VA Class:HS851
ATC Class:H03AA01
Levothyroxine sodium, the sodium salt of the l-isomer of thyroxine, is a thyroid agent.
Levothyroxine sodium is used as replacement or supplemental therapy in congenital or acquired hypothyroidism of any etiology, except transient hypothyroidism during the recovery phase of subacute thyroiditis.140, 141, 142, 143, 160 Levothyroxine sodium is specifically indicated for use in the management of subclinical hypothyroidism and primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) hypothyroidism.140, 141, 142, 143, 160 Primary hypothyroidism may result from functional deficiency, primary atrophy, partial or complete absence of the thyroid gland, or from the effects of surgery, radiation, or antithyroid agents, with or without the presence of goiter.140, 141, 142, 143
Replacement therapy with levothyroxine sodium must be maintained continuously to control the symptoms of hypothyroidism. Levothyroxine sodium generally is the preferred thyroid agent for replacement therapy because its hormonal content is standardized and its effect is therefore predictable.
Levothyroxine sodium also is considered the drug of choice for the treatment of congenital hypothyroidism (cretinism). For a discussion on the use of levothyroxine in the treatment of congenital hypothyroidism, see Cautions: Pediatric Precautions, in the Thyroid Agents General Statement 68:36.04.
Levothyroxine sodium IV injection is used in the treatment of myxedema coma.155, 165 Levothyroxine sodium injection has been used in other conditions when rapid thyroid replacement is required†;161 however, this is not an FDA-labeled use for the currently available injection.165
Levothyroxine sodium may be used with antithyroid agents in the treatment of thyrotoxicosis to prevent goitrogenesis and hypothyroidism. While administration of levothyroxine occasionally may be useful to prevent antithyroid agent-induced hypothyroidism in the management of thyrotoxicosis during pregnancy, combination therapy generally is considered unnecessary since it may increase the requirement for antithyroid agents and therefore the risk of fetal hypothyroidism, which is not amenable to exogenous thyroid agent therapy.
Levothyroxine sodium may be used to suppress the secretion of thyrotropin (thyroid-stimulating hormone, TSH) in the treatment or prevention of various types of euthyroid goiters, including thyroid nodules, subacute or chronic lymphocytic thyroiditis (Hashimoto's thyroiditis), and multinodular goiter.140, 141, 142, 160 Levothyroxine sodium also is used as an adjunct to surgery and radioiodine therapy in the management of thyrotropin-dependent well-differentiated (papillary and follicular) thyroid cancer.140, 141, 142, 160
Reconstitution and Administration
Levothyroxine sodium is administered orally or by IV injection.140, 141, 142, 143, 160, 165 The drug also has been administered by IM injection†;161 however, the IV route is preferred since absorption may be variable following IM administration. IM administration is not an FDA-labeled route of administration for the currently available levothyroxine sodium injection.165
Levothyroxine sodium usually is administered orally on an empty stomach, preferably one-half to one hour before breakfast or the first food of the day.140, 141, 142, 143, 160 Because Levoxyl® tablets may rapidly swell and disintegrate following oral administration (resulting in choking, gagging, or difficulty in swallowing), the manufacturer states that Levoxyl® tablets should be taken with a full glass of water.141
In individuals who are unable to swallow the intact tablets (e.g., pediatric patients), the appropriate dose of levothyroxine tablets may be crushed and placed in a small amount (5-10 mL) of water; the resultant suspension should be administered by spoon or dropper immediately and should not be stored.140, 141, 142, 152
Foods that decrease absorption of levothyroxine (e.g., soybean infant formula, soybean flour, cotton seed meal) should not be used for administering levothyroxine.140, 141, 142 (See Pharmacokinetics: Absorption.) Oral levothyroxine sodium should be administered at least 4 hours apart from drugs that are known to interfere with its absorption (e.g., antacids, bile acid sequestrants, cation-exchange resins, ferrous sulfate, sucralfate, simethicone, calcium carbonate). 140, 141, 142, 154, 160 See Drug Interactions in the Thyroid Agents General Statement 68:36.04.
Levothyroxine sodium also is administered by IV injection.165
Levothyroxine sodium powder for injection should be reconstituted by adding 5 mL of 0.9% sodium chloride injection to a vial labeled as containing 100, 200, or 500 mcg of the drug, and shaking the vial to mix completely.165 The resultant solutions contain approximately 20, 40, or 100 mcg/mL, respectively, of levothyroxine sodium.165 Prior to administration, the reconstituted solution should be inspected visually for particulate matter and discoloration whenever solution and container permit.165 Reconstituted solutions of levothyroxine sodium should be used immediately and any unused portions discarded; the solutions should not be admixed with IV infusion solutions.165 (See Chemistry and Stability: Stability.)
The FDA states that all approved levothyroxine sodium preparations157 should be considered therapeutically in equivalent unless equivalence has been established and noted in FDA's Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book).144 Theoretically, such preparations can be used interchangeably, and in some cases, pharmacists may be able to substitute generic for proprietary (brand) preparations without notifying the prescriber.162, 163, 164 However, because of the narrow therapeutic index of the drug, the American Thyroid Association (ATA) and the American Association of Clinical Endocrinologists (AACE) state that levothyroxine sodium preparations generally should not be used interchangeably.157, 163 If a patient switches levothyroxine sodium preparations (e.g., from brand to generic), pharmacists are encouraged to notify the patient and prescriber of the switch.162, 163 In addition, serum thyrotropin (thyroid-stimulating hormone, TSH) concentration should be measured about 4-8 weeks after starting the new preparation and the levothyroxine dosage adjusted if needed.162, 163
Dosage of levothyroxine sodium must be carefully adjusted according to individual requirements and response. The age, body weight, and general physical condition of the patient and the severity and duration of hypothyroid symptoms determine the initial dosage and rate at which dosage may be increased to the eventual maintenance dosage. Under- or over-treatment, which may result in adverse effects on growth and development in pediatric patients, cardiovascular function, bone metabolism, reproductive function, cognitive function, emotional state, GI function, and glucose and lipid metabolism, should be avoided.140, 141, 142
Dosage should be initiated at a lower level in geriatric patients, in patients with functional or ECG evidence of cardiovascular disease, and in patients with severe, long-standing hypothyroidism,145, 146, 147 since an abrupt increase in metabolic rate and demand for increased cardiac output associated with levothyroxine therapy may precipitate angina pectoris, myocardial infarction, congestive heart failure, arrhythmias, or sudden cardiac death in such patients.145, 148 In patients with severe, long-standing hypothyroidism in whom pituitary and adrenal function may be secondarily decreased, rapid replacement therapy with levothyroxine sodium also may precipitate adrenal insufficiency;149 in addition, psychosis or agitation occasionally may develop during initiation of levothyroxine therapy, necessitating a lower initial dosage in these patients.147 Adjustment of thyroid replacement therapy should be determined mainly by the patient's clinical response and confirmed by appropriate laboratory tests.
The manufacturer of levothyroxine sodium for injection states that caution should be used when switching patients from oral to IV levothyroxine sodium since the relative bioavailability and an accurate dosing conversion between the oral and IV preparations have not been established.165 Relative bioavailability between oral and IV administration has been estimated to range from 48-74%.165
For the management of hypothyroidism in otherwise healthy individuals younger than 50 years of age and in those older than 50 years of age who have been recently treated for hyperthyroidism or who have been hypothyroid for only a short time (i.e., several months), the usual initial oral dosage (full replacement dosage) of levothyroxine sodium is 1.7 mcg/kg daily (e.g., 100-125 mcg daily for a 70-kg adult) given as a single dose.135, 140, 141, 142, 143, 160 Older patients may require less than 1 mcg/kg daily.135, 140, 141, 142 In one study, the usual maintenance dosage for geriatric patients was about 25% less than that for younger and heavier adults. Some manufacturers state that levothyroxine sodium dosages greater than 200 mcg daily are seldom required, and that failure to respond adequately to oral dosages of 300 mcg daily or greater is rare and should prompt reevaluation of the diagnosis, or suggest the presence of malabsorption, patient noncompliance, and/or drug interactions.140, 141, 142, 160
Patients should be evaluated initially about every 6-8 weeks to monitor the response to therapy.135, 140, 141, 142 Once normalization of thyroid function and serum thyrotropin (thyroid-stimulating hormone, TSH) concentrations has been achieved, patients may be evaluated less frequently (i.e., every 6-12 months).135 However, if the dosage of levothyroxine sodium tablets is changed, serum TSH concentrations should be measured after 8-12 weeks135, 140, 141, 142 or 4-8 weeks after switching from one levothyroxine sodium preparation to another.162, 163
For most patients older than 50 years of age or in patients younger than 50 years of age with underlying cardiovascular disease, the usual initial oral dosage of levothyroxine sodium is 25-50 mcg daily given as a single dose;135, 140, 141, 142, 143, 146, 147, 150, 160 dosage may be increased at intervals of 6-8 weeks.140, 141, 142, 143 The usual initial dosage in geriatric patients with underlying cardiovascular disease is 12.5-25 mcg daily, with gradual dosage increments at intervals of 4-6 weeks.140, 141, 142, 143, 149 Dosage may be increased by increments of 12.5-25 mcg at recommended intervals until the patient becomes euthyroid and serum TSH concentrations return to normal.140, 141, 142
For the management of severe, long-standing hypothyroidism in adults, the usual initial oral dosage of levothyroxine sodium is 12.5-25 mcg daily given as a single dose.140, 141, 142, 160 Although the manufacturers state that dosage may be increased by increments of 25 mcg at intervals of 2-4 weeks until serum TSH concentrations return to normal,140, 141, 142, 160 some clinicians suggest that dosage may be adjusted at intervals of 4-8 weeks.143, 145, 147
If treatment is considered necessary in patients with subclinical hypothyroidism, the manufacturers state that lower initial levothyroxine dosages (e.g., 1 mcg/kg daily) may be adequate to normalize TSH concentrations.140, 141, 142, 160 If levothyroxine replacement therapy is not initiated, patients still should be monitored annually for changes in clinical status and thyroid laboratory parameters.140, 141, 142, 160
Although the average full replacement dosage of levothyroxine sodium is about 1.6-1.7 mcg/kg daily,135, 136, 140, 141, 142, 143 some patients (e.g., younger pediatric patients, pregnant women) may require higher dosages.135, 142, 143, 150
Despite the smaller body size of pediatric patients, the dosage of levothyroxine sodium (on a weight basis) required to sustain a full rate of growth, development, and general thriving is higher in these patients than in adults.135, 140, 141, 142, 143, 159, 160 In general, levothyroxine sodium therapy should be initiated at full replacement dosages in pediatric patients as soon as possible after diagnosis of hypothyroidism to prevent deleterious effects on intellectual and physical growth and development; however, dosage should be initiated at a lower level in children with long-standing or severe hypothyroidism.140, 141, 142, 160
For the treatment of congenital hypothyroidism (cretinism) or acquired hypothyroidism in pediatric patients, levothyroxine sodium therapy usually is initiated at full replacement dosages; daily dose per body weight decreases with age.140, 141, 142 The following dosages have been recommended:
Age | Daily Dose |
|---|---|
0-3 months | 10-15 mcg/kg |
3-6 months | 25-50 mcg or 8-10 mcg/kg |
6-12 months | 50-75 mcg or 6-8 mcg/kg |
1-5 years | 75-100 mcg or 5-6 mcg/kg |
6-12 years | 100-150 mcg or 4-5 mcg/kg |
Older than 12 years | > 150 mcg or 2-3 mcg/kg |
Growth and puberty complete | 1.6-1.7 mcg/kg |
The usual initial oral dosage of levothyroxine sodium in otherwise healthy, full-term neonates is 10-15 mcg/kg daily given as a single dose.140, 141, 142, 143, 151, 152, 153, 154 A lower initial dosage (e.g., 25 mcg daily) should be considered in neonates at risk of cardiac failure; dosage may be increased at intervals of 4-6 weeks as needed based on clinical and laboratory response to treatment.140, 141, 142, 143, 160 In neonates with very low (less than 5 mcg/dL) or undetectable serum thyroxine (T4) concentrations, the usual initial dosage is 50 mcg daily.140, 141, 142, 152, 160
The manufacturers state that hyperactivity in an older child may be minimized by initiating therapy at a dosage approximately one-fourth of the recommended full replacement dosa the dosage may then be increased by an amount equal to one-fourth the full recommended replacement dosage at weekly intervals until the full recommended replacement dosage is reached.140, 141, 142, 160
For the treatment of severe, long-standing hypothyroidism in pediatric patients, the usual initial oral dosage of levothyroxine sodium is 25 mcg daily.140, 141, 142, 160 Dosage may be increased in increments of 25 mcg at intervals of 2-4 weeks until the desired response is obtained.140, 141, 142, 160
For the treatment of myxedema coma, levothyroxine sodium is given by IV injection;165 oral administration is not recommended because absorption of the drug from the GI tract is unpredictable in such patients.140, 141, 142, 143
Initial and maintenance dosages of IV levothyroxine sodium should be selected after taking into account the age, general physical condition, and cardiac risk factors of the patient, as well as the clinical severity and duration of myxedema symptoms.165 The manufacturer states that the initial adult IV loading dose for the treatment of myxedema coma is 300-500 mcg;165 however, some clinicians recommend an initial dose of 100-500 mcg.155 Lower IV maintenance dosages of 50-100 mcg once daily should be administered thereafter as clinically indicated until the patient's condition is stabilized and the drug can be given orally.165
In the geriatric population and in patients with underlying cardiovascular disease, administration of IV levothyroxine sodium, especially loading doses exceeding 500 mcg, may precipitate severe adverse cardiovascular effects (e.g., arrhythmias, tachycardia, myocardial ischemia or infarction, worsening of heart failure, death).145, 165 The manufacturer states that cautious use (e.g., dosages in the lower end of the recommended range) of IV levothyroxine sodium may be warranted in geriatric patients and in those with known cardiac risk factors.165
Some manufacturers caution that the target level for TSH suppression in the management of well-differentiated thyroid cancer and thyroid nodules has not been established.141, 142, 160 In addition, the efficacy of TSH suppression for benign nodular disease remains controversial.141, 142 Therefore, dosage of levothyroxine sodium used for TSH suppression should be individualized based on patient characteristics and the nature of the disease.141, 142, 160
For the management of thyrotropin-dependent well-differentiated (papillary and follicular) thyroid cancer, an oral levothyroxine sodium replacement dosage of greater than 2 mcg/kg daily given as a single dose has been recommended to suppress TSH concentrations to less than 0.1 mU/L.140, 141, 142, 160 In patients with high-risk tumors, the target level for TSH suppression may be less than 0.01 mU/L.141, 160
For the management of benign nodules and nontoxic multinodular goiter, TSH concentrations generally are suppressed to a higher target (e.g., 0.1-0.5 mU/L for nodules and 0.5-1 mU/L for multinodular goiter) than that used for the treatment of thyroid cancer.140, 142, 143, 160
Levothyroxine sodium shares the toxic potentials of other thyroid agents and the usual precautions of thyroid agent therapy should be observed. (See Cautions in the Thyroid Agents General Statement 68:36.04.) Adverse reactions to levothyroxine sodium result from overdosage and are manifested principally as signs and symptoms of hyperthyroidism (e.g., chest pain, palpitations, cardiac arrhythmias, difficulty in sleeping). Hyperthyroidism is a risk factor for osteoporosis.138 Evidence from several studies in premenopausal women receiving levothyroxine sodium for replacement or suppressive therapy suggests that subclinical hyperthyroidism is associated with bone loss.138 Therefore, to minimize the risk of osteoporosis, dosage of levothyroxine sodium should be titrated to the lowest possible effective level.138 (See Dosage and Administration: Dosage.) In addition, hypothyroidism manifested by severe depression, fatigue, weight gain, constipation, cold intolerance, edema, and difficulty in concentration may occur in patients receiving levothyroxine sodium preparations with inadequate potency.138
Choking, gagging, dysphagia, or lodging of a tablet in the throat has been reported with Levoxyl®, particularly when the tablets were not administered with water.141 Therefore, the manufacturer states that Levoxyl® tablets should be taken with a full glass of water.141
Patients with a history of lactose intolerance may be sensitive to Levothroid®, Synthroid®, and Unithroid® tablets, since lactose is used in the manufacture of the tablets.140, 142
The principal pharmacologic effect of exogenous thyroid hormones is to increase the metabolic rate of body tissues. Thyroid hormones are also involved in the regulation of cell growth and differentiation. Although the precise mechanism of action by which thyroid hormones affect metabolism and cellular growth and differentiation is not clearly established, it is known that these physiologic effects are mediated at the cellular level, principally via triiodothyronine; a major portion of triiodothyronine is derived from thyroxine by deiodination in peripheral tissues. Thyroxine is the major component of normal secretions of the thyroid gland and is therefore the principal determinant of normal thyroid function. For further information, see Pharmacology in the Thyroid Agents General Statement 68:36.04.
Levothyroxine is variably absorbed from the GI tract (range: 40-80%).137, 140, 141, 142, 143, 159, 160 In animals, levothyroxine is absorbed in the proximal and middle jejunum; the drug is not absorbed from the stomach or distal colon and little, if any, absorption occurs in the duodenum. Studies in humans indicate that levothyroxine is absorbed from the jejunum and ileum and some absorption also occurs in the duodenum. The degree of absorption of levothyroxine from the GI tract depends on the product formulation and type of intestinal contents, including plasma protein and soluble dietary factors that may bind thyroid hormone and make it unavailable for diffusion. In addition, concurrent oral administration of infant soybean formula, soybean flour, cotton seed meal, walnuts, foods containing large amounts of fiber, ferrous sulfate, antacids, sucralfate, calcium carbonate, cation-exchange resins (e.g., sodium polystyrene sulfonate), simethicone, or bile acid sequestrants may decrease absorption of levothyroxine.139, 140, 141, 142 The extent of levothyroxine absorption is increased in the fasting state and decreased in malabsorption states (e.g., sprue); absorption also may decrease with age.140, 141, 142
The absorption of levothyroxine is variable following IM administration (not an FDA-labeled route of administration for the currently available levothyroxine sodium injection).165
In the past, results of studies evaluating the bioequivalence and interchangeability of various commercially available oral preparations of levothyroxine have been conflicting.101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134 Results of several early studies indicated that various commercially available levothyroxine sodium tablets (i.e., Levothroid®, Synthroid® [formulation available prior to 1982], several nonproprietary [generic] preparations) were not bioequivalent based on measurements of thyroxine content in the tablets and of thyroid function in patients receiving the preparations.101, 102, 103, 104, 115 Potency of oral levothyroxine sodium preparations manufactured in the US after 1985 reportedly was more uniform since USP required all manufacturers of the drug to monitor levothyroxine content and ensure tablet potency.105, 118 Several reports published after 1984 indicated that the drug content of various levothyroxine preparations (Synthroid®, Levothroid®, Levoxine®, and certain nonproprietary preparations) was within FDA specifications (i.e., no less than 90% and no more than 110% of labeled potency).105, 115 However, the FDA concluded in 1997 that stability problems with oral levothyroxine sodium preparations commercially available at that time continued to result in unpredictable drug potency and announced that orally administered levothyroxine sodium products are considered new drugs; manufacturers wishing to market levothyroxine preparations were required to submit a new drug application (NDA) to the FDA.138, 144 (See Chemistry and Stability: Stability.) Results of one single-blind, randomized, 4-way cross-over study in women with hypothyroidism who were clinically and chemically euthyroid and who received levothyroxine sodium 100 or 150 mcg daily for a minimum of 3 months prior to study entry suggested that the commercially available levothyroxine sodium tablets tested in this study (i.e., Levoxyl® [formerly Levoxine®], Synthroid®, 2 nonproprietary preparations) were bioequivalent and interchangeable in the majority of patients receiving such preparations, based on measurements of levothyroxine sodium content in the tablets and of patient thyroid function.105, 106, 107, 108, 109, 110, 112 However, the FDA states that all approved levothyroxine sodium preparations157 should be considered therapeutically in equivalent unless equivalency has been established and noted in FDA's Approved Drug Products with Therapeutic Equivalency Evaluations (Orange Book).144 (See Dosage and Administration: Dosage.)
Because thyroxine is more highly and firmly protein bound than triiodothyronine, levothyroxine has a much slower onset of pharmacologic action and a longer duration of action than liothyronine.
The usual plasma half-lives of thyroxine and triiodothyronine are 6-7 days and approximately 1-2 days, respectively. The plasma half-lives of thyroxine and triiodothyronine are decreased in patients with hyperthyroidism and increased in those with hypothyroidism.
Levothyroxine sodium is commercially available as tablets for oral administration and as a lyophilized powder for injection for IV administration.140, 141, 142, 160, 165
Levothyroxine sodium is the monosodium salt of the levo isomer of thyroxine, the principal secretion of the thyroid gland. The commercially available drug is prepared synthetically. Structurally, levothyroxine sodium differs from liothyronine sodium only in the presence of an iodine atom in the 5' position.
Levothyroxine sodium occurs as a light yellow to buff-colored, odorless, tasteless, hygroscopic powder and is very slightly soluble in water and slightly soluble in alcohol.
Levothyroxine sodium is stable in dry air but may acquire a slight pink color upon exposure to light. Commercially available preparations of levothyroxine sodium should be stored in tight, light-resistant containers. Levothyroxine sodium is unstable in the presence of light, heat, air, and humidity.138 The manufacturers' labeling should be consulted for recommended storage temperatures, which can vary depending on the specific manufacturer and preparation.138 In some cases, tablets of the drug have been unstable even at room temperature, and storage at temperatures of 8-15°C were required to maintain potency.138
In 1997, the FDA138 determined that important stability and potency problems existed for oral levothyroxine sodium preparations, and such problems potentially could result in serious health consequences because of inconsistent drug potency.101, 102, 103, 138 It appeared that many oral levothyroxine sodium preparations that were commercially available at that time failed to maintain potency throughout their customary 2-year shelf-life even when stored as directed, and it was suggested that this shelf-life might not be appropriate for these preparations because of accelerated degradation secondary to a variety of factors (e.g., light, temperature, air, humidity).138 In addition, some excipients contained in oral levothyroxine sodium preparations might hasten such degradation.138 Results of some stability studies indicate that levothyroxine sodium exhibits biphasic, first-order degradation with an initial fast degradation rate (which is temperature dependent), followed by a slower terminal phase.138 To compensate for the initial fast degradation rate, some manufacturers used excessive amounts of active ingredient, which could result in superpotency.138 It appeared that oral levothyroxine sodium preparations failed to maintain potency throughout their shelf-life, and the amount of active ingredient varied from lot to lot in identical-strength tablets supplied by the same manufacturer.138 As a result of stability problems and manufacturing practices used to compensate for instability of the drug, potency of a given preparation could not be ensured, even when the same brand of oral levothyroxine sodium preparation was used.138
Levothyroxine sodium was introduced into the US market before 1962 without an approved new drug application (NDA), apparently with the belief that it was not a new drug.138 In patients with diminished or absent thyroid function, uniform potency and bioavailability of levothyroxine sodium tablets are very important since hypothyroidism or hyperthyroidism may result from administration of preparations with less or more than the specified potency and bioavailability, respectively.103, 104, 105, 138 (See Cautions.) Between 1987 and 1994, the FDA received 58 reports of adverse drug reactions (e.g., manifestations of hypothyroidism or hyperthyroidism) apparently associated with irregular potency, mainly subpotency but also superpotency, of levothyroxine sodium preparations.138 Some of these adverse effects occurred following a switch in the brand of levothyroxine sodium, while others may have occurred secondary to inconsistent stability, potency, and bioavailability of a given preparation supplied by the same manufacturer.138 Since levothyroxine sodium preparations were marketed without an approved NDA, manufacturers were required to report only unexpected and severe adverse drug reactions to FDA; therefore, it is believed that this reported incidence of adverse effects secondary to potency problems may be conservative because of underreporting of such effects.138 In addition, since manufacturers were not required to obtain FDA approval to reformulate preparations containing levothyroxine sodium, preparations with substantially increased potency and associated severe adverse effects occasionally were marketed.138
Because of reported potency and stability problems, the FDA announced in 1997 that oral preparations containing levothyroxine sodium were considered new drugs.138 Manufacturers who wished to continue marketing oral preparations containing levothyroxine sodium were required to submit an NDA to the FDA by August 14, 2000.138 Oral levothyroxine sodium preparations commercially available in the US after August 14, 2003 have been approved by the FDA and are considered to be safe and effective for their intended uses.144 The current edition of FDA's Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book; [Web]) should be consulted to determine which levothyroxine sodium preparations the FDA has evaluated and deemed as being therapeutically equivalent (i.e., as bioequivalent and expected to have the same clinical effect and safety profile when administered appropriately). (See Dosage and Administration: Dosage.)
Levothyroxine sodium powder for injection should be stored at 20-25°C and protected from light.165 Following reconstitution, the drug is stable for 4 hours; however, the manufacturer states that reconstituted solutions of levothyroxine sodium should be used immediately and should not be added to other IV fluids.165 Any unused portion should be discarded.165
Additional Information
For further information on chemistry, pharmacology, pharmacokinetics, uses, toxicity, cautions, acute toxicity, drug interactions, laboratory test interferences, and dosage and administration of levothyroxine sodium, see the Thyroid Agents General Statement 68:36.04.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets | 25 mcg* | ||
Levothyroxine Sodium Tablets | ||||
Levoxyl® (scored) | ||||
Synthroid® (scored) | ||||
50 mcg* | Levothroid® | Forest | ||
Levothyroxine Sodium Tablets | ||||
Levoxyl® (scored) | Jones | |||
Synthroid® (scored) | Abbott | |||
Unithroid® | Watson | |||
75 mcg* | Levothroid® | Forest | ||
Levothyroxine Sodium Tablets | ||||
Levoxyl® (scored) | Jones | |||
Synthroid® (scored) | Abbott | |||
Unithroid® | Watson | |||
88 mcg* | Levothroid® | Forest | ||
Levothyroxine Sodium Tablets | ||||
Levoxyl® (scored) | Jones | |||
Synthroid® (scored) | Abbott | |||
Unithroid® | Watson | |||
100 mcg* | Levothroid® | Forest | ||
Levothyroxine Sodium Tablets | ||||
Levoxyl® (scored) | Jones | |||
Synthroid® (scored) | Abbott | |||
Unithroid® | Watson | |||
112 mcg* | Levothroid® | Forest | ||
Levothyroxine Sodium Tablets | ||||
Levoxyl® (scored) | Jones | |||
Synthroid® (scored) | Abbott | |||
Unithroid® | Watson | |||
125 mcg* | Levothroid® | Forest | ||
Levothyroxine Sodium Tablets | ||||
Levoxyl® (scored) | Jones | |||
Synthroid® (scored) | Abbott | |||
Unithroid® | Watson | |||
137 mcg* | Levothroid® | Forest | ||
Levothyroxine Sodium Tablets | ||||
Levoxyl® (scored) | Jones | |||
Synthroid® (scored) | Abbott | |||
150 mcg* | Levothroid® | Forest | ||
Levothyroxine Sodium Tablets | ||||
Levoxyl® (scored) | Jones | |||
Synthroid® (scored) | Abbott | |||
Unithroid® | Watson | |||
175 mcg* | Levothroid® | Forest | ||
Levothyroxine Sodium Tablets | ||||
Levoxyl® (scored) | Jones | |||
Synthroid® (scored) | Abbott | |||
Unithroid® | Watson | |||
200 mcg* | Levothroid® | Forest | ||
Levothyroxine Sodium Tablets | ||||
Levoxyl® (scored) | Jones | |||
Synthroid® (scored) | Abbott | |||
Unithroid® | Watson | |||
300 mcg* | Levothroid® | Forest | ||
Levothyroxine Sodium Tablets | ||||
Levoxyl® (scored) | Jones | |||
Synthroid® (scored) | Abbott | |||
Unithroid® | Watson | |||
Parenteral | For injection | 100 mcg* | ||
200 mcg* | Levothyroxine Sodium for Injection | |||
500 mcg* | Levothyroxine Sodium for Injection |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Only references cited for selected revisions after 1984 are available electronically.
101. Shroff AP, Jones JK. Standards for levothyroxine preparations. JAMA . 1980; 244:658-9. [PubMed 7392162]
102. Stoffer SS, Szpunar WE. Potency of brand name and generic levothyroxine products. JAMA . 1980; 244:1704-5. [PubMed 7411829]
103. Ramos-Gabatin A, Jacobson JM, Young RL. In vivo comparison of levothyroxine preparations. JAMA . 1982; 247:203-5. [PubMed 7053460]
104. Jacobson JM, Ramos-Gabatin A, Young RL et al. Nonequality of brand name thyroxine preparations. JAMA . 1980; 243:733. [PubMed 7351814]
105. Dong BJ, Hauck WW, Gambertoglio JG et al. Bioequivalence of generic and brand-name levothyroxine products in the treatment of hypothyroidism. JAMA . 1997; 277:1205-13. [PubMed 9103344]
106. Rennie D. Thyroid storm. JAMA . 1997; 277:1238-43. [PubMed 9103350]
107. Spigelman MK. Bioequivalence of levothyroxine preparations for treatment of hypothyroidism. JAMA . 1997; 277:1199. [PubMed 9103337]
108. Dong BJ, Gambertoglio JG, Greenspan FS et al. Bioequivalence of levothyroxine preparations for treatment of hypothyroidism. JAMA . 1997; 277:1199-200. [PubMed 9103337]
109. Eckert CH. Bioequivalence of levothyroxine preparations: industry sponsorship and academic freedom. JAMA . 1997; 277:1200. [PubMed 9103338]
110. Dong BJ, Gambertoglio JG, Gee L et al. Bioequivalence of levothyroxine preparations: industry sponsorship and academic freedom. JAMA . 1997; 277:1200-1. [PubMed 9103338]
111. Martin JB. Bioequivalence of levothyroxine preparations: industry sponsorship and academic freedom. JAMA . 1997; 277:1201.
112. Knoll Pharmaceutical Company. Knoll Pharmaceutical Company statement in response to UCSF study publication in JAMA . Mount Olive, NJ; 1997 Apr 16. Press release.
113. Zinberg DS. A cautionary tale. Science . 1996; 273:411. [PubMed 8677431]
114. Escalante DA, Arem N, Arem R. Assessment of interchangeability of two brands of levothyroxine preparations with a third-generation TSH assay. Am J Med . 1995; 98:374-8. [PubMed 7709950]
115. Dong BJ, Young VR, Rapoport B. The nonequivalence of levothyroxine products. Drug Intell Clin Pharm . 1986; 20:77-8. [PubMed 3943462]
116. Curry SH, Gums JG, Williams LL et al. Levothyroxine sodium tablets: chemical equivalence and bioequivalence. Drug Intell Clin Pharm . 1988; 22:589-91. [PubMed 3046889]
117. Blouin RA, Clifton GD, Adams MA et al. Biopharmaceutical comparison of two levothyroxine sodium products. Clin Pharm . 1989; 8:588-92. [PubMed 2504532]
118. The United States pharmacopeia, 23rd rev, and The national formulary, 18th ed. Rockville, MD: The United States Pharmacopeial Convention, Inc; 1995:883-4.
119. Mayor GH, Orlando T, Kurtz NM. Limitations of levothyroxine bioequivalence evaluation: analysis of an attempted study. Am J Ther . 1995; 2:417-32. [PubMed 11850687]
120. Berg JA, Mayor GH. A study in normal human volunteers to compare the rate and extent of levothyroxine absorption from Synthroid® and Levoxine®. J Clin Pharmacol . 1993; 33:1135-40.
121. DeGroot LJ. Interchangeability of levothyroxine preparations. Am J Med . 1996; 100:244-5. [PubMed 8629664]
122. Davies TF. Interchangeability of levothyroxine preparations. Am J Med . 1996; 100:245. [PubMed 8629665]
123. Ridgway EC. Interchangeability of levothyroxine preparations. Am J Med . 1996; 100:245-6. [PubMed 8629666]
124. Arem R. Interchangeability of levothyroxine preparations. Am J Med . 1996; 100:246-7.
125. Bootman JL. Interchangeability of levothyroxine preparations. Am J Med . 1996; 100:247-8. [PubMed 8629667]
126. Arem R. Interchangeability of levothyroxine preparations. Am J Med . 1996; 100:248-9.
127. Wolfson BB. Comment: therapeutic failure with levothyroxine brand interchange. Ann Pharmacother . 1995; 29:1049-50. [PubMed 8845549]
128. Copeland PM. Two cases of therapeutic failure associated with levothyroxine brand interchange. Ann Pharmacother . 1995; 29:482 -5. [PubMed 7655130]
129. Benet LZ. Morality play. Science . 1996; 273:1782. [PubMed 8815536]
130. Debler WR. Morality play. Science . 1996; 273:1783. [PubMed 8815537]
131. Thomen JR. Morality play. Science . 1996; 273:1783-4. [PubMed 8815538]
132. Hook EB. Morality play. Science . 1996; 273:1784. [PubMed 8815534]
133. Eckert C. Morality play. Science . 1996; 273:1784. [PubMed 8815539]
134. Zinberg DS. Morality play. Science . 1996; 273:1784-5.
135. Singer PA, Cooper DS, Levy EG et al. Treatment guidelines for patients with hyperthyroidism and hypothyroidism. JAMA . 1995; 273:808-12. [PubMed 7532241]
136. American Association of Clinical Endocrinologists. AACE clinical practice guidelines for the evaluation and treatment of hyperthyroidism and hypothyroidism. 1995 Jan.
137. Farwell AP, Braverman LE. Thyroid and antithyroid drugs. In: Hardman JG, Limbird LE, Molinoff PB et al, eds. Goodman and Gilman's the pharmacological basis of therapeutics. 9th ed. New York: McGraw-Hill; 1995:1383-1409.
138. Food and Drug Administration. Prescription Drug products; levothyroxine sodium. Notice of proposed rulemaking. Docket No. 97N-0314; Fed Regist. (undated)
139. Singh N, Singh PN, Hershman JM. Effect of calcium carbonate on the absorption of levothyroxine. JAMA . 2000; 283:2822-5. [PubMed 10838651]
140. Watson Pharma, Inc. Unithroid® (levothyroxine sodium tablets, USP) prescribing information. Corona, CA; 2000 Oct.
141. Jones Pharma, Inc. Levoxyl® (levothyroxine sodium tablets, USP) prescribing information. St. Louis, MO; 2004 May.
142. Abbott Laboratories. Synthroid® (levothyroxine sodium tablets, USP) prescribing information. North Chicago, IL; 2002 Jul.
143. Temeck J. Unithroid (levothyroxine sodium tablets) Medical Officer Review. 2000 Jul 21. From FDA website. [Web]
144. US Food and Drug Administration Center for Drug Evaluation and Research. Guidance for industry: Levothyroxine sodium products enforcement of August 14, 2001, compliance date and submission of new applications. 2001 Jul. From FDA website. [Web]
145. Shapiro LE, Surks MI. Hypothyroidism. In: Becker KL, Bilezikian JP, Bremner WJ et al, eds. Principles and practice of endocrinology and metabolism. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2001:445-54.
146. Waldstein SS. Replacement and suppressive treatment. In: Falk SA, ed. Thyroid disease: endocrinology, surgery, nuclear medicine, and radiotherapy. 2nd ed. Philadelphia: Lippincott-Raven; 1997:475-94.
147. Anon. Adult hypothyroidism. In: De Groot LJ, Larsen PR, and Hennemann G, eds. The thyroid and its diseases. 6th ed. New York: Churchill Livingstone; 1996:323-70.
148. Weeke J. In: Dukes MNG and Aronson JK, eds. Meyler's side effects of drugs. 4th ed. New York: Elsevier; 2000:1485-500.
149. Larsen PR, Davies TF, and Hay ID. The thyroid gland. In: Wilson JD, Foster DW, Kronenberg HM et al, eds. Williams textbook of endocrinology. 9th ed. Philadelphia: W.B. Saunders Company; 1998:389-515.
150. Mandel SJ, Brent GA, and Larsen PR. Levothyroxine therapy in patients with thyroid disease. Ann Intern Med . 1993; 119:492-502. [PubMed 8357116]
151. Germak JA and Foley TP. Longitudinal assessment of L-thyroxine therapy for congenital hypothyroidism. J Pediatr . 1990; 117:211-9. [PubMed 2380819]
152. American Academy of Pediatrics. Newborn screening for congenital hypothyroidism: recommended guidelines. Pediatricts . 1993; 91:1203-9.
153. Van Vliet G. Treatment of congenital hypothyroidism. Lancet . 2001; 358:86-7. [PubMed 11463405]
154. Anon. Hypothyroidism. In: Behrman RE, Kliegman RM, and Jenson HB, eds. Nelson textbook of pediatrics. 16th ed. Philadelphia: W.B. Saunders Company; 2000:1698-1704.
155. Wall CR. Myxedema coma: diagnosis and treatment. Am Fam Physician . 2000; 62:2485-90. [PubMed 11130234]
156. Anon. FDA issues guidance on levothyroxine sodium products compliance. FDA Talk Paper. Rockville, MD: Food and Drug Administration; 2001 Jul 12.
157. The American Thyroid Association. How the Food and Drug Administration's ruling on thyroxine products affects patients and physicians. Updated September 28, 2002. From the American Thyroid Association website. [Web]
158. Forest Pharmaceuticals, Inc; St. Louis, MO: Personal communication.
159. Food and Drug Administration. CDER New and generic drug approvals: 1998-2002. From the FDA website. [Web]
160. Forest Laboratories. Levothroid® (levothyroxine sodium tablets, USP) prescribing information. St. Louis, MO; 2003 Sep.
161. Abbott Laboratories. Synthroid® (levothyroxine sodium, USP) for injection prescribing information. North Chicago, IL; 2001 Oct.
162. Anon. Generic levothyroxine. Med Lett Drugs Ther . 2004; 46:77-8. [PubMed 15452463]
163. The American Thyroid Association. Thyroid experts warn of clinically important differences in potency of FDA-approved levothyroxine products. Released August 11, 2004. From the American Thyroid Association web site. [Web]
164. Approved Drug Products with Therapeutic Equivalence Evaluations (Electronic Orange Book). Accessed October 2004. From FDA website. [Web]
165. Fresenius Kabi USA, LLC. Levothyroxine sodium for injection prescribing information. Lake Zurich, IL; 2013 Apr.