kg/day PO in geriatric patients. PATIENTS WITH SEVERE LONGSTANDING HYPOTHYROIDISM: Initially, 12.5 to 25 mcg/day PO with increases of 12.5 to 25 mcg/day every 2 to 4 weeks until at effective target dose. PREGNANT WOMEN WITH NEW-ONSET HYPOTHYROIDISM: For moderate to severe signs and symptoms, initiate at full replacement dosage of roughly 1.6 mcg/kg/day PO. For mild hypothyroidism (TSH less than 10 mIU/L), initiate at 1 mcg/kg/day PO. Adult Max: Greater than 200 mcg/day PO is rarely required. Rare patients may require up to 300 mcg/day PO. Inadequate response to more than 300 mcg/day may indicate poor compliance, malabsorption, drug interactions, or a combination of these factors.
Adolescents in whom growth and puberty are complete: 1.6 mcg/kg/day PO once daily. Adjust by increments of 12.5 to 25 mcg/day every 4 to 6 weeks until the patient has the proper clinical and TSH response. Hyperactivity can be minimized if initiated at a dose that is 25% of the recommended replacement dose, with a weekly titration of approximately 25% of the full recommended replacement dose to attain clinical goals. In severe longstanding hypothyroidism, initiate with 12.5 mcg to 25 mcg/day, and increase by 12.5 mcg to 25 mcg every 2 to 4 weeks until the patient is clinically euthyroid and the serum TSH level is normalized. Max: Greater than 200 mcg/day PO is rarely required. Rare patients may require up to 300 mcg/day PO. Inadequate response to more than 300 mcg/day may indicate poor compliance, malabsorption, drug interactions, or a combination of these factors.
Adolescents in whom growth and puberty are incomplete: 2 to 3 mcg/kg/day PO once daily. Hyperactivity can be minimized if initiated at a dose that is 25% of the recommended replacement dose. The dose can be increased weekly by an amount equal to 25% of the full recommended replacement dose until the desired effect is reached.
Children 6 to 12 years: 4 to 5 mcg/kg/day PO once daily. Hyperactivity in older children can be minimized if initiated at a dose that is 25% of the recommended replacement dose. The dose can be increased weekly by an amount equal to 25% of the full recommended replacement dose until the recommended dose is reached.
Children 1 to 5 years: 5 to 6 mcg/kg/day PO once daily. Hyperactivity can be minimized if initiated at a dose that is 25% of the recommended replacement dose. The dose can be increased weekly by an amount equal to 25% of the full recommended replacement dose until the recommended dose is reached.
Infants 6 to 12 months: 6 to 8 mcg/kg/day PO once daily.
Infants 3 to 5 months: 8 to 10 mcg/kg/day PO once daily.
Neonates and Infants less than 3 months: 10 to 15 mcg/kg/day PO once daily. The dose may be increased every 4 to 6 weeks as needed. Consider lower initial doses (e.g., 25 mcg/day) in neonates/infants with risks for cardiac failure. In neonates/infants with very low (less than 5 mcg/dL) or undetectable serum T4, the initial starting dose is 50 mcg/day PO once daily.
Oral dosage (oral solution):
Adults: IF OTHERWISE HEALTHY: May initiate at full replacement dosage of roughly 1.6 mcg/kg/day PO. Adjust the dose by 12.5 mcg to 25 mcg increments every 4 to 6 weeks until desired response. GERIATRIC PATIENTS OR IF CARDIAC DISEASE PRESENT: Initiate with 12.5 to 25 mcg PO once daily with gradual (12.5 to 25 mcg) increments at 6 to 8-week intervals as needed. The full replacement dose may be less than 1 mcg/kg/day PO in geriatric patients. PATIENTS WITH SEVERE LONGSTANDING HYPOTHYROIDISM: Initially, 12.5 to 25 mcg/day PO with increases of 12.5 to 25 mcg/day every 2 to 4 weeks until at effective target dose. PREGNANT WOMEN WITH NEW-ONSET HYPOTHYROIDISM: For moderate to severe signs and symptoms, initiate at full replacement dosage of roughly 1.6 mcg/kg/day PO. For mild hypothyroidism (TSH less than 10 mIU/L), initiate at 1 mcg/kg/day PO. Adult Max: Greater than 200 mcg/day PO is rarely required. Rare patients may require up to 300 mcg/day PO. Inadequate response to more than 300 mcg/day may indicate poor compliance, malabsorption, drug interactions, or a combination of these factors.
Adolescents in whom growth and puberty are complete: 1.6 mcg/kg/day PO once daily. Hyperactivity can be minimized if therapy is initiated at a dose that is 25% of the recommended replacement dose. The dose can be increased weekly by an amount equal to 25% of the full recommended replacement dose until the desired effect is reached. In severe hypothyroidism, initiate with 12.5 mcg to 25 mcg/day, and increase by 12.5 mcg to 25 mcg every 2 to 4 weeks until the patient is clinically euthyroid and the serum TSH level is normalized. Max: Greater than 200 mcg/day is rarely required. Rare patients may require up to 300 mcg/day PO. Inadequate response to more than 300 mcg/day may indicate poor compliance, malabsorption, drug interactions, or a combination of these factors.
Adolescents in whom growth and puberty are incomplete: 2 to 3 mcg/kg/day PO once daily. Hyperactivity can be minimized if initiated at a dose that is 25% of the recommended replacement dose. The dose can be increased weekly by an amount equal to 25% of the full recommended replacement dose until the desired effect is reached.
Children 6 to 12 years: 4 to 5 mcg/kg/day PO once daily. Hyperactivity in older children can be minimized if initiated at a dose that is 25% of the recommended replacement dose. The dose can be increased weekly by an amount equal to 25% of the full recommended replacement dose until the recommended dose is reached.
Children 1 to 5 years: 5 to 6 mcg/kg/day PO once daily. Hyperactivity in older children can be minimized if initiated at a dose that is 25% of the recommended replacement dose. The dose can be increased weekly by an amount equal to 25% of the full recommended replacement dose until the recommended dose is reached.
Infants 6 to 12 months: 6 to 8 mcg/kg/day PO once daily.
Infants 3 to 5 months: 8 to 10 mcg/kg/day PO once daily.
Neonates and Infants less than 3 months: 10 to 15 mcg/kg/day PO once daily in the morning 30 to 60 minutes before a meal. The dose may be increased every 4 to 6 weeks as needed. Consider lower initial doses in neonates/infants with risks for cardiac failure.
Intravenous* dosage or Intramuscular* dosage:
Adults: According to guidelines for the treatment of hypothyroidism, the equivalent IV dose is approximately 75% of the previously established oral dosage, assuming the enteral levothyroxine dose had achieved euthyroidism. Some patients may need titration after this initial dosage selection to maintain euthyroid status. Based on medical practice, the relative bioavailability between oral and IV administration is estimated to be 48% to 74%. Differences in absorption characteristics of patients and how they take their oral medication necessitate the use of TSH measurements a few weeks after initiating therapy to ensure proper dose adjustments. Conversely, if a patient is stabilized on IV or IM dosage, when it is time to convert back to oral dosage, many clinicians use an initial 20% to 25% increase in the IV or IM dosage to convert to an initial oral dosage, with subsequent dosage titration based on clinical and laboratory status to individualize dose and achieve euthyroidism.
Infants, Children, and Adolescents: 50% to 75% of the previously established oral dosage, given IV or IM once daily in patients unable to take oral doses. Hypothyroidism guidelines recommend 75% of the previously established oral dosage, assuming the enteral levothyroxine dose had achieved euthyroidism. Some patients may need titration after this initial dosage selection to maintain euthyroid status. Based on medical practice, the relative bioavailability between oral and IV administration is estimated to be 48% to 74%. Differences in absorption characteristics of patients and how they take their oral medication necessitate the use of TSH measurements a few weeks after initiating therapy to ensure proper dose adjustments.
Neonates: Initially, 5 to 8 mcg/kg/day IV or IM in patients initiating levothyroxine who are unable to take oral doses. In patients already taking an oral dose of levothyroxine who require parenteral administration, give 50% to 75% of the oral dose IV or IM once daily. Use TSH measurements to ensure proper dose adjustments.
For the treatment of myxedema coma:
Intravenous dosage:
Adults: 300 to 500 mcg IV initially. Continuous daily administration of 50 to 100 mcg IV should be given until the patient is stabilized, and oral administration is feasible. Guidelines state that levothyroxine IV alone is the preferred therapy for most patients and recommend an initial loading dose of 200 to 400 mcg IV with a daily replacement dose of 1.2 mcg/kg/day IV. Consider lower doses for smaller or older patients and those with coronary disease or arrhythmia. Institute oral therapy after the patient is clinically stable and can take oral medication. Simultaneous administration of glucocorticoids is recommended at or before the start of treatment to prevent acute adrenocortical insufficiency and shock.
As an adjunct to surgery and radioiodine (RAI) therapy in the management of well-differentiated thyroid cancer:
Oral dosage:
Adults: Individualize the dose of levothyroxine based on the target level of TSH suppression for the stage of thyroid cancer and the clinical status of the patient.
For use as hormonal replacement therapy for organ preservation* in brain dead donors before organ procurement:
Intravenous dosage:
Adolescents 17 years and older: 0.8 mcg/kg/dose IV bolus, then 0.8 mcg/kg/hour continuous IV infusion. Hormone replacement therapy should be considered early in the course of management. Therapy may allow for weaning of inotropic support.
Children and Adolescents 12 to 16 years: 1.5 mcg/kg/dose IV bolus, then 0.8 mcg/kg/hour continuous IV infusion. Hormone replacement therapy should be considered early in the course of management. Therapy may allow for weaning of inotropic support.
Children 6 to 11 years: 2.5 mcg/kg/dose IV bolus, then 1 mcg/kg/hour continuous IV infusion. Hormone replacement therapy should be considered early in the course of management. Therapy may allow for weaning of inotropic support.
Children 1 to 5 years: 3 mcg/kg/dose IV bolus, then 1.2 mcg/kg/hour continuous IV infusion. Hormone replacement therapy should be considered early in the course of management. Therapy may allow for weaning of inotropic support.
Infants 6 to 12 months: 4 mcg/kg/dose IV bolus, then 1.3 mcg/kg/hour continuous IV infusion. Hormone replacement therapy should be considered early in the course of management. Therapy may allow for weaning of inotropic support.
Neonates and Infants 1 to 5 months: 5 mcg/kg/dose IV bolus, then 1.4 mcg/kg/hour continuous IV infusion. Hormone replacement therapy should be considered early in the course of management. Therapy may allow for weaning of inotropic support.
For the treatment of subclinical hypothyroidism*:
Oral dosage:
Adults: 25 to 75 mcg PO once daily, titrate according to clinical response and TSH values. GERIATRIC PATIENTS OR IF CARDIAC DISEASE PRESENT: Initiate with 12.5 to 25 mcg PO once daily. Assess serum TSH levels 6 weeks after initiation, and at 6-week intervals after subsequent dose changes. Once TSH target has been achieved, test thyroid function annually. Treatment is controversial since it has consistently demonstrated no clinically relevant benefits for quality of life or thyroid related symptoms; however, guidelines recommend treating patients with TSH greater than 20 mIU/L and with normal T4 levels.
Therapeutic Drug Monitoring:
General Recommendations
-Thyroid function tests to aid in assessing response to thyroid hormone therapy. Age appropriate references for normal values should be used. Frequently used tests include:-thyroid stimulating hormone (TSH)
-total serum thyroxine (T4)
-free thyroxine (unbound T4).
-Factors that influence the laboratory results of thyroid function tests must be monitored. These include, but are not limited to, drugs, acute and chronic disease states, age, endogenous proteins, etc. Complete clinical evaluation to monitor improvement in signs and symptoms of hypothyroidism and hyperthyroidism is required. Inadequate response to higher than usual maximum doses may indicate poor compliance, malabsorption, or drug interactions.
-In patients with secondary and tertiary hypothyroidism, serum TSH is not a reliable measure of dose adequacy and should not be used; monitor serum free-T4 levels and titrate until the patient is clinically euthyroid and the serum free-T4 level is restored to the upper half of the normal range.
-In pediatric patients, failure of T4 to increase into the upper half of the normal range within 2 weeks of levothyroxine initiation or failure of TSH to decrease below 20 milliunits/L within 4 weeks should prompt therapy evaluation, with consideration given to patient compliance and concomitant medical conditions or medications.-In neonates, caution is necessary for interpreting the results of thyroid function tests since serum T4 concentrations are transiently elevated and T3 concentrations are transiently low. Also, the immature pituitary gland is relatively insensitive to the negative feedback effect of thyroid hormones, and therefore TSH may not normalize.
-During the first 2 weeks of therapy, infants should be closely monitored for cardiac overload, arrhythmias, and aspiration from avid suckling.
Frequency of Monitoring
-In adults with primary hypothyroidism, serum TSH concentrations are adequate for monitoring therapy. The recommended frequency of monitoring during dose titration is every 6 to 8 weeks until normalization. Once normalized or if the brand or dosage of levothyroxine is changed, the serum TSH concentration should be monitored every 6 to 12 months and whenever there is a change in the patient's clinical status. After that, the TSH should be monitored at least annually, unless the patient's clinical status warrants more frequent monitoring.
-In pediatric patients, during the first 3 years of life, the serum total or free T4 should be maintained in the upper half of the normal range.-In the first year of life, monitoring should occur 2 and 4 weeks after drug initiation, then every 1 to 2 months. After 1 year of age, monitoring can occur every 2 to 3 months until the child is 3 years of age. Guidelines from the American Academy of Pediatrics, the American Thyroid Association, and the Lawson Wilkins Pediatric Endocrine Society suggest that after 6 months of age, monitoring every 3 to 4 months until the child is 3 years of age is adequate.
-In children over 3 years of age, monitor every 3 to 12 months until growth is completed. Others suggest that monitoring every 6 to 12 months is adequate in children over 3 years of age with stable thyroid function.
-If there is a change in the dosage of levothyroxine, the manufacturer recommends that a TSH and T4 concentration be monitored 2 weeks after the change. Others recommend a free T4 and TSH concentrations be obtained 4 weeks after a dose change.
Maximum Dosage Limits:
Narrow therapeutic index; dosage must be individualized.
-Adults
Doses more than 200 mcg/day PO are rarely needed. However, rare patients may require up to 300 mcg/day PO for treating hypothyroidism or thyroid cancer. Inadequate response to 300 mcg/day or more may indicate poor compliance, malabsorption, drug interactions, or a combination of these factors.
-Geriatric
Doses more than 200 mcg/day PO are rarely needed. However, rare patients may require up to 300 mcg/day PO for treating hypothyroidism or thyroid cancer. Inadequate response to 300 mcg/day or more may indicate poor compliance, malabsorption, drug interactions, or a combination of these factors.
-Adolescents
Adolescents in whom growth and puberty are complete: Doses rarely exceed 200 mcg/day PO. However, rare patients may require up to 300 mcg/day PO for treating hypothyroidism or thyroid cancer. Inadequate response to 300 mcg/day or more may indicate poor compliance, malabsorption, drug interactions, or a combination of these factors.
-Children
Dosage must be individualized to age, weight, growth, and clinical status; if more than 3 years of age, adult dosages may be required (usual adult Max: 200 mcg/day PO).
-Infants
Individualize dosage.
-Neonates
Individualize dosage.
Patients with Hepatic Impairment Dosing
No specific dosage adjustments are needed for patients with hepatic impairment; dosing is individualized to achieve therapeutic goals.
Patients with Renal Impairment Dosing
No specific dosage adjustments are needed for patients with renal impairment; dosing is individualized to achieve therapeutic goals.
*non-FDA-approved indication
Acarbose: (Minor) Addition of thyroid hormones to antidiabetic or insulin therapy may result in increased dosage requirements of the antidiabetic agents. Blood sugars should be carefully monitored when thyroid therapy is added, dosages are changed, or if thyroid hormones are discontinued.
Acetohexamide: (Minor) Addition of thyroid hormones to antidiabetic or insulin therapy may result in increased dosage requirements of the antidiabetic agents. Blood sugars should be carefully monitored when thyroid therapy is added, discontinued or doses changed.
Albiglutide: (Minor) When thyroid hormones are added to existing diabetes therapy, the glucose-lowering effect may be reduced. Close monitoring of blood glucose is necessary for individuals who use antidiabetic agents whenever there is a change in thyroid treatment. It may be necessary to adjust the dose of antidiabetic agents if thyroid hormones are added or discontinued. Thyroid hormones are important in the regulation of carbohydrate metabolism, gluconeogenesis, the mobilization of glycogen stores, and protein synthesis.
Alendronate: (Moderate) Separating times of administration of alendronate from levothyroxine and other medications will maximize alendronate absorption and clinical benefit. For example, administering the levothyroxine dose at bedtime can avoid this interaction with alendronate. The bioavailability of alendronate was slightly decreased when alendronate and levothyroxine were co-administered to healthy subjects The mean AUC and Cmax of alendronate decreased by 7% and 9%, respectively. Alendronate should always be administered upon arising for the day and at least 30 minutes before the first food, beverage, or other medication of the day. To minimize interactions, levothyroxine is also best taken on an empty stomach with a glass of water.
Alendronate; Cholecalciferol: (Moderate) Separating times of administration of alendronate from levothyroxine and other medications will maximize alendronate absorption and clinical benefit. For example, administering the levothyroxine dose at bedtime can avoid this interaction with alendronate. The bioavailability of alendronate was slightly decreased when alendronate and levothyroxine were co-administered to healthy subjects The mean AUC and Cmax of alendronate decreased by 7% and 9%, respectively. Alendronate should always be administered upon arising for the day and at least 30 minutes before the first food, beverage, or other medication of the day. To minimize interactions, levothyroxine is also best taken on an empty stomach with a glass of water.
Alogliptin: (Minor) Thyroid hormones are important in the regulation of carbohydrate metabolism, gluconeogenesis, the mobilization of glycogen stores, and protein synthesis. When thyroid hormones are added to existing diabetes therapy, the glucose-lowering effect may be reduced. Close monitoring of blood glucose is necessary for individuals who use oral antidiabetic agents whenever there is a change in thyroid treatment. It may be necessary to adjust the dose of antidiabetic agents if thyroid hormones are added or discontinued.
Alogliptin; Metformin: (Minor) Thyroid hormone use may result in increased blood sugar and a loss of glycemic control in some patients. Interactions may or may not be clinically significant at usual replacement doses. Monitor blood sugars carefully when thyroid therapy is added, changed, or discontinued in patients receiving metformin. (Minor) Thyroid hormones are important in the regulation of carbohydrate metabolism, gluconeogenesis, the mobilization of glycogen stores, and protein synthesis. When thyroid hormones are added to existing diabetes therapy, the glucose-lowering effect may be reduced. Close monitoring of blood glucose is necessary for individuals who use oral antidiabetic agents whenever there is a change in thyroid treatment. It may be necessary to adjust the dose of antidiabetic agents if thyroid hormones are added or discontinued.
Alogliptin; Pioglitazone: (Minor) Addition of thyroid hormones to antidiabetic or insulin therapy may result in increased dosage requirements of the antidiabetic agents. Blood sugars should be carefully monitored when thyroid therapy is added, dosages are changed, or if thyroid hormones are discontinued. (Minor) Thyroid hormones are important in the regulation of carbohydrate metabolism, gluconeogenesis, the mobilization of glycogen stores, and protein synthesis. When thyroid hormones are added to existing diabetes therapy, the glucose-lowering effect may be reduced. Close monitoring of blood glucose is necessary for individuals who use oral antidiabetic agents whenever there is a change in thyroid treatment. It may be necessary to adjust the dose of antidiabetic agents if thyroid hormones are added or discontinued.
Alpha-glucosidase Inhibitors: (Minor) Addition of thyroid hormones to antidiabetic or insulin therapy may result in increased dosage requirements of the antidiabetic agents. Blood sugars should be carefully monitored when thyroid therapy is added, dosages are changed, or if thyroid hormones are discontinued.
Aluminum Hydroxide: (Moderate) To minimize an interaction, administer thyroid hormones at least 4 hours before or after antacids or other drugs containing aluminum hydroxide. Aluminum hydroxide, often found in antacids, interferes with the intestinal absorption of thyroid hormones. Gastric acidity is an essential requirement for adequate absorption of levothyroxine.
Aluminum Hydroxide; Magnesium Carbonate: (Moderate) To minimize an interaction, administer thyroid hormones at least 4 hours before or after antacids or other drugs containing aluminum hydroxide. Aluminum hydroxide, often found in antacids, interferes with the intestinal absorption of thyroid hormones. Gastric acidity is an essential requirement for adequate absorption of levothyroxine.
Aluminum Hydroxide; Magnesium Hydroxide: (Moderate) To minimize an interaction, administer thyroid hormones at least 4 hours before or after antacids or other drugs containing aluminum hydroxide. Aluminum hydroxide, often found in antacids, interferes with the intestinal absorption of thyroid hormones. Gastric acidity is an essential requirement for adequate absorption of levothyroxine.
Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Moderate) Oral thyroid hormones should be administered at least 4 hours before or after a dose of simethicone. Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing oral absorption, potentially resulting in hypothyroidism. Simethicone has been reported to chelate oral levothyroxine within the GI tract when administered simultaneously, leading to decreased thyroid hormone absorption. (Moderate) To minimize an interaction, administer thyroid hormones at least 4 hours before or after antacids or other drugs containing aluminum hydroxide. Aluminum hydroxide, often found in antacids, interferes with the intestinal absorption of thyroid hormones. Gastric acidity is an essential requirement for adequate absorption of levothyroxine.
Aluminum Hydroxide; Magnesium Trisilicate: (Moderate) To minimize an interaction, administer thyroid hormones at least 4 hours before or after antacids or other drugs containing aluminum hydroxide. Aluminum hydroxide, often found in antacids, interferes with the intestinal absorption of thyroid hormones. Gastric acidity is an essential requirement for adequate absorption of levothyroxine.
Amiodarone: (Moderate) Amiodarone has a complex effect on the metabolism of thyroid hormones and can alter thyroid function tests in many patients. Since approximately 37% of amiodarone (by weight) is iodine, maintenance doses of 200 to 600 mg of amiodarone/day result in ingestion of 75 to 225 mg/day of organic iodide, resulting in much higher total iodine stores in the body. In addition, amiodarone decreases T4 5'-deiodinase activity, which decreases the peripheral conversion of T4 to T3, leading to decreased serum T3. Serum T4 levels are usually normal but may be slightly increased. TSH concentrations usually increase during amiodarone therapy, but after 3 months of continuous administration, TSH concentrations often return to normal. However, amiodarone can cause hypothyroidism or hyperthyroidism, including life-threatening thyrotoxicosis. Therefore, patients receiving levothyroxine and amiodarone should be monitored for changes in thyroid function; because of the slow elimination of amiodarone and its metabolites, abnormal thyroid function tests may persists for weeks or months after amiodarone drug discontinuation.
Amobarbital: (Minor) Hepatic enzyme-inducing drugs, including barbiturates, can increase the catabolism of thyroid hormones. Be alert for a decreased response to thyroid replacement agents with dosage adjustments, discontinuation or addition of barbiturates during thyroid hormone replacement therapy.
Amoxapine: (Minor) Thyroid hormones may increase receptor sensitivity and enhance the effects of amoxapine. Although this drug combination appears to be safe, clinicians should be aware of the remote possibility of exaggerated cardiovascular side effects such as arrhythmias and CNS stimulation.
Amoxicillin; Clarithromycin; Omeprazole: (Moderate) The use of proton pump inhibitors may result in decreased effectiveness of thyroid hormone therapy. Monitor clinically for signs and symptoms of hypothyroidism and altered response to thyroid hormone therapy. Periodically assess the TSH during use of these drugs together. Gastric acidity is an essential requirement for proper and adequate absorption of levothyroxine and other thyroid hormones. Proton pump inhibitors may cause hypochlorhydria, affect intragastric pH, and reduce thyroid hormone absorption.
Asparaginase Erwinia chrysanthemi: (Moderate) Some hypothyroid patients receiving asparaginase may require reduced doses of thyroid hormone. Other patients may remain euthyroid during combined treatment. Monitor TSH levels and monitor for symptoms of hyperthyroidism; a free-T4 concentration may be useful to assess euthyroidism. Asparaginase may decrease the serum TBG (thyroxine-binding globulin) concentration. Decreased amounts of TBG may result in an increased clinical response to thyroid hormones.
Aspirin, ASA; Butalbital; Caffeine: (Minor) Hepatic enzyme-inducing drugs, including barbiturates, can increase the catabolism of thyroid hormones. Be alert for a decreased response to thyroid replacement agents with dosage adjustments, discontinuation or addition of barbiturates during thyroid hormone replacement therapy.
Aspirin, ASA; Butalbital; Caffeine; Codeine: (Minor) Hepatic enzyme-inducing drugs, including barbiturates, can increase the catabolism of thyroid hormones. Be alert for a decreased response to thyroid replacement agents with dosage adjustments, discontinuation or addition of barbiturates during thyroid hormone replacement therapy.
Aspirin, ASA; Omeprazole: (Moderate) The use of proton pump inhibitors may result in decreased effectiveness of thyroid hormone therapy. Monitor clinically for signs and symptoms of hypothyroidism and altered response to thyroid hormone therapy. Periodically assess the TSH during use of these drugs together. Gastric acidity is an essential requirement for proper and adequate absorption of levothyroxine and other thyroid hormones. Proton pump inhibitors may cause hypochlorhydria, affect intragastric pH, and reduce thyroid hormone absorption.
Barbiturates: (Minor) Hepatic enzyme-inducing drugs, including barbiturates, can increase the catabolism of thyroid hormones. Be alert for a decreased response to thyroid replacement agents with dosage adjustments, discontinuation or addition of barbiturates during thyroid hormone replacement therapy.
Beta-agonists: (Moderate) Monitor blood pressure and heart rate during concomitant beta-agonist and thyroid hormone use. 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.
Beta-blockers: (Minor) Because thyroid hormones cause cardiac stimulation including increased heart rate and increased contractility, the effects of beta-blockers may be reduced by thyroid hormones. The reduction of effects may be especially evident when a patient goes from a hypothyroid to a euthyroid state or when excessive amounts of thyroid hormone is given to the patient.
Butabarbital: (Minor) Hepatic enzyme-inducing drugs, including barbiturates, can increase the catabolism of thyroid hormones. Be alert for a decreased response to thyroid replacement agents with dosage adjustments, discontinuation or addition of barbiturates during thyroid hormone replacement therapy.
Butalbital; Acetaminophen: (Minor) Hepatic enzyme-inducing drugs, including barbiturates, can increase the catabolism of thyroid hormones. Be alert for a decreased response to thyroid replacement agents with dosage adjustments, discontinuation or addition of barbiturates during thyroid hormone replacement therapy.
Butalbital; Acetaminophen; Caffeine: (Minor) Hepatic enzyme-inducing drugs, including barbiturates, can increase the catabolism of thyroid hormones. Be alert for a decreased response to thyroid replacement agents with dosage adjustments, discontinuation or addition of barbiturates during thyroid hormone replacement therapy.
Butalbital; Acetaminophen; Caffeine; Codeine: (Minor) Hepatic enzyme-inducing drugs, including barbiturates, can increase the catabolism of thyroid hormones. Be alert for a decreased response to thyroid replacement agents with dosage adjustments, discontinuation or addition of barbiturates during thyroid hormone replacement therapy.
Calcium Acetate: (Moderate) Thyroid hormones should be administered at least 4 hours before or after the ingestion of oral calcium supplements. Calcium salts have been reported to chelate oral thyroid hormones within the GI tract when administered simultaneously, leading to decreased thyroid hormone absorption. Some case reports have described clinical hypothyroidism resulting from coadministration of thyroid hormones with oral calcium supplements.
Calcium Carbonate: (Moderate) Thyroid hormones should be administered at least 4 hours before or after the ingestion of oral calcium supplements. Calcium salts have been reported to chelate oral thyroid hormones within the GI tract when administered simultaneously, leading to decreased thyroid hormone absorption. Some case reports have described clinical hypothyroidism resulting from coadministration of thyroid hormones with oral calcium supplements.
Calcium Carbonate; Famotidine; Magnesium Hydroxide: (Moderate) Thyroid hormones should be administered at least 4 hours before or after the ingestion of oral calcium supplements. Calcium salts have been reported to chelate oral thyroid hormones within the GI tract when administered simultaneously, leading to decreased thyroid hormone absorption. Some case reports have described clinical hypothyroidism resulting from coadministration of thyroid hormones with oral calcium supplements.
Calcium Carbonate; Magnesium Hydroxide: (Moderate) Thyroid hormones should be administered at least 4 hours before or after the ingestion of oral calcium supplements. Calcium salts have been reported to chelate oral thyroid hormones within the GI tract when administered simultaneously, leading to decreased thyroid hormone absorption. Some case reports have described clinical hypothyroidism resulting from coadministration of thyroid hormones with oral calcium supplements.
Calcium Carbonate; Magnesium Hydroxide; Simethicone: (Moderate) Thyroid hormones should be administered at least 4 hours before or after the ingestion of oral calcium supplements. Calcium salts have been reported to chelate oral thyroid hormones within the GI tract when administered simultaneously, leading to decreased thyroid hormone absorption. Some case reports have described clinical hypothyroidism resulting from coadministration of thyroid hormones with oral calcium supplements.
Calcium Carbonate; Risedronate: (Moderate) Thyroid hormones should be administered at least 4 hours before or after the ingestion of oral calcium supplements. Calcium salts have been reported to chelate oral thyroid hormones within the GI tract when administered simultaneously, leading to decreased thyroid hormone absorption. Some case reports have described clinical hypothyroidism resulting from coadministration of thyroid hormones with oral calcium supplements.
Calcium Carbonate; Simethicone: (Moderate) Thyroid hormones should be administered at least 4 hours before or after the ingestion of oral calcium supplements. Calcium salts have been reported to chelate oral thyroid hormones within the GI tract when administered simultaneously, leading to decreased thyroid hormone absorption. Some case reports have described clinical hypothyroidism resulting from coadministration of thyroid hormones with oral calcium supplements.
Calcium Chloride: (Moderate) Thyroid hormones should be administered at least 4 hours before or after the ingestion of oral calcium supplements. Calcium salts have been reported to chelate oral thyroid hormones within the GI tract when administered simultaneously, leading to decreased thyroid hormone absorption. Some case reports have described clinical hypothyroidism resulting from coadministration of thyroid hormones with oral calcium supplements.
Calcium Gluconate: (Moderate) Thyroid hormones should be administered at least 4 hours before or after the ingestion of oral calcium supplements. Calcium salts have been reported to chelate oral thyroid hormones within the GI tract when administered simultaneously, leading to decreased thyroid hormone absorption. Some case reports have described clinical hypothyroidism resulting from coadministration of thyroid hormones with oral calcium supplements.
Calcium: (Moderate) Thyroid hormones should be administered at least 4 hours before or after the ingestion of oral calcium supplements. Calcium salts have been reported to chelate oral thyroid hormones within the GI tract when administered simultaneously, leading to decreased thyroid hormone absorption. Some case reports have described clinical hypothyroidism resulting from coadministration of thyroid hormones with oral calcium supplements.
Calcium; Vitamin D: (Moderate) Thyroid hormones should be administered at least 4 hours before or after the ingestion of oral calcium supplements. Calcium salts have been reported to chelate oral thyroid hormones within the GI tract when administered simultaneously, leading to decreased thyroid hormone absorption. Some case reports have described clinical hypothyroidism resulting from coadministration of thyroid hormones with oral calcium supplements.
Canagliflozin: (Minor) Thyroid hormones are important in the regulation of carbohydrate metabolism, gluconeogenesis, the mobilization of glycogen stores, and protein synthesis. When thyroid hormones are added to existing diabetes therapy, the glucose-lowering effect may be reduced. Close monitoring of blood glucose is necessary for individuals who use oral antidiabetic agents whenever there is a change in thyroid treatment. It may be necessary to adjust the dose of antidiabetic agents if thyroid hormones are added or discontinued.
Canagliflozin; Metformin: (Minor) Thyroid hormone use may result in increased blood sugar and a loss of glycemic control in some patients. Interactions may or may not be clinically significant at usual replacement doses. Monitor blood sugars carefully when thyroid therapy is added, changed, or discontinued in patients receiving metformin. (Minor) Thyroid hormones are important in the regulation of carbohydrate metabolism, gluconeogenesis, the mobilization of glycogen stores, and protein synthesis. When thyroid hormones are added to existing diabetes therapy, the glucose-lowering effect may be reduced. Close monitoring of blood glucose is necessary for individuals who use oral antidiabetic agents whenever there is a change in thyroid treatment. It may be necessary to adjust the dose of antidiabetic agents if thyroid hormones are added or discontinued.
Carbamazepine: (Minor) Use carbamazepine and thyroid hormones together with caution. Carbamazepine may inhibit the binding of thyroid hormones to carrier proteins, resulting in a transient increase in free thyroid hormones followed by an overall decrease in total thyroid hormone concentrations. Carbamazepine reduces 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. Monitor thyroid hormone parameters.
Chlorpropamide: (Minor) Addition of thyroid hormones to antidiabetic or insulin therapy may result in increased dosage requirements of the antidiabetic agents. Blood sugars should be carefully monitored when thyroid therapy is added, discontinued or doses changed.
Cholestyramine: (Moderate) Administer oral levothyroxine or other oral thyroid hormones at least 4 hours before a dose of cholestyramine. Cholestyramine and other bile acid sequestrants have been shown to decrease the oral absorption of thyroid hormones. Monitor thyroid function periodically to ensure proper clinical management.
Chromium: (Moderate) Advise patients to separate chromium supplement ingestion from taking their oral thyroid hormone. For example, taking oral thyroid hormones 1 hours before or 3 hours after chromium picolinate ingestion should minimize an interaction. Chromium could potentially decrease the oral absorption of thyroid hormones. In one study of normal volunteers, the subjects (n = 7) ingested levothyroxine sodium, either taken separately or co-administered with chromium picolinate. Serum thyroxine was measured at intervals over a 6-hour period following drug ingestion. Chromium picolinate significantly decreased the serum thyroxine concentrations. (Moderate) Thyroid hormones should be administered at least 4 hours before or after the ingestion of oral calcium supplements. Calcium salts have been reported to chelate oral thyroid hormones within the GI tract when administered simultaneously, leading to decreased thyroid hormone absorption. Some case reports have described clinical hypothyroidism resulting from coadministration of thyroid hormones with oral calcium supplements.
Cocaine: (Moderate) The concomitant use of sympathomimetics and thyroid hormones can enhance the effects on the cardiovascular system. Patients with coronary artery disease have an increased risk of coronary insufficiency from either agent. Concomitant use of these agents may increase this risk further.
Colesevelam: (Moderate) Administer oral levothyroxine or other oral thyroid hormones at least 4 hours before a dose of colesevelam. Colesevelam and other bile acid sequestrants have been shown to decrease the oral absorption of thyroid hormones. Monitor thyroid function periodically to ensure proper clinical management.
Colestipol: (Moderate) Administer oral levothyroxine or other oral thyroid hormones at least 4 hours before a dose of colestipol. Colestipol and other bile acid sequestrants have been shown to decrease the oral absorption of thyroid hormones. Monitor thyroid function periodically to ensure proper clinical management.
Cyclosporine: (Moderate) Serum trough cyclosporine concentrations appear to be reduced by concurrent oral cyclosporine and levothyroxine use. Claosely monitor cyclosporine concentrations with concomitant levothyroxine therapy. Among 10 patients who took cyclosporine (Neoral) capsules twice daily for at least a year and oral levothyroxine 100 mcg daily for at least 3 months, the trough serum cyclosporine concentration was significantly lower as compared with values from 30 patients who only took cyclosporine. The mechanism of the interaction may be decreased oral cyclosporine absorption. Cyclosporine is a substrate of P-glycoprotein (P-gp), and levothyroxine appears to be an inducer of intestinal P-gp.
Dapagliflozin: (Minor) Thyroid hormones are important in the regulation of carbohydrate metabolism, gluconeogenesis, the mobilization of glycogen stores, and protein synthesis. When thyroid hormones are added to existing diabetes therapy, the glucose-lowering effect may be reduced. Close monitoring of blood glucose is necessary for individuals who use oral antidiabetic agents whenever there is a change in thyroid treatment. It may be necessary to adjust the dose of antidiabetic agents if thyroid hormones are added or discontinued.
Dapagliflozin; Metformin: (Minor) Thyroid hormone use may result in increased blood sugar and a loss of glycemic control in some patients. Interactions may or may not be clinically significant at usual replacement doses. Monitor blood sugars carefully when thyroid therapy is added, changed, or discontinued in patients receiving metformin. (Minor) Thyroid hormones are important in the regulation of carbohydrate metabolism, gluconeogenesis, the mobilization of glycogen stores, and protein synthesis. When thyroid hormones are added to existing diabetes therapy, the glucose-lowering effect may be reduced. Close monitoring of blood glucose is necessary for individuals who use oral antidiabetic agents whenever there is a change in thyroid treatment. It may be necessary to adjust the dose of antidiabetic agents if thyroid hormones are added or discontinued.
Dapagliflozin; Saxagliptin: (Minor) Addition of thyroid hormones to antidiabetic or insulin therapy may result in increased dosage requirements of the antidiabetic agents. Blood sugars should be carefully monitored when thyroid therapy is added, discontinued or doses changed. (Minor) Thyroid hormones are important in the regulation of carbohydrate metabolism, gluconeogenesis, the mobilization of glycogen stores, and protein synthesis. When thyroid hormones are added to existing diabetes therapy, the glucose-lowering effect may be reduced. Close monitoring of blood glucose is necessary for individuals who use oral antidiabetic agents whenever there is a change in thyroid treatment. It may be necessary to adjust the dose of antidiabetic agents if thyroid hormones are added or discontinued.
Dexlansoprazole: (Moderate) The use of proton pump inhibitors may result in decreased effectiveness of thyroid hormone therapy. Monitor clinically for signs and symptoms of hypothyroidism and altered response to thyroid hormone therapy. Periodically assess the TSH during use of these drugs together. Gastric acidity is an essential requirement for proper and adequate absorption of levothyroxine and other thyroid hormones. Proton pump inhibitors may cause hypochlorhydria, affect intragastric pH, and reduce thyroid hormone absorption.
Didanosine, ddI: (Moderate) Oral thyroid hormones should be taken at least 2 hours before the administration of certain didanosine formulations to avoid an interaction. Certain didanosine, ddI formulations contain buffers (e.g., chewable/dispersible tablets and oral powder for solution) or are mixed with antacids (e.g., pediatric powder for oral solution). Thyroid hormones are susceptible to drug interactions with buffers/antacids containing aluminum, magnesium, or calcium, which may chelate thyroid hormones within the GI tract and decrease oral thyroid hormone absorption. Gastric acidity is also an essential requirement for adequate absorption of levothyroxine. Hypothyroidism may occur if doses are not separated. The delayed-release didanosine capsules (e.g., Videx EC) do not contain a buffering agent and are not expected to interact with thyroid hormones.
Digoxin: (Minor) Thyroid disease is known to alter the response to digoxin. Digoxin toxicity is more likely to occur in patients with hypothyroidism, while the response to digoxin is diminished in patients with hyperthyroidism. These reactions should be kept in mind when therapy with thyroid hormones is begun or interrupted. When hypothyroid patients are administered thyroid hormone, the dose requirement of digoxin may be increased.
Dulaglutide: (Minor) When thyroid hormones are added to existing diabetes therapy, the glucose-lowering effect may be reduced. Close monitoring of blood glucose is necessary for individuals who use antidiabetic agents whenever there is a change in thyroid treatment. It may be necessary to adjust the dose of antidiabetic agents if thyroid hormones are added or discontinued. Thyroid hormones are important in the regulation of carbohydrate metabolism, gluconeogenesis, the mobilization of glycogen stores, and protein synthesis.
Empagliflozin: (Minor) Thyroid hormones are important in the regulation of carbohydrate metabolism, gluconeogenesis, the mobilization of glycogen stores, and protein synthesis. When thyroid hormones are added to existing diabetes therapy, the glucose-lowering effect may be reduced. Close monitoring of blood glucose is necessary for individuals who use oral antidiabetic agents whenever there is a change in thyroid treatment. It may be necessary to adjust the dose of antidiabetic agents if thyroid hormones are added or discontinued.
Empagliflozin; Linagliptin: (Minor) Thyroid hormones are important in the regulation of carbohydrate metabolism, gluconeogenesis, the mobilization of glycogen stores, and protein synthesis. When thyroid hormones are added to existing diabetes therapy, the glucose-lowering effect may be reduced. Close monitoring of blood glucose is necessary for individuals who use oral antidiabetic agents whenever there is a change in thyroid treatment. It may be necessary to adjust the dose of antidiabetic agents if thyroid hormones are added or discontinued. (Minor) Thyroid hormones are important in the regulation of carbohydrate metabolism, gluconeogenesis, the mobilization of glycogen stores, and protein synthesis. When thyroid hormones are added to existing diabetes therapy, the glucose-lowering effect may be reduced. Close monitoring of blood glucose is necessary for individuals who use oral antidiabetic agents whenever there is a change in thyroid treatment. It may be necessary to adjust the dose of antidiabetic agents, such as linagliptin, if thyroid hormones are added or discontinued.
Empagliflozin; Linagliptin; Metformin: (Minor) Thyroid hormone use may result in increased blood sugar and a loss of glycemic control in some patients. Interactions may or may not be clinically significant at usual replacement doses. Monitor blood sugars carefully when thyroid therapy is added, changed, or discontinued in patients receiving metformin. (Minor) Thyroid hormones are important in the regulation of carbohydrate metabolism, gluconeogenesis, the mobilization of glycogen stores, and protein synthesis. When thyroid hormones are added to existing diabetes therapy, the glucose-lowering effect may be reduced. Close monitoring of blood glucose is necessary for individuals who use oral antidiabetic agents whenever there is a change in thyroid treatment. It may be necessary to adjust the dose of antidiabetic agents if thyroid hormones are added or discontinued. (Minor) Thyroid hormones are important in the regulation of carbohydrate metabolism, gluconeogenesis, the mobilization of glycogen stores, and protein synthesis. When thyroid hormones are added to existing diabetes therapy, the glucose-lowering effect may be reduced. Close monitoring of blood glucose is necessary for individuals who use oral antidiabetic agents whenever there is a change in thyroid treatment. It may be necessary to adjust the dose of antidiabetic agents, such as linagliptin, if thyroid hormones are added or discontinued.
Empagliflozin; Metformin: (Minor) Thyroid hormone use may result in increased blood sugar and a loss of glycemic control in some patients. Interactions may or may not be clinically significant at usual replacement doses. Monitor blood sugars carefully when thyroid therapy is added, changed, or discontinued in patients receiving metformin. (Minor) Thyroid hormones are important in the regulation of carbohydrate metabolism, gluconeogenesis, the mobilization of glycogen stores, and protein synthesis. When thyroid hormones are added to existing diabetes therapy, the glucose-lowering effect may be reduced. Close monitoring of blood glucose is necessary for individuals who use oral antidiabetic agents whenever there is a change in thyroid treatment. It may be necessary to adjust the dose of antidiabetic agents if thyroid hormones are added or discontinued.
Enteral Feedings: (Contraindicated) Certain foods, beverages, and enteral feedings can inhibit the absorption of thyroid hormones. To minimize the risk of an interaction, thyroid hormones should be administered on an empty stomach with a glass of water at least 30 to 60 minutes prior to food or enteral feedings. Foods that may decrease thyroid hormone absorption include soybean flour and soy-based infant formulas or enteral feedings, as well as high fiber diets, cottonseed meal, and walnuts. In addition to decreasing the oral absorption of thyroid hormones, limited data indicate that soy containing foods and supplements may also influence thyroid physiology. Concentrated soy isoflavones (e.g., genistein and daidzein) may interfere with thyroid peroxidase catalyzed iodination of thyroglobulin, resulting in a decreased production of thyroid hormones and an increased secretion of TSH endogenously. More studies are required to assess the exact mechanism of this interaction. Caution should be used in administering soy isoflavone supplements concurrently with thyroid hormones. Limited data show that coffee has the potential to impair T4 intestinal absorption. In one report, T4 intestinal absorption was evaluated after the administration of 200 mcg L-thyroxine (L-T4) swallowed with coffee/espresso, water, or water followed 60 minutes later by coffee/espresso. Researchers found that administration with coffee/espresso significantly lowered average serum T4 (p<0.001) and peak serum T4 concentrations (p<0.05) when compared to L-T4 taken with water alone. Coffee/espresso taken 60 minutes after L-T4 ingestion had no significant effect on T4 intestinal absorption. It is prudent to remind patients that thyroid hormones should be separated from food and beverages (other than water), including coffee, by at least 30 to 60 minutes.
Ertugliflozin; Metformin: (Minor) Thyroid hormone use may result in increased blood sugar and a loss of glycemic control in some patients. Interactions may or may not be clinically significant at usual replacement doses. Monitor blood sugars carefully when thyroid therapy is added, changed, or discontinued in patients receiving metformin.
Ertugliflozin; Sitagliptin: (Minor) Addition of thyroid hormones to antidiabetic or insulin therapy may result in increased dosage requirements of the antidiabetic agents. Blood sugars should be carefully monitored when thyroid therapy is added, discontinued or doses changed.
Esomeprazole: (Moderate) The use of proton pump inhibitors may result in decreased effectiveness of thyroid hormone therapy. Monitor clinically for signs and symptoms of hypothyroidism and altered response to thyroid hormone therapy. Periodically assess the TSH during use of these drugs together. Gastric acidity is an essential requirement for proper and adequate absorption of levothyroxine and other thyroid hormones. Proton pump inhibitors may cause hypochlorhydria, affect intragastric pH, and reduce thyroid hormone absorption.
Estrogens: (Minor) The administration of estrogens can increase circulating concentrations of thyroxine-binding globulin, sex hormone-binding globulin, and cortisol-binding globulin. Increased amounts of thyroxine-binding globulin may result in a reduced clinical response to thyroid hormones. Some hypothyroid patients on estrogen may require larger doses of thyroid hormones. Monitor thyroid-stimulating hormone (TSH) level and follow the recommendation for thyroid hormone replacement.
Exenatide: (Minor) When thyroid hormones are added to existing diabetes therapy, the glucose-lowering effect may be reduced. Close monitoring of blood glucose is necessary for individuals who use antidiabetic agents whenever there is a change in thyroid treatment. It may be necessary to adjust the dose of antidiabetic agents if thyroid hormones are added or discontinued. Thyroid hormones are important in the regulation of carbohydrate metabolism, gluconeogenesis, the mobilization of glycogen stores, and protein synthesis.
Ferric Maltol: (Moderate) Oral thyroid hormones should be administered at least 4 hours before or after the ingestion of iron supplements. Oral iron salts have been reported to chelate oral thyroid hormones within the GI tract when administered simultaneously, leading to decreased oral absorption of the thyroid hormone. For example, ferrous sulfate likely forms a ferric-thyroxine complex.
Fluoxymesterone: (Moderate) Coadministration may result in increased thyroid hormone concentrations. Monitor thyroid function during concomitant use in patients taking thyroid hormones. In some patients, the thyroid hormone dosage may need to be reduced. Androgens, such as fluoxymesterone may decrease levels of thyroxine-binding globulin, resulting in decreased total T4 serum levels and increased resin uptake of T3 and T4. Free thyroid hormone levels remain unchanged, however, and there is no clinical evidence of thyroid dysfunction in patients without thyroid disease. However, a lowered need for thyroid hormone has been noticed in hypothyroid patients in one publication.
Folic Acid, Vitamin B9: (Moderate) Thyroid hormones should be administered at least 4 hours before or after the ingestion of oral calcium supplements. Calcium salts have been reported to chelate oral thyroid hormones within the GI tract when administered simultaneously, leading to decreased thyroid hormone absorption. Some case reports have described clinical hypothyroidism resulting from coadministration of thyroid hormones with oral calcium supplements.
Food: (Contraindicated) Certain foods, beverages, and enteral feedings can inhibit the absorption of thyroid hormones. To minimize the risk of an interaction, thyroid hormones should be administered on an empty stomach with a glass of water at least 30 to 60 minutes prior to food or enteral feedings. Foods that may decrease thyroid hormone absorption include soybean flour and soy-based infant formulas or enteral feedings, as well as high fiber diets, cottonseed meal, and walnuts. In addition to decreasing the oral absorption of thyroid hormones, limited data indicate that soy containing foods and supplements may also influence thyroid physiology. Concentrated soy isoflavones (e.g., genistein and daidzein) may interfere with thyroid peroxidase catalyzed iodination of thyroglobulin, resulting in a decreased production of thyroid hormones and an increased secretion of TSH endogenously. More studies are required to assess the exact mechanism of this interaction. Caution should be used in administering soy isoflavone supplements concurrently with thyroid hormones. Limited data show that coffee has the potential to impair T4 intestinal absorption. In one report, T4 intestinal absorption was evaluated after the administration of 200 mcg L-thyroxine (L-T4) swallowed with coffee/espresso, water, or water followed 60 minutes later by coffee/espresso. Researchers found that administration with coffee/espresso significantly lowered average serum T4 (p<0.001) and peak serum T4 concentrations (p<0.05) when compared to L-T4 taken with water alone. Coffee/espresso taken 60 minutes after L-T4 ingestion had no significant effect on T4 intestinal absorption. It is prudent to remind patients that thyroid hormones should be separated from food and beverages (other than water), including coffee, by at least 30 to 60 minutes.
Furosemide: (Moderate) Use high doses (more than 80 mg) of furosemide and thyroid hormones together with caution. High doses of furosemide may inhibit the binding of thyroid hormones to carrier proteins, resulting in a transient increase in free thyroid hormones followed by an overall decrease in total thyroid hormone concentrations.
Glimepiride: (Minor) Addition of thyroid hormones to antidiabetic or insulin therapy may result in increased dosage requirements of the antidiabetic agents. Blood sugars should be carefully monitored when thyroid therapy is added, discontinued or doses changed.
Glimepiride; Rosiglitazone: (Minor) Addition of thyroid hormones to antidiabetic or insulin therapy may result in increased dosage requirements of the antidiabetic agents. Blood sugars should be carefully monitored when thyroid therapy is added, discontinued or doses changed. (Minor) Addition of thyroid hormones to antidiabetic or insulin therapy may result in increased dosage requirements of the antidiabetic agents. Blood sugars should be carefully monitored when thyroid therapy is added, dosages are changed, or if thyroid hormones are discontinued.
Glipizide: (Minor) Addition of thyroid hormones to antidiabetic or insulin therapy may result in increased dosage requirements of the antidiabetic agents. Blood sugars should be carefully monitored when thyroid therapy is added, discontinued or doses changed.
Glipizide; Metformin: (Minor) Addition of thyroid hormones to antidiabetic or insulin therapy may result in increased dosage requirements of the antidiabetic agents. Blood sugars should be carefully monitored when thyroid therapy is added, discontinued or doses changed. (Minor) Thyroid hormone use may result in increased blood sugar and a loss of glycemic control in some patients. Interactions may or may not be clinically significant at usual replacement doses. Monitor blood sugars carefully when thyroid therapy is added, changed, or discontinued in patients receiving metformin.
Glyburide: (Minor) Addition of thyroid hormones to antidiabetic or insulin therapy may result in increased dosage requirements of the antidiabetic agents. Blood sugars should be carefully monitored when thyroid therapy is added, discontinued or doses changed.
Glyburide; Metformin: (Minor) Addition of thyroid hormones to antidiabetic or insulin therapy may result in increased dosage requirements of the antidiabetic agents. Blood sugars should be carefully monitored when thyroid therapy is added, discontinued or doses changed. (Minor) Thyroid hormone use may result in increased blood sugar and a loss of glycemic control in some patients. Interactions may or may not be clinically significant at usual replacement doses. Monitor blood sugars carefully when thyroid therapy is added, changed, or discontinued in patients receiving metformin.
Hydantoins: (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of thyroid hormones, leading to reduced efficacy of the thyroid hormone.
Imatinib: (Moderate) Monitor thyroid stimulating hormone (TSH) concentrations carefully when tyrosine kinase inhibitors like imatinib are used in patients taking thyroid hormones. Cases of clinical hypothyroidism have occurred in patients taking imatinib.
Indinavir: (Moderate) Closely monitor the thyroid status of any patient taking thyroid hormones concurrently with indinavir. Hyperthyroidism was reported in a patient when indinavir was added to a stable levothyroxine dosing regimen. Indinavir inhibits UDP-glucuronosyl transferase, which may have decreased the metabolism of the thyroid hormone and may explain the increased thyroxine levels observed. Patients receiving levothyroxine should be carefully monitored when indinavir is started; if hyperthyroidism is detected, reducing the levothyroxine dose should reestablish a euthyroid state. Theoretically, similar interactions may occur between indinavir and other thyroid hormones, given that both T4 and T3 are metabolized to some degree via hepatic UDP-glucuronosyl transferase.
Insulin Degludec; Liraglutide: (Minor) When thyroid hormones are added to existing diabetes therapy, the glucose-lowering effect may be reduced. Close monitoring of blood glucose is necessary for individuals who use antidiabetic agents whenever there is a change in thyroid treatment. It may be necessary to adjust the dose of antidiabetic agents if thyroid hormones are added or discontinued. Thyroid hormones are important in the regulation of carbohydrate metabolism, gluconeogenesis, the mobilization of glycogen stores, and protein synthesis.
Insulin Glargine; Lixisenatide: (Minor) When thyroid hormones are added to existing diabetes therapy, the glucose-lowering effect may be reduced. Close monitoring of blood glucose is necessary for individuals who use antidiabetic agents whenever there is a change in thyroid treatment. It may be necessary to adjust the dose of antidiabetic agents if thyroid hormones are added or discontinued. Thyroid hormones are important in the regulation of carbohydrate metabolism, gluconeogenesis, the mobilization of glycogen stores, and protein synthesis.
Insulins: (Minor) Monitor patients receiving insulin closely for changes in diabetic control whenever there is a change in thyroid treatment. It may be necessary to adjust the dose of antidiabetic agents if thyroid hormones are added or discontinued. Thyroid hormones are important in the regulation of carbohydrate metabolism, gluconeogenesis, the mobilization of glycogen stores, and protein synthesis. When thyroid hormones are added to existing diabetes therapy, the glucose-lowering effect may be reduced.
Iodine; Potassium Iodide, KI: (Moderate) Antithyroid agents should generally not be administered with the thyroid hormones due to their opposing effects. However, in selected cases some clinicians coadminister T4 (e.g., levothyroxine) to circumvent drug-induced hypothyroidism when large suppressive doses of antithyroid agents are administered for long periods of time. However, clinical and biochemical euthyroid status may usually be maintained with careful titration of the antithyroid agent dosage alone.
Iodoquinol: (Moderate) Iodoquinol should be used with caution in patients treated with thyroid hormones. Iodine-containing compounds like iodoquinol may result in overt thyroid disease. Increased uptake of iodine by the thyroid may lead to changes in thyroid status, especially in patients with pre-existing thyroid disease. Iodoquinol has been shown to interfere with thyroid function tests for up to 6 months.
Iron Salts: (Moderate) Oral thyroid hormones should be administered at least 4 hours before or after the ingestion of iron supplements. Oral iron salts have been reported to chelate oral thyroid hormones within the GI tract when administered simultaneously, leading to decreased oral absorption of the thyroid hormone. For example, ferrous sulfate likely forms a ferric-thyroxine complex.
Iron Sucrose, Sucroferric Oxyhydroxide: (Moderate) Administer oral thyroid hormones at least 4 hours before or after oral iron sucrose, sucroferric oxyhydroxide. Oral iron salts have been reported to chelate oral thyroid hormones within the GI tract when administered simultaneously, leading to decreased thyroid hormone absorption. Some case reports have described clinical hypothyroidism resulting from coadministration of thyroid hormones with oral iron supplements.
Iron: (Moderate) Oral thyroid hormones should be administered at least 4 hours before or after the ingestion of iron supplements. Oral iron salts have been reported to chelate oral thyroid hormones within the GI tract when administered simultaneously, leading to decreased oral absorption of the thyroid hormone. For example, ferrous sulfate likely forms a ferric-thyroxine complex.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Rifampin increases thyroid hormone metabolism by inducing uridine 5-diphospho-glucuronosyltransferase (UGT) and leads to lower T4 serum levels. Clinicians should be alert for a decreased response to thyroid hormones if rifampin is used during thyroid hormone therapy.
Isoniazid, INH; Rifampin: (Moderate) Rifampin increases thyroid hormone metabolism by inducing uridine 5-diphospho-glucuronosyltransferase (UGT) and leads to lower T4 serum levels. Clinicians should be alert for a decreased response to thyroid hormones if rifampin is used during thyroid hormone therapy.
Ketamine: (Moderate) Ketamine should be administered cautiously to patients receiving levothyroxine because concomitant use can cause marked hypertension and tachycardia.
Lansoprazole: (Moderate) The use of proton pump inhibitors may result in decreased effectiveness of thyroid hormone therapy. Monitor clinically for signs and symptoms of hypothyroidism and altered response to thyroid hormone therapy. Periodically assess the TSH during use of these drugs together. Gastric acidity is an essential requirement for proper and adequate absorption of levothyroxine and other thyroid hormones. Proton pump inhibitors may cause hypochlorhydria, affect intragastric pH, and reduce thyroid hormone absorption.
Lansoprazole; Amoxicillin; Clarithromycin: (Moderate) The use of proton pump inhibitors may result in decreased effectiveness of thyroid hormone therapy. Monitor clinically for signs and symptoms of hypothyroidism and altered response to thyroid hormone therapy. Periodically assess the TSH during use of these drugs together. Gastric acidity is an essential requirement for proper and adequate absorption of levothyroxine and other thyroid hormones. Proton pump inhibitors may cause hypochlorhydria, affect intragastric pH, and reduce thyroid hormone absorption.
Lansoprazole; Naproxen: (Moderate) The use of proton pump inhibitors may result in decreased effectiveness of thyroid hormone therapy. Monitor clinically for signs and symptoms of hypothyroidism and altered response to thyroid hormone therapy. Periodically assess the TSH during use of these drugs together. Gastric acidity is an essential requirement for proper and adequate absorption of levothyroxine and other thyroid hormones. Proton pump inhibitors may cause hypochlorhydria, affect intragastric pH, and reduce thyroid hormone absorption.
Lanthanum Carbonate: (Moderate) Administer oral thyroid hormones at least 4 hours before or after the administration of lanthanum carbonate. Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing oral absorption, potentially resulting in hypothyroidism. Thyroid stimulating hormone (TSH) concentrations should be carefully monitored. The bioavailability of levothyroxine was decreased by approximately 40% when administered with lanthanum carbonate.
L-Asparaginase Escherichia coli: (Moderate) Some hypothyroid patients receiving asparaginase may require reduced doses of thyroid hormone. Other patients may remain euthyroid during combined treatment. Monitor TSH levels and monitor for symptoms of hyperthyroidism; a free-T4 concentration may be useful to assess euthyroidism. Asparaginase may decrease the serum TBG (thyroxine-binding globulin) concentration. Decreased amounts of TBG may result in an increased clinical response to thyroid hormones.
Linagliptin: (Minor) Thyroid hormones are important in the regulation of carbohydrate metabolism, gluconeogenesis, the mobilization of glycogen stores, and protein synthesis. When thyroid hormones are added to existing diabetes therapy, the glucose-lowering effect may be reduced. Close monitoring of blood glucose is necessary for individuals who use oral antidiabetic agents whenever there is a change in thyroid treatment. It may be necessary to adjust the dose of antidiabetic agents, such as linagliptin, if thyroid hormones are added or discontinued.
Linagliptin; Metformin: (Minor) Thyroid hormone use may result in increased blood sugar and a loss of glycemic control in some patients. Interactions may or may not be clinically significant at usual replacement doses. Monitor blood sugars carefully when thyroid therapy is added, changed, or discontinued in patients receiving metformin. (Minor) Thyroid hormones are important in the regulation of carbohydrate metabolism, gluconeogenesis, the mobilization of glycogen stores, and protein synthesis. When thyroid hormones are added to existing diabetes therapy, the glucose-lowering effect may be reduced. Close monitoring of blood glucose is necessary for individuals who use oral antidiabetic agents whenever there is a change in thyroid treatment. It may be necessary to adjust the dose of antidiabetic agents, such as linagliptin, if thyroid hormones are added or discontinued.
Liraglutide: (Minor) When thyroid hormones are added to existing diabetes therapy, the glucose-lowering effect may be reduced. Close monitoring of blood glucose is necessary for individuals who use antidiabetic agents whenever there is a change in thyroid treatment. It may be necessary to adjust the dose of antidiabetic agents if thyroid hormones are added or discontinued. Thyroid hormones are important in the regulation of carbohydrate metabolism, gluconeogenesis, the mobilization of glycogen stores, and protein synthesis.
Lixisenatide: (Minor) When thyroid hormones are added to existing diabetes therapy, the glucose-lowering effect may be reduced. Close monitoring of blood glucose is necessary for individuals who use antidiabetic agents whenever there is a change in thyroid treatment. It may be necessary to adjust the dose of antidiabetic agents if thyroid hormones are added or discontinued. Thyroid hormones are important in the regulation of carbohydrate metabolism, gluconeogenesis, the mobilization of glycogen stores, and protein synthesis.
Lonapegsomatropin: (Minor) Excessive use of thyroid hormones with growth hormone (somatropin, rh-GH) may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to somatropin. Patients receiving concomitant therapy should be monitored closely to ensure appropriate therapeutic response to somatropin.
Magnesium: (Moderate) Administer thyroid hormones at least 4 hours before or after antacids, dietary supplements, or other drugs containing magnesium. Magnesium salts have been reported to chelate oral thyroid hormones within the GI tract when administered simultaneously, leading to decreased thyroid hormone absorption. Some case reports have described clinical hypothyroidism resulting from coadministration of levothyroxine with products containing oral cations, such as antacids or dietary supplements.
Maprotiline: (Minor) Thyroid hormones may increase receptor sensitivity and enhance the effects of maprotiline.
Meglitinides: (Minor) Addition of thyroid hormones to antidiabetic or insulin therapy may result in increased dosage requirements of the antidiabetic agents. Blood sugars should be carefully monitored when thyroid therapy is added, discontinued or doses changed.
Metformin: (Minor) Thyroid hormone use may result in increased blood sugar and a loss of glycemic control in some patients. Interactions may or may not be clinically significant at usual replacement doses. Monitor blood sugars carefully when thyroid therapy is added, changed, or discontinued in patients receiving metformin.
Metformin; Repaglinide: (Minor) Thyroid hormone use may result in increased blood sugar and a loss of glycemic control in some patients. Interactions may or may not be clinically significant at usual replacement doses. Monitor blood sugars carefully when thyroid therapy is added, changed, or discontinued in patients receiving metformin.
Metformin; Rosiglitazone: (Minor) Addition of thyroid hormones to antidiabetic or insulin therapy may result in increased dosage requirements of the antidiabetic agents. Blood sugars should be carefully monitored when thyroid therapy is added, dosages are changed, or if thyroid hormones are discontinued. (Minor) Thyroid hormone use may result in increased blood sugar and a loss of glycemic control in some patients. Interactions may or may not be clinically significant at usual replacement doses. Monitor blood sugars carefully when thyroid therapy is added, changed, or discontinued in patients receiving metformin.
Metformin; Saxagliptin: (Minor) Addition of thyroid hormones to antidiabetic or insulin therapy may result in increased dosage requirements of the antidiabetic agents. Blood sugars should be carefully monitored when thyroid therapy is added, discontinued or doses changed. (Minor) Thyroid hormone use may result in increased blood sugar and a loss of glycemic control in some patients. Interactions may or may not be clinically significant at usual replacement doses. Monitor blood sugars carefully when thyroid therapy is added, changed, or discontinued in patients receiving metformin.
Metformin; Sitagliptin: (Minor) Addition of thyroid hormones to antidiabetic or insulin therapy may result in increased dosage requirements of the antidiabetic agents. Blood sugars should be carefully monitored when thyroid therapy is added, discontinued or doses changed. (Minor) Thyroid hormone use may result in increased blood sugar and a loss of glycemic control in some patients. Interactions may or may not be clinically significant at usual replacement doses. Monitor blood sugars carefully when thyroid therapy is added, changed, or discontinued in patients receiving metformin.
Methohexital: (Minor) Hepatic enzyme-inducing drugs, including barbiturates, can increase the catabolism of thyroid hormones. Be alert for a decreased response to thyroid replacement agents with dosage adjustments, discontinuation or addition of barbiturates during thyroid hormone replacement therapy.
Miglitol: (Minor) Addition of thyroid hormones to antidiabetic or insulin therapy may result in increased dosage requirements of the antidiabetic agents. Blood sugars should be carefully monitored when thyroid therapy is added, dosages are changed, or if thyroid hormones are discontinued.
Naproxen; Esomeprazole: (Moderate) The use of proton pump inhibitors may result in decreased effectiveness of thyroid hormone therapy. Monitor clinically for signs and symptoms of hypothyroidism and altered response to thyroid hormone therapy. Periodically assess the TSH during use of these drugs together. Gastric acidity is an essential requirement for proper and adequate absorption of levothyroxine and other thyroid hormones. Proton pump inhibitors may cause hypochlorhydria, affect intragastric pH, and reduce thyroid hormone absorption.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Oral thyroid hormones should be administered at least 4 hours before or after the ingestion of iron supplements. Oral iron salts have been reported to chelate oral thyroid hormones within the GI tract when administered simultaneously, leading to decreased oral absorption of the thyroid hormone. For example, ferrous sulfate likely forms a ferric-thyroxine complex.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Oral thyroid hormones should be administered at least 4 hours before or after the ingestion of iron supplements. Oral iron salts have been reported to chelate oral thyroid hormones within the GI tract when administered simultaneously, leading to decreased oral absorption of the thyroid hormone. For example, ferrous sulfate likely forms a ferric-thyroxine complex.
Omeprazole: (Moderate) The use of proton pump inhibitors may result in decreased effectiveness of thyroid hormone therapy. Monitor clinically for signs and symptoms of hypothyroidism and altered response to thyroid hormone therapy. Periodically assess the TSH during use of these drugs together. Gastric acidity is an essential requirement for proper and adequate absorption of levothyroxine and other thyroid hormones. Proton pump inhibitors may cause hypochlorhydria, affect intragastric pH, and reduce thyroid hormone absorption.
Omeprazole; Amoxicillin; Rifabutin: (Moderate) The use of proton pump inhibitors may result in decreased effectiveness of thyroid hormone therapy. Monitor clinically for signs and symptoms of hypothyroidism and altered response to thyroid hormone therapy. Periodically assess the TSH during use of these drugs together. Gastric acidity is an essential requirement for proper and adequate absorption of levothyroxine and other thyroid hormones. Proton pump inhibitors may cause hypochlorhydria, affect intragastric pH, and reduce thyroid hormone absorption.
Omeprazole; Sodium Bicarbonate: (Moderate) The use of proton pump inhibitors may result in decreased effectiveness of thyroid hormone therapy. Monitor clinically for signs and symptoms of hypothyroidism and altered response to thyroid hormone therapy. Periodically assess the TSH during use of these drugs together. Gastric acidity is an essential requirement for proper and adequate absorption of levothyroxine and other thyroid hormones. Proton pump inhibitors may cause hypochlorhydria, affect intragastric pH, and reduce thyroid hormone absorption.
Orlistat: (Moderate) Oral thyroid hormones should be administered at least 4 hours before or after a dose of orlistat. Concurrent use may reduce the efficacy of thyroid hormones by binding and delaying or preventing oral absorption, potentially resulting in hypothyroidism. Monitor TSH while orlistat is used concurrently. Hypothyroidism has been reported in patients treated concomitantly with orlistat and levothyroxine postmarketing.
Pantoprazole: (Moderate) The use of proton pump inhibitors may result in decreased effectiveness of thyroid hormone therapy. Monitor clinically for signs and symptoms of hypothyroidism and altered response to thyroid hormone therapy. Periodically assess the TSH during use of these drugs together. Gastric acidity is an essential requirement for proper and adequate absorption of levothyroxine and other thyroid hormones. Proton pump inhibitors may cause hypochlorhydria, affect intragastric pH, and reduce thyroid hormone absorption.
Pentobarbital: (Minor) Hepatic enzyme-inducing drugs, including barbiturates, can increase the catabolism of thyroid hormones. Be alert for a decreased response to thyroid replacement agents with dosage adjustments, discontinuation or addition of barbiturates during thyroid hormone replacement therapy.
Phenobarbital: (Minor) Hepatic enzyme-inducing drugs, including barbiturates, can increase the catabolism of thyroid hormones. Be alert for a decreased response to thyroid replacement agents with dosage adjustments, discontinuation or addition of barbiturates during thyroid hormone replacement therapy.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Minor) Hepatic enzyme-inducing drugs, including barbiturates, can increase the catabolism of thyroid hormones. Be alert for a decreased response to thyroid replacement agents with dosage adjustments, discontinuation or addition of barbiturates during thyroid hormone replacement therapy.
Pioglitazone: (Minor) Addition of thyroid hormones to antidiabetic or insulin therapy may result in increased dosage requirements of the antidiabetic agents. Blood sugars should be carefully monitored when thyroid therapy is added, dosages are changed, or if thyroid hormones are discontinued.
Pioglitazone; Glimepiride: (Minor) Addition of thyroid hormones to antidiabetic or insulin therapy may result in increased dosage requirements of the antidiabetic agents. Blood sugars should be carefully monitored when thyroid therapy is added, discontinued or doses changed. (Minor) Addition of thyroid hormones to antidiabetic or insulin therapy may result in increased dosage requirements of the antidiabetic agents. Blood sugars should be carefully monitored when thyroid therapy is added, dosages are changed, or if thyroid hormones are discontinued.
Pioglitazone; Metformin: (Minor) Addition of thyroid hormones to antidiabetic or insulin therapy may result in increased dosage requirements of the antidiabetic agents. Blood sugars should be carefully monitored when thyroid therapy is added, dosages are changed, or if thyroid hormones are discontinued. (Minor) Thyroid hormone use may result in increased blood sugar and a loss of glycemic control in some patients. Interactions may or may not be clinically significant at usual replacement doses. Monitor blood sugars carefully when thyroid therapy is added, changed, or discontinued in patients receiving metformin.
Polycarbophil: (Moderate) Administer thyroid hormones at least 2 hours before or after the ingestion of calcium polycarbophil. Thyroid hormones are best taken on an empty stomach, and, administration should be separated from medications that might interfere with absorption. Monitor the patient's thyroid function and clinical status if the patient is on calcium polycarbophil treatment. Dietary fiber may bind and decrease the absorption of thyroid hormones from the gastrointestinal tract. Each 625 mg of calcium polycarbophil contains a substantial amount of calcium (approximately 125 mg). Calcium salts can chelate oral thyroid hormones within the GI tract when administered simultaneously, also leading to decreased thyroid hormone absorption. Some case reports have described clinical hypothyroidism resulting from calcium supplements and thyroid hormone interactions. In a study of 8 volunteers, the absorption of levothyroxine decreased from 89% when administered alone to only 86% when administered concomitantly with 1,000 mg of calcium polycarbophil.
Polysaccharide-Iron Complex: (Moderate) Oral thyroid hormones should be administered at least 4 hours before or after the ingestion of iron supplements. Oral iron salts have been reported to chelate oral thyroid hormones within the GI tract when administered simultaneously, leading to decreased oral absorption of the thyroid hormone. For example, ferrous sulfate likely forms a ferric-thyroxine complex.
Potassium Iodide, KI: (Moderate) Antithyroid agents should generally not be administered with the thyroid hormones due to their opposing effects. However, in selected cases some clinicians coadminister T4 (e.g., levothyroxine) to circumvent drug-induced hypothyroidism when large suppressive doses of antithyroid agents are administered for long periods of time. However, clinical and biochemical euthyroid status may usually be maintained with careful titration of the antithyroid agent dosage alone.
Pramlintide: (Minor) Addition of thyroid hormones to antidiabetic or insulin therapy may result in increased dosage requirements of the antidiabetic agents. Blood sugars should be carefully monitored when thyroid therapy is added, dosages are changed, or if thyroid hormones are discontinued.
Primidone: (Minor) Hepatic enzyme-inducing drugs, including barbiturates, can increase the catabolism of thyroid hormones. Be alert for a decreased response to thyroid replacement agents with dosage adjustments, discontinuation or addition of barbiturates during thyroid hormone replacement therapy.
Propylthiouracil, PTU: (Major) Antithyroid agents should generally not be administered with the thyroid hormones due to their opposing effects. However, in selected cases some clinicians co-administer T4 (e.g., levothyroxine) to circumvent drug-induced hypothyroidism when large suppressive doses of antithyroid agents are administered for long periods of time. However, clinical and biochemical euthyroid status may usually be maintained with careful titration of the antithyroid agent dosage alone.
Proton pump inhibitors: (Moderate) The use of proton pump inhibitors may result in decreased effectiveness of thyroid hormone therapy. Monitor clinically for signs and symptoms of hypothyroidism and altered response to thyroid hormone therapy. Periodically assess the TSH during use of these drugs together. Gastric acidity is an essential requirement for proper and adequate absorption of levothyroxine and other thyroid hormones. Proton pump inhibitors may cause hypochlorhydria, affect intragastric pH, and reduce thyroid hormone absorption.
Pyridoxine, Vitamin B6: (Moderate) Thyroid hormones should be administered at least 4 hours before or after the ingestion of oral calcium supplements. Calcium salts have been reported to chelate oral thyroid hormones within the GI tract when administered simultaneously, leading to decreased thyroid hormone absorption. Some case reports have described clinical hypothyroidism resulting from coadministration of thyroid hormones with oral calcium supplements.
Rabeprazole: (Moderate) The use of proton pump inhibitors may result in decreased effectiveness of thyroid hormone therapy. Monitor clinically for signs and symptoms of hypothyroidism and altered response to thyroid hormone therapy. Periodically assess the TSH during use of these drugs together. Gastric acidity is an essential requirement for proper and adequate absorption of levothyroxine and other thyroid hormones. Proton pump inhibitors may cause hypochlorhydria, affect intragastric pH, and reduce thyroid hormone absorption.
Raloxifene: (Moderate) Patients prescribed raloxifene while taking thyroid hormones should be advised to take the drugs at separate times (e.g., 12 hours apart) until more data are available. Raloxifene may delay and reduce the oral absorption of levothyroxine (T4). In a case report, a patient with chronic but treated hypothyroidism was taking a stable dose of levothyroxine. The patient required increasing doses of levothyroxine when raloxifene was coadministered; the TSH level remained elevated and serum T4 remained decreased despite an increase in oral levothyroxine dosage. An absorption interaction was suspected and the patient rechallenged on two occasions; a decrease in serum T4 was observed whenever raloxifene and levothyroxine were administered concurrently. The patient's levothyroxine dosage requirements returned to baseline and the TSH value normalized when levothyroxine and raloxifene were administered 12 hours apart rather than simultaneously. The mechanism for the observed interaction is unknown. In theory, raloxifene might cause oral malabsorption of any thyroid hormone containing T4 (e.g., desiccated thyroid, levothyroxine, liotrix) if administered at the same time.
Rifampin: (Moderate) Rifampin increases thyroid hormone metabolism by inducing uridine 5-diphospho-glucuronosyltransferase (UGT) and leads to lower T4 serum levels. Clinicians should be alert for a decreased response to thyroid hormones if rifampin is used during thyroid hormone therapy.
Rosiglitazone: (Minor) Addition of thyroid hormones to antidiabetic or insulin therapy may result in increased dosage requirements of the antidiabetic agents. Blood sugars should be carefully monitored when thyroid therapy is added, dosages are changed, or if thyroid hormones are discontinued.
Saxagliptin: (Minor) Addition of thyroid hormones to antidiabetic or insulin therapy may result in increased dosage requirements of the antidiabetic agents. Blood sugars should be carefully monitored when thyroid therapy is added, discontinued or doses changed.
Secobarbital: (Minor) Hepatic enzyme-inducing drugs, including barbiturates, can increase the catabolism of thyroid hormones. Be alert for a decreased response to thyroid replacement agents with dosage adjustments, discontinuation or addition of barbiturates during thyroid hormone replacement therapy.
Semaglutide: (Moderate) Consider additional thyroid function monitoring during concomitant use of oral thyroid hormones and oral semaglutide. Advise patients to take oral semaglutide 30 minutes before other oral medications. Concomitant use has been observed to increase levothyroxine exposure by 33% which may increase the risk for symptoms of hyperthyroidism or require a dosage adjustment. Semaglutide delays gastric emptying which may affect the absorption of other orally administered medications. This absorption interaction is not expected with subcutaneous semaglutide or intravenous levothyroxine. Additionally, levothyroxine may worsen glycemic control in patients with diabetes.
Sevelamer: (Moderate) Thyroid hormone oral administration should be separated from sevelamer administration by 4 hours. Sevelamer appears to decrease the oral absorption of thyroid hormones. In one study of normal volunteers, the subjects (n = 7) ingested orally levothyroxine sodium, either taken separately or coadministered with sevelamer. Serum thyroxine was measured at intervals over a 6-hour period following drug ingestion. Sevelamer significantly decreased the the serum thyroxine concentration. The authors concluded that patients should be advised to separate the time of ingestion of sevelamer from their thyroid hormone preparation.
Simethicone: (Moderate) Oral thyroid hormones should be administered at least 4 hours before or after a dose of simethicone. Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing oral absorption, potentially resulting in hypothyroidism. Simethicone has been reported to chelate oral levothyroxine within the GI tract when administered simultaneously, leading to decreased thyroid hormone absorption.
Simvastatin; Sitagliptin: (Minor) Addition of thyroid hormones to antidiabetic or insulin therapy may result in increased dosage requirements of the antidiabetic agents. Blood sugars should be carefully monitored when thyroid therapy is added, discontinued or doses changed.
Sitagliptin: (Minor) Addition of thyroid hormones to antidiabetic or insulin therapy may result in increased dosage requirements of the antidiabetic agents. Blood sugars should be carefully monitored when thyroid therapy is added, discontinued or doses changed.
Sodium Ferric Gluconate Complex; ferric pyrophosphate citrate: (Moderate) Oral thyroid hormones should be administered at least 4 hours before or after the ingestion of iron supplements. Oral iron salts have been reported to chelate oral thyroid hormones within the GI tract when administered simultaneously, leading to decreased oral absorption of the thyroid hormone. For example, ferrous sulfate likely forms a ferric-thyroxine complex.
Sodium Iodide: (Major) In order to increase thyroid uptake and optimize exposure of thyroid tissue to the radionucleotide, patients must discontinue all medications and supplements that may interfere with iodide uptake into thyroid tissue prior to therapy with sodium iodide I-131, including thyroid hormones. Although various protocols are used, the following withdrawal timing recommendations were set forth in a procedure guideline published by the Society of Nuclear Medicine in February 2002. It is recommended to hold alll T4 thyroid hormones (e.g., levothyroxine) 4 to 6 weeks prior, and to hold all T3 thyroid hormones (e.g., liothyronine) 2 weeks prior, to sodium iodide I-131 therapy.
Sodium Polystyrene Sulfonate: (Moderate) Administer thyroid hormones at least 4 hours apart from cation exchange resins, like sodium polystyrene sulfonate. Cation exchange resins can bind thyroxine or levothyroxine in the GI tract and inhibit oral absorption, potentially leading to hypothyroidism.
Somatropin, rh-GH: (Minor) Excessive use of thyroid hormones with growth hormone (somatropin, rh-GH) may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to somatropin. Patients receiving concomitant therapy should be monitored closely to ensure appropriate therapeutic response to somatropin.
Soy Isoflavones: (Moderate) Concentrated soy isoflavones (e.g., genistein and daidzein) may interfere with thyroid peroxidase catalyzed iodination of thyroglobulin, resulting in a decreased production of thyroid hormones and an increased secretion of TSH endogenously. Caution should be used in administering soy isoflavone supplements concurrently with thyroid hormones. More studies are required to assess the exact mechanism of this interaction.
Sucralfate: (Moderate) Administer levothyroxine at least 4 hours apart from a dose of sucralfate. Patients treated concomitantly with these drugs should be monitored for changes in thyroid function. Consider an alternative to sucralfate, if appropriate. Concurrent use of sucralfate may reduce the efficacy of levothyroxine and other thyroid hormones by binding and delaying or preventing oral absorption, potentially resulting in hypothyroidism.
Sulfonylureas: (Minor) Addition of thyroid hormones to antidiabetic or insulin therapy may result in increased dosage requirements of the antidiabetic agents. Blood sugars should be carefully monitored when thyroid therapy is added, discontinued or doses changed.
Sympathomimetics: (Moderate) Monitor hemodynamic parameters during concomitant sympathomimetic agent and thyroid hormone use; dosage adjustments may be necessary. Concomitant use may increase the effects of sympathomimetics or thyroid hormone.
Teduglutide: (Moderate) Monitor thyroid status and for symptoms of increased thyroid effect. Based upon the pharmacodynamic effect of teduglutide, there is a potential for increased absorption of concomitant oral medications, which should be considered if these drugs require titration or have a narrow therapeutic index, such as orally administered thyroid hormones.
Theophylline, Aminophylline: (Minor) Correction of hypothyroidism to the euthyroid state may precipitate certain drug interactions. For example, hypothyroidism causes decreased clearance of theophylline, which returns to normal in the euthyroid state. Aminophylline is converted to theophylline in the body. Aminophylline dosage adjustments may be needed with thyroid hormone replacement. (Minor) Correction of hypothyroidism to the euthyroid state may precipitate certain drug interactions. For example, hypothyroidism causes decreased clearance of theophylline, which returns to normal in the euthyroid state. Theophylline dosage adjustments may be needed with thyroid hormone replacement.
Thiazolidinediones: (Minor) Addition of thyroid hormones to antidiabetic or insulin therapy may result in increased dosage requirements of the antidiabetic agents. Blood sugars should be carefully monitored when thyroid therapy is added, dosages are changed, or if thyroid hormones are discontinued.
Tirofiban: (Minor) Data from the PRISM study, indicate that patients who received levothyroxine or omeprazole concomitantly with tirofiban had a higher rate of tirofiban clearance than patients who did not receive levothyroxine or omeprazole. The clinical significance of this is unknown.
Tirzepatide: (Minor) When thyroid hormones are added to existing diabetes therapy, the glucose-lowering effect may be reduced. Close monitoring of blood glucose is necessary for individuals who use antidiabetic agents whenever there is a change in thyroid treatment. It may be necessary to adjust the dose of antidiabetic agents if thyroid hormones are added or discontinued. Thyroid hormones are important in the regulation of carbohydrate metabolism, gluconeogenesis, the mobilization of glycogen stores, and protein synthesis.
Tolazamide: (Minor) Addition of thyroid hormones to antidiabetic or insulin therapy may result in increased dosage requirements of the antidiabetic agents. Blood sugars should be carefully monitored when thyroid therapy is added, discontinued or doses changed.
Tolbutamide: (Minor) Addition of thyroid hormones to antidiabetic or insulin therapy may result in increased dosage requirements of the antidiabetic agents. Blood sugars should be carefully monitored when thyroid therapy is added, discontinued or doses changed.
Tretinoin, ATRA: (Moderate) The concomitant use of systemic tretinoin, ATRA and thyroid hormones should be done cautiously due to the potential for increased intracranial pressure and an increased risk of pseudotumor cerebri (benign intracranial hypertension). Early signs and symptoms of pseudotumor cerebri include papilledema, headache, nausea, vomiting, and visual disturbances.
Tricyclic antidepressants: (Minor) Thyroid hormones may increase receptor sensitivity and enhance the effects of tricyclic antidepressants. Although this drug combination appears to be safe, be aware of the possibility of exaggerated cardiovascular side effects such as arrhythmias and CNS stimulation.
Vonoprazan; Amoxicillin: (Moderate) Monitor for altered response to thyroid hormones if coadministered with vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of oral thyroid hormones reducing their efficacy.
Vonoprazan; Amoxicillin; Clarithromycin: (Moderate) Monitor for altered response to thyroid hormones if coadministered with vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of oral thyroid hormones reducing their efficacy.
Warfarin: (Moderate) The concurrent use of thyroid hormones and warfarin potentiates anticoagulation effects of warfarin. The mechanism of this interaction may be the increased catabolism of vitamin K clotting factors as the hypothyroid state is corrected. As a result, the hypoprothrombinemic response to warfarin occurs earlier and to a greater degree. Dextrothyroxine has been shown to potentiate the effects of warfarin. Dextrothyroxine may increase the affinity of warfarin for its receptor sites in addition to increasing the catabolism of vitamin K dependent clotting factors. A reduction in the dosage of warfarin is recommended with concomitant therapy.
Levothyroxine exhibits all the actions of endogenous thyroid hormone. Liothyronine (T3) is the principal hormone that exhibits these actions whereas levothyroxine (T4) is the major hormone secreted by the thyroid gland and is metabolically deiodinated to T3 in peripheral tissues. Approximately 80% of a levothyroxine dose is deiodinated to T3 and reverse T3, and virtually all of the activity of levothyroxine can be ascribed to the conversion of the drug to T3. Serum concentrations of T4 and TSH are typically used as the primary monitoring parameters for determining thyroid function.
In general, thyroid hormones influence the growth and maturation of tissues, increase energy expenditure, and affect the turnover of essentially all substrates. These effects are mediated through control of DNA transcription and, ultimately, protein synthesis. Thyroid hormones play an integral role in both anabolic and catabolic processes and are particularly important to the development of the central nervous system in newborns. They regulate cell differentiation and proliferation and aid in the myelination of nerves and the development of axonal and dendritic processes in the nervous system. Thyroid hormones, along with somatotropin, are responsible for regulating growth, particularly of bones and teeth. Thyroid hormones also decrease cholesterol concentrations in the liver and the bloodstream and have a direct cardiostimulatory action. Cardiac consumption is increased by the administration of thyroid hormone, resulting in increased cardiac output. Administration of exogenous thyroid hormone to patients with hypothyroidism increases the metabolic rate by enhancing protein and carbohydrate metabolism, increasing gluconeogenesis, facilitating the mobilization of glycogen stores, and increasing protein synthesis. In response to reestablishing physiologic levels of thyroid hormone, thyroid-stimulating hormone (TSH) concentrations correct if the primary disorder is at the level of the thyroid.
The release of endogenous T3 and T4 from the thyroid gland into the systemic circulation is regulated by TSH (thyrotropin, also known as thyroid stimulating hormone), which is secreted by the anterior pituitary gland. Thyrotropin release is controlled by the secretion of thyroid-releasing hormone (TRH) from the hypothalamus and by a feedback mechanism dependent on the concentrations of circulating thyroid hormones. When circulating T3 and T4 levels increase, the activities of TRH and TSH decrease. Because of this feedback mechanism, the administration of pharmacologic doses of exogenous thyroid hormone to patients with a normal thyroid suppresses endogenous thyroid hormone secretion.
Levothyroxine is administered orally or intravenously. Over 99% of levothyroxine (T4) is bound to proteins, primarily thyroxine-binding globulin (TGB), prealbumin, and albumin. These proteins have a higher affinity for T4 than for liothyronine (T3). Many medications and concurrent clinical conditions may affect T4 protein-binding, resulting in clinically significant changes in thyroid hormone activity since free (unbound) drug is metabolically active. Thyroid hormones do not readily cross the placental barrier, and only minimal amounts are distributed into breast milk.
Levothyroxine (T4) exhibits a slow metabolic clearance. The major pathway of thyroid hormone metabolism is through sequential deiodination. Approximately 80% of circulating T3 is derived from peripheral T4 by monodeiodination. The liver is the major site of degradation for both T4 and T3, with T4 deiodination also occurring at a number of additional sites, including the kidney and other tissues. Approximately 80% of the daily dose of T4 is deiodinated to yield equal amounts of T3 and reverse T3 (rT3). T3 and rT3 are further deiodinated to diiodothyronine. Thyroid hormones are also metabolized via conjugation with glucuronides and sulfates and excreted directly into the bile and gut where they undergo enterohepatic recirculation. Thyroid hormones are primarily eliminated by the kidneys. A portion of the conjugated hormone reaches the colon unchanged and is eliminated in the feces. Approximately 20% of T4 is eliminated in the feces. Urinary excretion of T4 decreases with age. The elimination half-life of levothyroxine is 6 to 7 days in euthyroid patients, 9 to 10 days in hypothyroid patients, and 3 to 4 days in hyperthyroid patients. The elimination half-life of T3 is 2 days or less. Levothyroxine has a slower onset of action and a longer duration than liothyronine. Full therapeutic effects of levothyroxine may not be evident for 1 to 3 weeks following oral administration and persist for the same amount of time following cessation of therapy. As the hypothyroid patient becomes euthyroid, TSH secretion decreases.
Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: uridine 5'-diphospho-glucuronosyltransferase (UGT), and possibly intestinal P-glycoprotein (P-gp)
The induction of uridine 5'-diphospho-glucuronosyltransferase (UGT) by other medications increases L-thyroxine hepatic metabolism and leads to a lower T4 serum levels. The literature has reported that levothyroxine might inhibit P-gp, and lower cyclosporine concentrations; however, this action of levothyroxine requires further study.
-Route-Specific Pharmacokinetics
Oral Route
Absorption of orally administered levothyroxine (T4) from the gastrointestinal tract ranges from 40% to 80%. Based on medical practice, the relative bioavailability of oral levothyroxine is 48 to 74% that of the injectable levothyroxine sodium. The majority of the levothyroxine dose is absorbed from the jejunum and upper ileum. The relative bioavailability of the oral tablets, compared to an equal nominal dose of oral levothyroxine sodium solution, is approximately 93%. T4 absorption is increased by fasting, and decreased in malabsorption syndromes and by certain foods such as soybeans. Dietary fiber decreases bioavailability of T4. Absorption may also decrease with age. In addition, many drugs and foods affect T4 absorption. Certain foods, like soybean infant formula, enteral feedings, and dietary fiber, decrease T4 absorption.
Consistent tablet potency was an issue with oral levothyroxine products prior to 1984. In 1984, the USP required all manufacturers to use HPLC to monitor levothyroxine tablet content to ensure tablet potency. With the new manufacturing and testing processes, oral levothyroxine product potency issues have not been a significant problem.
Intravenous Route
Following intravenous (IV) administration, the synthetic levothyroxine is 100% available and cannot be distinguished from the natural hormone that is secreted endogenously. Levothyroxine injection produces a gradual increase in the circulating concentrations of the hormone with an approximate half-life of 9 to 10 days in hypothyroid patients. Intravenous levothyroxine treatment in severely hypothyroid patients may lead to improvement in cardiovascular, renal, pulmonary, and metabolic parameters within a week. Serum thyroxine and triiodothyronine concentrations may improve or normalize with a similar time frame, with more gradual improvement in serum TSH.
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