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Levothyroxine

Pronunciation

(lee voe thye ROKS een)

Index Terms

  • L-Thyroxine Sodium
  • Levothroid
  • Levothyroxine Sodium
  • T4
  • Tirosint-Sol

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Capsule, Oral, as sodium:

Tirosint: 13 mcg, 25 mcg, 50 mcg, 75 mcg, 88 mcg, 100 mcg, 112 mcg, 125 mcg, 137 mcg, 150 mcg

Solution Reconstituted, Intravenous, as sodium [preservative free]:

Generic: 100 mcg (1 ea); 200 mcg (1 ea); 500 mcg (1 ea)

Tablet, Oral, as sodium:

Levoxyl: 25 mcg [scored; contains fd&c yellow #6 aluminum lake]

Levoxyl: 50 mcg [scored]

Levoxyl: 75 mcg [scored; contains fd&c blue #1 aluminum lake]

Levoxyl: 88 mcg [scored; contains fd&c blue #1 aluminum lake, fd&c yellow #10 aluminum lake, fd&c yellow #6 aluminum lake]

Levoxyl: 100 mcg [scored; contains fd&c yellow #10 aluminum lake, fd&c yellow #6 aluminum lake]

Levoxyl: 112 mcg [scored; contains fd&c red #40 aluminum lake, fd&c yellow #6 aluminum lake]

Levoxyl: 125 mcg [scored; contains fd&c red #40 aluminum lake, fd&c yellow #10 aluminum lake]

Levoxyl: 137 mcg, 150 mcg [scored; contains fd&c blue #1 aluminum lake]

Levoxyl: 175 mcg [scored; contains fd&c blue #1 aluminum lake, fd&c yellow #10 aluminum lake]

Levoxyl: 200 mcg [scored; contains fd&c yellow #10 aluminum lake]

Synthroid: 25 mcg [scored; contains fd&c yellow #6 aluminum lake]

Synthroid: 50 mcg [scored; contains corn starch]

Synthroid: 75 mcg [scored; contains corn starch, fd&c blue #2 aluminum lake, fd&c red #40 aluminum lake]

Synthroid: 88 mcg [scored; contains corn starch, fd&c blue #1 aluminum lake, fd&c yellow #10 aluminum lake, fd&c yellow #6 aluminum lake]

Synthroid: 100 mcg [scored; contains corn starch, fd&c yellow #10 aluminum lake, fd&c yellow #6 aluminum lake]

Synthroid: 112 mcg [scored; contains corn starch]

Synthroid: 125 mcg [scored; contains corn starch, fd&c blue #1 aluminum lake, fd&c red #40 aluminum lake, fd&c yellow #6 aluminum lake]

Synthroid: 137 mcg [scored; contains fd&c blue #1 aluminum lake]

Synthroid: 150 mcg [scored; contains fd&c blue #2 aluminum lake]

Synthroid: 175 mcg [scored; contains fd&c blue #1 aluminum lake]

Synthroid: 200 mcg [scored; contains fd&c red #40 aluminum lake]

Synthroid: 300 mcg [scored; contains fd&c blue #1 aluminum lake, fd&c yellow #10 aluminum lake, fd&c yellow #6 aluminum lake]

Unithroid: 25 mcg [contains fd&c yellow #6 aluminum lake]

Unithroid: 25 mcg [DSC] [scored; contains fd&c yellow #6 aluminum lake]

Unithroid: 50 mcg

Unithroid: 50 mcg [DSC], 75 mcg [DSC] [scored]

Unithroid: 75 mcg [contains fd&c blue #2 aluminum lake, fd&c red #40 aluminum lake]

Unithroid: 88 mcg [DSC] [scored]

Unithroid: 88 mcg [contains fd&c blue #1 aluminum lake, fd&c yellow #10 aluminum lake, fd&c yellow #6 aluminum lake]

Unithroid: 100 mcg [contains fd&c yellow #10 aluminum lake, fd&c yellow #6 aluminum lake]

Unithroid: 100 mcg [DSC] [scored; contains fd&c yellow #10 aluminum lake, fd&c yellow #6 aluminum lake]

Unithroid: 112 mcg

Unithroid: 112 mcg [DSC] [scored]

Unithroid: 125 mcg [contains fd&c blue #1 aluminum lake, fd&c red #40 aluminum lake, fd&c yellow #6 aluminum lake]

Unithroid: 125 mcg [DSC] [scored; contains fd&c blue #1 aluminum lake, fd&c red #40 aluminum lake, fd&c yellow #6 aluminum lake]

Unithroid: 137 mcg [contains fd&c blue #1 aluminum lake]

Unithroid: 150 mcg [contains fd&c blue #2 aluminum lake]

Unithroid: 150 mcg [DSC] [scored; contains fd&c blue #2 aluminum lake]

Unithroid: 175 mcg [DSC] [scored]

Unithroid: 175 mcg [contains fd&c blue #1 aluminum lake]

Unithroid: 200 mcg [DSC] [scored]

Unithroid: 200 mcg [contains fd&c red #40 aluminum lake]

Unithroid: 300 mcg [contains fd&c blue #1 aluminum lake, fd&c yellow #10 (quinoline yellow), fd&c yellow #6 aluminum lake]

Unithroid: 300 mcg [DSC] [scored; contains fd&c blue #1 aluminum lake, fd&c yellow #10 aluminum lake, fd&c yellow #6 aluminum lake]

Unithroid Direct: 25 mcg [scored; contains fd&c yellow #6 aluminum lake]

Unithroid Direct: 50 mcg [scored]

Unithroid Direct: 75 mcg, 88 mcg [scored; contains fd&c blue #1 aluminum lake, fd&c blue #2 aluminum lake, fd&c red #40 aluminum lake, fd&c yellow #10 aluminum lake, fd&c yellow #6 aluminum lake]

Unithroid Direct: 100 mcg [scored; contains fd&c yellow #10 aluminum lake, fd&c yellow #6 aluminum lake]

Unithroid Direct: 112 mcg [scored]

Unithroid Direct: 125 mcg [scored; contains fd&c blue #1 aluminum lake, fd&c red #40 aluminum lake, fd&c yellow #6 aluminum lake]

Unithroid Direct: 150 mcg [scored; contains fd&c blue #2 aluminum lake]

Unithroid Direct: 175 mcg [scored; contains fd&c blue #1 aluminum lake]

Unithroid Direct: 200 mcg [scored; contains fd&c red #40 aluminum lake]

Unithroid Direct: 300 mcg [scored; contains fd&c blue #1 aluminum lake, fd&c yellow #10 aluminum lake, fd&c yellow #6 aluminum lake]

Generic: 25 mcg, 50 mcg, 75 mcg, 88 mcg, 100 mcg, 112 mcg, 125 mcg, 137 mcg, 150 mcg, 175 mcg, 200 mcg, 300 mcg

Brand Names: U.S.

  • Levoxyl
  • Synthroid
  • Tirosint
  • Unithroid
  • Unithroid Direct

Pharmacologic Category

  • Thyroid Product

Pharmacology

Levothyroxine (T4) is a synthetic form of thyroxine, an endogenous hormone secreted by the thyroid gland. T4 is converted to its active metabolite, L-triiodothyronine (T3). Thyroid hormones (T4 and T3) then bind to thyroid receptor proteins in the cell nucleus and exert metabolic effects through control of DNA transcription and protein synthesis; involved in normal metabolism, growth, and development; promotes gluconeogenesis, increases utilization and mobilization of glycogen stores, and stimulates protein synthesis, increases basal metabolic rate

Absorption

Oral: Erratic (40% to 80% [per manufacturer]); may be decreased by age and specific foods and drugs

Metabolism

Hepatic to triiodothyronine (T3; active); ~80% thyroxine ( T4) deiodinated in kidney and periphery; glucuronidation/conjugation also occurs; undergoes enterohepatic recirculation

Excretion

Urine (major route of elimination; decreases with age); feces (~20%)

Onset of Action

Oral: 3 to 5 days; IV: Within 6 to 8 hours

Time to Peak

Serum: 2 to 4 hours

Half-Life Elimination

Euthyroid: 6 to 8 days; Hypothyroid: 9 to 10 days; Hyperthyroid: 3 to 4 days

Protein Binding

>99% bound to plasma proteins including thyroxine-binding globulin, thyroxine-binding prealbumin, and albumin

Use: Labeled Indications

Oral:

Hypothyroidism: Replacement or supplemental therapy in congenital or acquired hypothyroidism of any etiology. Specific indications include primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) hypothyroidism. Note: ATA guidelines recommend levothyroxine monotherapy as the preferred thyroid preparation for the treatment of hypothyroidism (ATA [Jonklaas 2014]).

Pituitary thyrotropin-stimulating hormone suppression: An adjunct to surgery and radioiodine therapy in the management of thyrotropin-dependent well-differentiated thyroid cancer.

Injectable: Treatment of myxedema coma

Off Label Uses

Cadaveric organ recovery (hormonal resuscitation)

Data from a retrospective review of brain-dead donors who successfully donated organs supports the use of intravenous levothyroxine given concomitantly with an ampule of 50% dextrose, methylprednisolone sodium succinate, and regular insulin (goal blood glucose: 120 to 180 mg/dL) in hemodynamically unstable brain-dead donors who require significant vasopressor support to increase the quantity and quality of organs available for transplantation [Salim 2007]. Early use of levothyroxine therapy (with aggressive blood product resuscitation) may significantly increase the number of solid organs donated per donor [Joseph 2014]. Additional data may be necessary to further define the role of levothyroxine in this setting. Another protocol using liothyronine (T3) has been used with success and is recommended over the use of levothyroxine [Rosendale 2003a], [Rosendale 2003b], [Rosengard 2002], [Zaroff 2002].

Subclinical hypothyroidism

The American Association of Clinical Endocrinologists/American Thyroid Association Clinical Practice Guidelines for Hypothyroidism in Adults and the European Thyroid Association Guideline for Management of Subclinical Hypothyroidism recommend thyroid replacement with levothyroxine in select patients with subclinical hypothyroidism (persistently elevated TSH with free T4 within normal range). In non-elderly patients (<65 to 70 years of age), treatment is recommended if TSH ≥10 milliunits/L (regardless of symptoms) and may also be considered in symptomatic patients with mild to moderate TSH elevation (4 to 10 milliunits/L). In elderly patients (>70 years of age), consider treatment if TSH ≥10 milliunits/L and clear symptoms of hypothyroidism present, or if high vascular risk factors present. In elderly patients with TSH <10 milliunits/L, lack of symptoms, or lack of risk factors, observation only is recommended [Garber 2012], [Pearce 2013].

Contraindications

Injection: There are no contraindications listed in the manufacturer's labeling when used for labeled indication (treatment of myxedema coma); consider contraindications for oral therapy if using as a temporary substitute for oral treatment (off-label use) in patients with chronic hypothyroidism.

Oral: Hypersensitivity to levothyroxine sodium or any component of the formulation; acute MI; untreated subclinical (suppressed serum TSH level with normal T3 and T4 levels) or overt thyrotoxicosis of any etiology; uncorrected adrenal insufficiency.

Capsule: Additional contraindication: Inability to swallow capsules (eg, infants, small children)

Canadian labeling: Additional contraindications (not in US labeling): Acute myocarditis; acute pancarditis

Dosing: Adult

Doses should be adjusted based on clinical response and laboratory parameters.

Hypothyroidism:

Oral:

Adults (healthy) who have been hypothyroid for only a few months: Initial: 1.6 mcg/kg/day; adjust dose by 12.5 to 25 mcg/day every 4 to 6 weeks as needed. Usual doses are ≤200 mcg/day (range: 100 to 125 mcg/day [70 kg adult]); doses ≥300 mcg/day are rare (consider poor compliance, malabsorption, and/or drug interactions).

Adults >50 years of age without evidence of coronary heart disease (off-label): Lower starting doses (eg, 50 mcg/day) may be preferred (ATA/AACE [Garber 2012]).

Adults with cardiac disease: Initial: 12.5 to 25 mcg/day; adjust dose by 12.5 to 25 mcg increments at 6- to 8-week intervals as needed

Adults with severe longstanding hypothyroidism: Initial: 12.5 to 25 mcg/day; adjust dose by 12.5 to 25 mcg/day every 2 to 4 weeks as appropriate

Pregnant patients: Dosage requirements may increase during pregnancy in patients with preexisting disease. If new onset hypothyroidism occurs initiate therapy with 1.6 mcg/kg/day (for severe hypothyroidism) or 1 mcg/kg/day (for mild hypothyroidism [TSH <10 milliunits/L]) followed by appropriate dosage adjustments every 4 weeks.

IM, IV (off-label route [IM] and off-label use): ~75% of the oral dose by IV administration (ATA [Jonklaas 2014]); alternatively 50% of the previously established oral dose by IV or IM administration has been recommended (Levothyroxine injection Canadian product labeling 2017). Note: Bioavailability of the oral formulation is highly variable, but absorption has been measured to be ~80%, when the oral tablet formulation was administered in the recommended fasting state (Dickerson 2010; Fish 1987).

TSH suppression: Oral:

Well-differentiated thyroid cancer (papillary and follicular): Highly individualized; Doses >2 mcg/kg/day may be needed to suppress TSH to <0.1 milliunits/L in high-risk tumors. For intermediate-risk tumors, initial TSH suppression to 0.1 to 0.5 milliunits/L is recommended; for low-risk tumors, TSH may be maintained at or slightly below the lower limit of normal (0.1 to 0.5 milliunits/L [if low serum thyroglobulin levels]) or at 0.5 to 2 milliunits/L [if undetectable serum thyroglobulin levels or post-lobectomy] (ATA [Haugen 2016]).

Benign nodules and nontoxic multinodular goiter: Routine use of T4 for TSH suppression is not recommended in patients with benign thyroid nodules. In patients deemed appropriate candidates, treatment should never be fully suppressive (TSH <0.1 milliunits/L) (AACE/ACE/AME [Gharib 2016]; ATA [Haugen 2016]).

Myxedema coma or stupor: IV: 300 to 500 mcg initially, followed by 50 to 100 mcg once daily until patient is able to tolerate oral administration; smaller doses should be considered in patients with cardiovascular disease

Alternate recommendations (off-label dose): Initial loading dose: 200 to 400 mcg; followed by a daily replacement dose of 1.2 mcg/kg/day (which is 75% of the 1.6 mcg/kg oral daily replacement dose reduced for IV administration); smaller doses should be considered for smaller or older patients and those with a history of coronary disease or arrhythmia; institute oral therapy after the patient improves clinically (ATA [Jonklaas 2014])

Cadaveric organ recovery (hormonal resuscitation) (off-label use): IV: Initial: 20 mcg bolus followed by a continuous infusion of 10 mcg/hour administered to the brain-dead donor who is hemodynamically unstable requiring significant vasopressor support; give concomitantly with methylprednisolone, dextrose, and regular insulin (Salim 2007).

Subclinical hypothyroidism (if treated) (off-label use): Oral: Initial: 25 to 75 mcg/day, with higher doses usually required for those presenting with higher TSH values (ATA/AACE [Garber 2012]) or 1.5 mcg/kg/day (for patients without heart disease) or 25 or 50 mcg/day (for patients with cardiac disease) (ETA [Pearce 2013]).

Dosing: Geriatric

Doses should be adjusted based on clinical response and laboratory parameters.

Hypothyroidism: Oral: Initial: 12.5 to 25 mcg/day; adjust dose every 6 to 8 weeks until euthyroid. Elderly patients may only require <1 mcg/kg/day.

Myxedema coma: Refer to adult dosing; lower doses may be needed.

Subclinical hypothyroidism (if treated) (off-label use): Oral: Initial dosing is generally lower than that required in the treatment of overt hypothyroidism; higher serum TSH targets may be appropriate in elderly patients (ATA/AACE [Garber 2012])

Dosing: Pediatric

Hypothyroidism: Infants and Children: Doses should be adjusted based on clinical response and laboratory parameters.

Oral: Daily dosage based on body weight and age as listed below:

1 to 3 months: 10 to 15 mcg/kg/day; if the infant is at risk for development of cardiac failure, use a lower starting dose of 25 mcg/day; if the initial serum T4 is very low (<5 mcg/dL) begin treatment at a higher dosage of approximately 50 mcg/day (12 to 17 mcg/kg/day) (AAP 2006; Selva 2002)

3 to 6 months: 8 to 10 mcg/kg/day

6 to 12 months: 6 to 8 mcg/kg/day

1 to 5 years: 5 to 6 mcg/kg/day

6 to 12 years: 4 to 5 mcg/kg/day

>12 years but growth and puberty incomplete: 2 to 3 mcg/kg/day

Growth and puberty complete: 1.6 mcg/kg/day; refer to adult dosing.

Note: Hyperactivity in older children may be minimized by starting at 25% of the recommended dose and increasing each week by that amount until the full dose is achieved (4 weeks).

Children with severe or chronic hypothyroidism should be started at 25 mcg/day; adjust dose by 25 mcg every 2 to 4 weeks.

IM (off-label route), IV: Refer to adult dosing.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer's labeling.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer's labeling.

Dosing: Adjustment for Toxicity

Cardiac symptoms (onset or worsening): Manufacturer labeling recommends reducing dosage or withholding therapy for 7 days and then resuming therapy at reduced dosage. Specific dosing recommendations are not provided.

Reconstitution

Dilute vial for injection with 5 mL normal saline. Reconstituted concentrations for the 100 mcg, 200 mcg and 500 mcg vials are 20 mcg/mL, 40 mcg/mL ,and 100 mcg/mL, respectively. Shake well and use immediately after reconstitution (manufacturer labeling suggests reconstituted vial is stable for 4 hours); discard any unused portions.

Extemporaneously Prepared

A 25 mcg/mL oral suspension may be made with tablets and 40 mL glycerol. Crush twenty-five 0.1 mg levothyroxine tablets in a mortar and reduce to a fine powder. Add small portions of glycerol and mix to a uniform suspension. Transfer to a calibrated 100 mL amber bottle; rinse the mortar with about 10 mL of glycerol and pour into the bottle; repeat until all 40 mL of glycerol is used. Add quantity of water sufficient to make 100 mL. Label "shake well" and "refrigerate". Stable for 8 days refrigerated.

Boulton DW, Fawcett JP, and Woods DJ, "Stability of an Extemporaneously Compounded Levothyroxine Sodium Oral Liquid," Am J Health Syst Pharm, 1996, 53(10):1157-61.8734676

Administration

Oral: Administer consistently in the morning on an empty stomach, at least 30 to 60 minutes before food. Alternatively, may consistently administer at night 3 to 4 hours after the last meal (AACE/ATA [Garber 2012]; ATA [Jonklaas 2014]).

Capsule: Must be swallowed whole; do not cut, crush, or attempt to dissolve capsules in water to prepare a suspension.

Tablet: May be crushed and suspended in 5 to 10 mL of water; suspension should be used immediately. Levoxyl should be administered with a full glass of water to prevent gagging (due to tablet swelling).

Nasogastric tube: Bioavailability of levothyroxine is reduced if administered with enteral tube feeds. Since holding feedings for at least 1 hour before and after levothyroxine administration may not completely resolve the interaction, an increase in dose (eg, additional 25 mcg) may be necessary (Dickerson 2010).

Parenteral: May be administered by IV injection; may also be administered IM when oral administration is not feasible (off-label route).

Cadaveric organ recovery (hormonal resuscitation) (off-label use): After IV bolus administration, may administer as a continuous infusion (Salim 2007).

Storage

Capsules and tablets: Store at 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F). Protect from light and moisture.

Injection: Store at 20°C to 25°C (68°F to 77°F). Protect from light.

Additional stability data:

Stability in polypropylene syringes (100 mcg/mL in NS) at 5°C ± 1°C is 7 days (Gupta 2000).

Stability in latex-free, PVC minibags protected from light and stored at 15°C to 30°C (59°F to 86°F) was 12 hours for a 2 mcg/mL concentration or 18 hours for a 0.4 mcg/mL concentration in NS. May be exposed to light; however, stability time is significantly reduced, especially for the 2 mcg/mL concentration (Strong 2010).

Drug Interactions

Aluminum Hydroxide: May decrease the serum concentration of Levothyroxine. Management: Separate administration of oral levothyroxine and aluminum hydroxide by at least 4 hours. Consider therapy modification

Amiodarone: May diminish the therapeutic effect of Thyroid Products. Monitor therapy

Bile Acid Sequestrants: May decrease the serum concentration of Thyroid Products. Management: Administer oral thyroid products at least 4 h prior to colesevelam, and at least 1 h before or 4-6 h after cholestyramine. Specific recommendations for colestipol are not available. Monitor for decreased concentrations/effects of the thyroid product. Consider therapy modification

Calcium Polystyrene Sulfonate: May decrease the serum concentration of Thyroid Products. Management: To minimize risk of interaction, separate dosing of oral calcium polystyrene sulfonate and thyroid products (eg, levothyroxine) or administer calcium polystyrene sulfonate rectally. Monitor for signs/symptoms of hypothyroidism with concomitant use (oral). Consider therapy modification

Calcium Salts: May diminish the therapeutic effect of Thyroid Products. Management: Separate the doses of the thyroid product and the oral calcium supplement by at least 4 hours. Consider therapy modification

CarBAMazepine: May decrease the serum concentration of Thyroid Products. Monitor therapy

Ciprofloxacin (Systemic): May decrease the serum concentration of Thyroid Products. Monitor therapy

Estrogen Derivatives: May diminish the therapeutic effect of Thyroid Products. Monitor therapy

Fosphenytoin: May decrease the serum concentration of Thyroid Products. Phenytoin may also displace thyroid hormones from protein binding sites. Monitor therapy

Iron Salts: May decrease the serum concentration of Levothyroxine. Management: Separate oral administration of iron salts and levothyroxine by at least 4 hours. Separation of doses is not required with parenterally administered iron salts or levothyroxine. Exceptions: Ferric Carboxymaltose; Ferric Gluconate; Ferric Hydroxide Polymaltose Complex; Ferric Pyrophosphate Citrate; Ferumoxytol; Iron Dextran Complex; Iron Isomaltoside; Iron Sucrose. Consider therapy modification

Lanthanum: May decrease the serum concentration of Thyroid Products. Management: Administer oral thyroid products at least two hours before or after lanthanum. Consider therapy modification

Magnesium Salts: May decrease the serum concentration of Levothyroxine. Management: Separate administration of oral levothyroxine and oral magnesium salts by at least 4 hours. Consider therapy modification

Multivitamins/Minerals (with ADEK, Folate, Iron): May decrease the serum concentration of Levothyroxine. Management: Separate oral administration of iron-containing multivitamins and levothyroxine by at least 4 hours. Consider therapy modification

Orlistat: May decrease the serum concentration of Levothyroxine. Management: Separate administration of oral levothyroxine and orlistat by a least 4 hours. Monitor patients closely for signs and symptoms of hypothyroidism. Consider therapy modification

Patiromer: May decrease the serum concentration of Levothyroxine. Management: Administer oral levothyroxine at least 3 hours before or 3 hours after patiromer. Consider therapy modification

Phenytoin: May decrease the serum concentration of Thyroid Products. Phenytoin may also displace thyroid hormones from protein binding sites. Monitor therapy

Piracetam: May enhance the adverse/toxic effect of Thyroid Products. Specifically, symptoms including confusion, irritability, and sleep disorder have been described during concomitant use. Monitor therapy

Polaprezinc: May decrease the serum concentration of Levothyroxine. Consider therapy modification

Raloxifene: May decrease the absorption of Levothyroxine. Consider therapy modification

RifAMPin: May decrease the serum concentration of Thyroid Products. Monitor therapy

Ritonavir: May diminish the therapeutic effect of Thyroid Products. Monitor therapy

Selective Serotonin Reuptake Inhibitors: May diminish the therapeutic effect of Thyroid Products. Thyroid product dose requirements may be increased. Monitor therapy

Sevelamer: May decrease the serum concentration of Levothyroxine. Management: Consider separating administration of sevelamer and levothyroxine by at least several hours whenever possible in order to decrease the risk of a significant interaction. Consider therapy modification

Sodium Iodide I131: Thyroid Products may diminish the therapeutic effect of Sodium Iodide I131. Avoid combination

Sodium Polystyrene Sulfonate: May decrease the serum concentration of Thyroid Products. Management: To minimize risk of interaction, separate dosing of oral sodium polystyrene sulfonate and thyroid products (e.g., levothyroxine) or administer sodium polystyrene sulfonate rectally. Monitor for signs/symptoms of hypothyroidism with concomitant use (oral). Consider therapy modification

Sucralfate: May decrease the serum concentration of Levothyroxine. Monitor therapy

Sucroferric Oxyhydroxide: May decrease the serum concentration of Levothyroxine. Management: Avoid the use of oral/enteral levothyroxine and sucroferric oxyhydroxide in combination. No interaction is anticipated with parenteral levothyroxine administration. Avoid combination

Theophylline Derivatives: Thyroid Products may increase the metabolism of Theophylline Derivatives. Exceptions: Dyphylline. Monitor therapy

Tricyclic Antidepressants: Thyroid Products may enhance the arrhythmogenic effect of Tricyclic Antidepressants. Thyroid Products may enhance the stimulatory effect of Tricyclic Antidepressants. Monitor therapy

Vitamin K Antagonists (eg, warfarin): Thyroid Products may enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Test Interactions

T4-binding globulin (TBG): Factors that alter binding in serum (ATA/AACE [Garber 2012]):

Note: T4 is ~99.97% protein bound. Factors that alter protein binding will affect serum total T4 levels; however, measurement of serum free T4 (the metabolically active moiety) has largely replaced serum total T4 for thyroid status assessment.

Conditions/states that increase TBG binding: Pregnancy, hepatitis, porphyria, neonatal state

Medications that increase TBG binding: Estrogens, 5-fluorouracil, heroin, methadone, mitotane, perphenazine, selective estrogen receptor modulators (eg, tamoxifen, raloxifene)

Conditions/states that decrease TBG binding: Hepatic failure, nephrosis, severe illness.

Medications that decrease TBG binding: Androgens, anabolic steroids, glucocorticoids, L-asparaginase, nicotinic acid

Thyroxine (T4) and triiodothyronine (T3): Serum binding inhibitors (ATA/AACE [Garber 2012]):

Medications that inhibit T4 and T3 binding: Carbamazepine, furosemide, free fatty acids, heparin, NSAIDS (variable, transient), phenytoin, salicylates

Thyroid gland hormone: Interference with production and secretion (ATA/AACE [Garber 2012]):

Medications affecting iodine uptake: Amiodarone, iodinated contrast agents, iodine, ethionamide

Medications affecting hormone production: Amiodarone, ethionamide, iodinated contrast agents, iodine, sulfonylureas, sulfonamides, thionamides (carbimazole, methimazole, propylthiouracil),

Medications affecting secretion: Amiodarone, iodinated contrast agents, iodine, lithium

Medications inducing thyroiditis: Alemtuzumab, amiodarone, antiangiogenic agents (lenalidomide, thalidomide), denileukin diftitoxin, interferon alpha, interleukins, lithium, tyrosine kinase inhibitors (sunitinib, sorafenib)

Medications potentially causing the development of Graves’: Alemtuzumab, interferon alpha, antiretroviral therapy

Medications potentially ameliorating thyroiditis (if autoimmune) or Graves’: Glucocorticoids

Hypothalamic-pituitary axis and TSH: Interference with secretion (ATA/AACE [Garber 2012]):

Medications decreasing TSH secretion: Bexarotene, dopamine, dopaminergic agonists (bromocriptine, cabergoline), glucocorticoids, interleukin-6, metformin, opiates, somatostatin analogues (octreotide, lanreotide), thyroid hormone analogues

Medications increasing TSH secretion: Amphetamine, interleukin 2, metoclopramide, ritonavir, St John's wort

Medications potentially causing hypophysitis: Ipilimumab

Adverse Reactions

Frequency not defined.

Cardiovascular: Angina pectoris, cardiac arrest, cardiac arrhythmia, congestive heart failure, flushing, hypertension, increased pulse, myocardial infarction, palpitations, tachycardia

Central nervous system: Anxiety, choking sensation (Levoxyl), emotional lability, fatigue, headache, heat intolerance, hyperactivity, insomnia, irritability, myasthenia, nervousness, pseudotumor cerebri (children), seizure (rare)

Dermatologic: Alopecia, diaphoresis

Endocrine & metabolic: Menstrual disease, weight loss

Gastrointestinal: Abdominal cramps, diarrhea, dysphagia (Levoxyl), gag reflex (Levoxyl), increased appetite, vomiting

Genitourinary: Infertility

Hepatic: Increased liver enzymes

Hypersensitivity: Hypersensitivity (to inactive ingredients; symptoms include urticaria, pruritus, rash, flushing, angioedema, GI symptoms, fever, arthralgia, serum sickness, wheezing)

Neuromuscular & skeletal: Decreased bone mineral density, slipped capital femoral epiphysis (children), tremor

Respiratory: Dyspnea

Miscellaneous: Fever

<1% (Limited to important or life-threatening): Dysgeusia (Syed 2016)

ALERT: U.S. Boxed Warning

Weight reduction:

Do not use thyroid hormones, including levothyroxine, either alone or with other therapeutic agents, for the treatment of obesity or for weight loss. In euthyroid patients, doses within the range of daily hormonal requirements are ineffective for weight reduction. Larger doses may produce serious or even life-threatening manifestations of toxicity, particularly when given in association with sympathomimetic amines such as those used for their anorectic effects.

Warnings/Precautions

Disease-related concerns:

• Adrenal insufficiency: Use with caution in patients with adrenal insufficiency; symptoms may be exaggerated or aggravated. Use is contraindicated in patients with uncorrected adrenal insufficiency. Treatment with glucocorticoids should precede levothyroxine therapy in patients with adrenal insufficiency.

• Benign thyroid nodules: Appropriate use: Routine use of T4 for TSH suppression is not recommended in patients with benign thyroid nodules. Treatment should never be fully suppressive (TSH <0.1 milliunits/L) (AACE/ACE/AME [Gharib 2016]; ATA [Haugen 2016]).

- Use of T4 may be considered in association with iodine supplementation only in young patients residing in iodine-deficient areas with small thyroid nodules and no evidence of functional autonomy (AACE/ACE/AME [Gharib 2016]).

- Use should be avoided in postmenopausal women, elderly patients, patients with cardiovascular disease, osteoporosis, large thyroid nodules or long-standing goiters, or low-normal TSH levels (AACE/ACE/AME [Gharib 2016]).

• Cardiovascular disease: Use with caution and reduce dosage in patients with cardiovascular disease; patients with developing or worsening cardiac symptoms should have their dose reduced or therapy withheld for 7 days and then resumed at a reduced dose. Chronic hypothyroidism predisposes patients to coronary artery disease; monitor patients closely for development of cardiac ischemia. Similarly, patients with heart failure and hypothyroidism should be closely followed.

• Diabetes: Use with caution in patients with diabetes mellitus and insipidus; symptoms may be exaggerated or aggravated.

• Osteoporosis: Long-term therapy can decrease bone mineral density. Postmenopausal women and women using suppressive doses should receive the lowest dose necessary for clinical response.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: Use with caution; suppressed TSH levels may increase risk of atrial fibrillation and mortality secondary to cardiovascular disease (Gharib 2016; Parle 2001). Increase dose slowly and monitor for signs/symptoms of angina.

Dosage form specific issues:

• Levoxyl: Product may rapidly swell and disintegrate, causing choking or gagging (should be administered with a full glass of water); use caution in patients with dysphagia or other swallowing disorders.

• Product interchangeability: Switching between different levothyroxine products may result in variations in the administered dose and altered TSH values and is not generally recommended; if formulations are changed, close monitoring of TSH is recommended (ATA [Jonklaas 2014]). Pediatric patients with congenital hypothyroidism may be more sensitive to changes in formulation (Carswell 2013).

Other warnings/precautions:

• Weight reduction (off-label use): [US Boxed Warning]: Thyroid supplements are ineffective and potentially toxic when used for the treatment of obesity or for weight reduction, especially in euthyroid patients. High doses may produce serious or even life-threatening toxic effects, particularly when used with some anorectic drugs (eg, sympathomimetic amines). Levothyroxine, either alone or with other concomitant therapeutic agents, should not be used for the treatment of obesity or for weight loss.

Monitoring Parameters

Infants: Monitor closely for cardiac overload, arrhythmias, and aspiration from avid suckling

Infants/children: Monitor closely for under/overtreatment. Undertreatment may decrease intellectual development and linear growth, and lead to poor school performance due to impaired concentration and slowed mentation. Overtreatment may adversely affect brain maturation, accelerate bone age (leading to premature closure of the epiphyses and reduced adult height); craniosynostosis has been reported in infants. Treated children may experience a period of catch-up growth. Monitor TSH and total or free T4 at 2 and 4 weeks after starting treatment; every 1 to 2 months for first year of life; every 2 to 3 months during years 1 to 3; every 3 to 12 months until growth completed. Perform routine clinical examinations at regular intervals (to assess mental and physical growth and development).

Adults: TSH 4 to 6 weeks after treatment initiation or dose changes, 4 to 6 months after adequate replacement dose determined, followed by every 12 months thereafter (or more frequently depending on clinical situation) (ATA [Jonklaas 2014]); T4; heart rate, blood pressure, clinical signs of hypo- and hyperthyroidism; TSH is the most reliable guide for evaluating adequacy of thyroid replacement dosage in primary thyroid dysfunction. TSH may be elevated during the first few months of thyroid replacement despite patients being clinically euthyroid. In cases where T4 remains low and TSH is within normal limits, an evaluation of “free” (unbound) T4 is needed to evaluate further increase in dosage. Free T4 (not TSH) should be monitored to guide treatment in patients with central hypothyroidism (ATA/AACE [Garber 2012]).

Bone mineral density (particularly with long term use in postmenopausal women)

Pregnancy Risk Factor

A

Pregnancy Considerations

Endogenous thyroid hormones minimally cross the placenta; the fetal thyroid becomes active around the end of the first trimester. Levothyroxine has not been shown to increase the risk of congenital abnormalities.

Uncontrolled maternal hypothyroidism may result in adverse neonatal outcomes (eg, premature birth, low birth weight, and respiratory distress) and adverse maternal outcomes (eg, spontaneous abortion, pre-eclampsia, stillbirth, and premature delivery). To prevent adverse events, normal maternal thyroid function should be maintained prior to conception and throughout pregnancy. TSH concentrations should be monitored every 4 weeks during the first half of pregnancy, at least once between weeks 26 and 32, and ~6 weeks postpartum. Levothyroxine is considered the treatment of choice for the control of hypothyroidism during pregnancy. Due to alterations of endogenous maternal thyroid hormones, the levothyroxine dose may need to be increased during pregnancy and the dose usually needs to be decreased after delivery (Stagnaro-Green 2011).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience hair loss. Have patient report immediately to prescriber angina, tachycardia, abnormal heartbeat, headache, shortness of breath, lack of appetite, increased appetite, excessive weight gain or loss, lump on the neck, swelling of arms or legs, diarrhea, abdominal cramps, vomiting, irritability, anxiety, tremors, insomnia, temperature sensitivity, sweating a lot, leg cramps, muscle weakness, or menstrual irregularities (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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