Unithroid (levothyroxine sodium tablets, USP)
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DESCRIPTION
---UNITHROID™ (levothyroxine sodium tablets, USP) contain synthetic crystalline L-3,3’,5,5’-tetraiodothyronine
sodium salt [levothyroxine (T4) sodium]. Synthetic T4 is identical to that produced in the human thyroid gland.
Levothyroxine (T4) sodium has an empirical formula of C15H10I4N NaO4 x H2O, molecular weight of 798.86 g/mol
(anhydrous), and structural formula as shown:
Inactive Ingredients
Colloidal silicon dioxide, lactose, magnesium stearate, microcrystalline cellulose, corn starch, acacia and sodium
starch glycolate. The following are the coloring additives per tablet strength:
Strength (mcg) Color additive(s)
25 FD&C Yellow No. 6 Aluminum Lake
50 None
75 FD&C Red No. 40 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake
88 D&C Yellow No. 10 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lake, FD&C Blue No. 1
Aluminum Lake
100 D&C Yellow No. 10 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lake
112 D&C Red No. 27 Aluminum Lake
125 FD&C Yellow No. 6 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, FD&C Blue No. 1 Aluminum
Lake
150 FD&C Blue No. 2 Aluminum Lake
175 FD&C Blue No. 1 Aluminum Lake, D&C Red No. 27 Aluminum Lake
200 FD&C Red No. 40 Aluminum Lake
300 D&C Yellow No. 10 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lake, FD&C Blue No. 1
Aluminum Lake
CLINICAL PHARMACOLOGY
Thyroid hormone synthesis and secretion is regulated by the hypothalamic-pituitary-thyroid axis. Thyrotropinreleasing
hormone (TRH) released from the hypothalamus stimulates secretion of thyrotropin-stimulating hormone,
TSH, from the anterior pituitary. TSH, in turn, is the physiologic stimulus for the synthesis and secretion of thyroid
hormones, L-thyroxine (T4) and L-triiodothyronine (T3), by the thyroid gland. Circulating serum T3 and T4 levels
exert a feedback effect on both TRH and TSH secretion. When serum T3 and T4 levels increase, TRH and TSH
secretion decrease. When thyroid hormone levels decrease, TRH and TSH secretion increase.
The mechanisms by which thyroid hormones exert their physiologic actions are not completely understood, but it is
thought that their principal effects are exerted through control of DNA transcription and protein synthesis. T3 and
T4 diffuse into the cell nucleus and bind to thyroid receptor proteins attached to DNA. This hormone nuclear
receptor complex activates gene transcription and synthesis of messenger RNA and cytoplasmic proteins.
HO
I
I
O CH2 C COONa * xH2O
I
I
NH2
H
Unithroid (levothyroxine sodium tablets, USP)
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Thyroid hormones regulate multiple metabolic processes and play an essential role in normal growth and
development, and normal maturation of the central nervous system and bone. The metabolic actions of thyroid
hormones include augmentation of cellular respiration and thermogenesis, as well as metabolism of proteins,
carbohydrates and lipids. The protein anabolic effects of thyroid hormones are essential to normal growth and
development.
The physiologic actions of thyroid hormones are produced predominately by T3, the majority of which
(approximately 80%) is derived from T4 by deiodination in peripheral tissues.
Levothyroxine, at doses individualized according to patient response, is effective as replacement or supplemental
therapy in hypothyroidism of any etiology, except transient hypothyroidism during the recovery phase of subacute
thyroiditis.
Levothyroxine is also effective in the suppression of pituitary TSH secretion in the treatment or prevention of various
types of euthyroid goiters, including thyroid nodules, Hashimoto’s thyroiditis, multinodular goiter and, as adjunctive
therapy in the management of thyrotropin-dependent well-differentiated thyroid cancer (see INDICATIONS AND
USAGE, PRECAUTIONS, DOSAGE ANDADMINISTRATION).
PHARMACOKINETICS
Absorption – Absorption of orally administered T4 from the gastrointestinal (GI) tract ranges from 40% to 80%. The
majority of the levothyroxine dose is absorbed from the jejunum and upper ileum. The relative bioavailability of
UNITHROID tablets, compared to an equal nominal dose of oral levothyroxine sodium solution, is approximately
99%. T4 absorption is increased by fasting, and decreased in malabsorption syndromes and by certain foods such as
soybean infant formula. Dietary fiber decreases bioavailability of T4. Absorption may also decrease with age. In
addition, many drugs and foods affect T4 absorption (see PRECAUTIONS, Drug Interactions and Drug-Food
Interactions).
Distribution – Circulating thyroid hormones are greater than 99% bound to plasma proteins, including thyroxinebinding
globulin (TBG), thyroxine-binding prealbumin (TBPA), and albumin (TBA), whose capacities and affinities
vary for each hormone. The higher affinity of both TBG and TBPA for T4 partially explains the higher serum levels,
slower metabolic clearance, and longer half-life of T4 compared to T3. Protein-bound thyroid hormones exist in
reverse equilibrium with small amounts of free hormone. On ly unbound hormone is metabolically active. Many
drugs and physiologic conditions affect the binding of thyroid hormones to serum proteins (see PRECAUTIONS,
Drug Interactions and Drug-Laboratory Test Interactions). Thyroid hormones do not readily cross the placental
barrier (see PRECAUTIONS, Pregnancy).
Metabolism – T4 is slowly eliminated (see TABLE 1). The major pathway of thyroid hormone metabolism is through
sequential deiodination. Approximately eighty-percent 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.
Elimination – 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 stool.
Urinary excretion of T4 decreases with age.
Unithroid (levothyroxine sodium tablets, USP)
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Table 1: Pharmacokinetic Parameters of Thyroid Hormones in Euthyroid Patients
Hormone Ratio Released from
Thyroid Gland
Biologic Potency t1/2 (days) Protein Binding (%)2
Levothyroxine (T4)
Liothyronine (T3)
20
1
1
4
6-71
£ 2
99.96
99.5
1 3 to 4 days in hyperthyroidism, 9 to 10 days in hypothyroidism; 2 Includes TBG, TBPA, and TBA
INDICATIONS AND USAGE
Levothyroxine sodium is used for the following indications:
Hypothyroidism – As replacement or supplemental therapy in congenital or acquired hypothyroidism of any
etiology, except transient hypothyroidism during the recovery phase of subacute thyroiditis. Specific indications
include: primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) hypothyroidism and subclinical
hypothyroidism. Primary hypothyroidism may result from functional deficiency, primary atrophy, partial or total
congenital absence of the thyroid gland, or from the effects of surgery, radiation, or drugs, with or without the
presence of goiter.
Pituitary TSH Suppression – In the treatment or prevention of various types of euthyroid goiters (see
PRECAUTIONS), including thyroid nodules (see PRECAUTIONS), subacute or chronic lymphocytic thyroiditis
(Hashimoto’s thyroiditis), multinodular goiter and, as an adjunct to surgery and radioiodine therapy in the
management of thyrotropin-dependent well-differentiated thyroid cancer.
CONTRAINDICATIONS
Levothyroxine is contraindicated in patients with untreated thyrotoxicosis of any etiology and in patients with acute
myocardial infarction. Levothyroxine is contraindicated in patients with uncorrected adrenal insufficiency since
thyroid hormones may precipitate an acute adrenal crisis by increasing the metabolic clearance of glucocorticoids
(see PRECAUTIONS). UNITHROID is contraindicated in patients with hypersensitivity to any of the inactive
ingredients in UNITHROID tablets. (See DESCRIPTION, Inactive Ingredients.)
WARNINGS
WARNING: Thyroid hormones, including UNITHROID, either alone or with other therapeutic agents, should not
be used for the treatment of obesity. 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.
Levothyroxine sodium should not be used in the treatment of male or female infertility unless this condition is
associated with hypothyroidism.
PRECAUTIONS
General
Levothyroxine has a narrow therapeutic index. Regardless of the indication for use, careful dosage titration is
necessary to avoid the consequences of over- or under-treatment. These consequences include, among others,
effects on growth and development, cardiovascular function, bone metabolism, reproductive function, cognitive
function, emotional state, gastrointestinal function, and on glucose and lipid metabolism.
Unithroid (levothyroxine sodium tablets, USP)
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Effects on bone mineral density- In women, long-term levothyroxine sodium therapy has been associated with
decreased bone mineral density, especially in postmenopausal women on greater than replacement doses or in
women who are receiving suppressive doses of levothyroxine sodium. Therefore, it is recommended that patients
receiving levothyroxine sodium be given the minimum dose necessary to achieve the desired clinical and biochemical
response.
Patients with underlying cardiovascular disease- Exercise caution when administering levothyroxine to patients with
cardiovascular disorders and to the elderly in whom there is an increased risk of occult cardiac disease. In these
patients, levothyroxine therapy should be initiated at lower doses than those recommended in younger individuals or
in patients without cardiac disease (see PRECAUTIONS, Geriatric Use and DOSAGE AND ADMINISTRATION). If
cardiac symptoms develop or worsen, the levothyroxine dose should be reduced or withheld for one week and then
cautiously restated at a lower dose. Overtreatment with levothyroxine sodium may have adverse cardiovascular
effects such as an increase in heart rate, cardiac wall thickness, and cardiac contractility and may precipitate angina
or arrhythmias. Patients with coronary artery disease who are receiving levothyroxine therapy should be monitored
closely during surgical procedures, since the possibility of precipitating cardiac arrhythmias may be greater in those
treated with levothyroxine. Concomitant administration of levothyroxine and sympathomimetic agents to patients
with coronary artery disease may precipitate coronary insufficiency.
Patients with autonomous thyroid tissue- Exercise caution when administering levothyroxine to patients with
autonomous thyroid tissue in order to prevent precipitation of thyrotoxicosis.
Associated endocrine disorders
Hypothalamic/pituitary hormone deficiencies- In patients with secondary or tertiary hypothyroidism, additional
hypothalamic/pituitary hormone deficiencies should be considered, and, if diagnosed, treated (see PRECAUTIONS,
Autoimmune polyglandular syndrome for adrenal insufficiency).
Autoimmune polyglandular syndrome- Occasionally, chronic autoimmune thyroiditis may occur in association with
other autoimmune disorders such as adrenal insufficiency, pernicious anemia, and insulin-dependent diabetes
mellitus. Patients with concomitant adrenal insufficiency should be treated with replacement glucocorticoids prior to
initiation of treatment with levothyroxine sodium. Failure to do so may precipitate an acute adrenal crisis when
thyroid hormone therapy is initiated, due to increased metabolic clearance of glucocorticoids by thyroid hormone.
Patients with diabetes mellitus may require upward adjustments of their antidiabetic therapeutic regimens when
treated with levothyroxine (see PRECAUTIONS, Drug Interactions).
Other associated medical conditions
Infants with congenital hypothyroidism appear to be at increased risk for other congenital anomalies, with
cardiovascular anomalies (pulmonary stenosis, atrial septal defect, and ventricular septal defect,) being the most
common association.
Information for Patients
Patients should be informed of the following information to aid in the safe and effective use of UNITHROID:
1. Notify your physician if you are allergic to any foods or medicines, are pregnant or intend to become pregnant,
are breast-feeding or are taking any other medications, including prescription and over-the-counter preparations.
2. Notify your physician of any other medical conditions you may have, particularly heart disease, diabetes,
clotting disorders, and adrenal or pituitary gland problems. Your dose of medications used to control these other
conditions may need to be adjusted while you are taking UNITHROID. If you have diabetes, monitor your blood
and/or urinary glucose levels as directed by your physician and immediately report any changes to your
physician. If you are taking anticoagulants (blood thinners), your clotting status should be checked frequently.
3. Use UNITHROID only as prescribed by your physician. Do not discontinue or change the amount you take or
how often you take it, unless directed to do so by your physician.
4. The levothyroxine in UNITHROID is intended to replace a hormone that is normally produced by your thyroid
gland. Generally, replacement therapy is to be taken for life, except in cases of transient hypothyroidism, which is
usually associated with an inflammation of the thyroid gland (thyroiditis).
Unithroid (levothyroxine sodium tablets, USP)
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5. Take UNITHROID as a single dose, preferably on an empty stomach, one-half to one hour before breakfast.
Levothyroxine absorption is increased on an empty stomach.
6. It may take several weeks before you notice an improvement in your symptoms.
7. Notify your physician if you experience any of the following symptoms: rapid or irregular heartbeat, chest pain,
shortness of breath, leg cramps, headache, nervousness, irritability, sleeplessness, tremors, change in appetite,
weight gain or loss, vomiting, diarrhea, excessive sweating, heat intolerance, fever, changes in menstrual periods,
hives or skin rash, or any other unusual medical event.
8. Notify your physician if you become pregnant while taking UNITHROID. It is likely that your dose of
UNITHROID will need to be increased while you are pregnant.
9. Notify your physician or dentist that you are taking UNITHROID prior to any surgery.
10. Partial hair loss may occur rarely during the first few months of UNITHROID therapy, but this is usually
temporary.
11. UNITHROID should not be used as a primary or adjunctive therapy in a weight control program.
12. Keep UNITHROID out of the reach of children. Store UNITHROID away from heat, moisture, and light.
Laboratory Tests
General
The diagnosis of hypothyroidism is confirmed by measuring TSH levels using a sensitive assay (second generation
assay sensitivity < 0.1 mIU/L or third generation assay sensitivity < 0.01 mIU/L) and measurement of free-T4.
The adequacy of therapy is determined by periodic assessment of appropriate laboratory tests and clinical
evaluation. The choice of laboratory tests depends on various factors including the etiology of the underlying
thyroid disease, the presence of concomitant medical conditions, including pregnancy, and the use of concomitant
medications (see PRECAUTIONS, Drug Interactions and Drug-Laboratory Test Interactions). Persistent clinical
and laboratory evidence of hypothyroidism despite an apparent adequate replacement dose of UNITHROID may be
evidence of inadequate absorption, poor compliance, drug interactions, or decreased T4 potency of the drug product.
Adults
In adult patients with primary (thyroidal) hypothyroidism, serum TSH levels (using a sensitive assay) alone may be
used to monitor therapy. The frequency of TSH monitoring during levothyroxine dose titration depends on the
clinical situation but it is generally recommended at 6-8 week intervals until normalization. For patients who have
recently initiated levothyroxine therapy and whose serum TSH has normalized or in patients who have had their
dosage or brand of levothyroxine changed, the serum TSH concentration should be measured after 8-12 weeks.
When the optimum replacement dose has been attained, clinical (physical examination) and biochemical monitoring
may be performed every 6-12 months, depending on the clinical situation, and whenever there is a change in the
patient’s status. It is recommended that a physical examination and a serum TSH measurement be performed at least
annually in patients receiving UNITHROID. (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).
Pediatrics
In patients with congenital hypothyroidism, the adequacy of replacement therapy should be assessed by measuring
both serum TSH (using a sensitive assay) and total- or free-T4. During the first three years of life, the serum total- or
free-T4 should be maintained at all times in the upper half of the normal range. While the aim of therapy is to also
normalize the serum TSH level, this is not always possible in a small percentage of patients, particularly in the first
few months of therapy. TSH may not normalize due to a resetting of the pituitary-thyroid feedback threshold as a
result of in utero hypothyroidism. Failure of the serum T4 to increase into the upper half of the normal range within 2
weeks of initiation of UNITHROID therapy and/or of the serum TSH to decrease below 20 mU/L within 4 weeks
should alert the physician to the possibility that the child is not receiving adequate therapy. Careful inquiry should
then be made regarding compliance, dose of medication administered, and method of administration prior to raising
the dose of UNITHROID.
Unithroid (levothyroxine sodium tablets, USP)
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The recommended frequency of monitoring of TSH and total or freeT4 in children is as follows: at 2 and 4 weeks after
the initiation of treatment; every 1-2 months during the first year of life; every 2-3 months between 1 and 3 years of
age; and every 3 to 12 months thereafter until growth is completed. More frequent intervals of monitoring may be
necessary if poor compliance is suspected or abnormal values are obtained. It is recommended that TSH and T4
levels, and a physical examination, if indicated, be performed 2 weeks after any change in UNITHROID dosage.
Routine clinical examination, including assessment of mental and physical growth and development, and bone
maturation, should be performed at regular intervals (see PRECAUTIONS, Pediatric Use and DOSAGE AND
ADMINISTRATION).
Secondary (pituitary) and tertiary (hypothalamic) hypothyroidism
Adequacy of therapy should be assessed by measuring serum free-T4 levels ,which should be maintained in the
upper half of the normal range in these patients.
Drug Interactions
Many drugs affect thyroid hormone pharmacokinetics and metabolism (e.g., absorption, synthesis, secretion,
catabolism, protein binding, and target tissue response) and may alter the therapeutic response to UNITHROID. In
addition, thyroid hormones and thyroid status have varied effects on the pharmacokinetics and action of other drugs.
A listing of drug-thyroidal axis interactions is contained in Table 2.
The list of drug-thyroidal axis interactions in Table 2 may not be comprehensive due to the introduction of new drugs
that interact with the thyroidal axis or the discovery of previously unknown interactions. The prescriber should be
aware of this fact and should consult appropriate reference sources. (e.g. package inserts of newly approved drugs,
medical literature) for additional information if a drug-drug interaction with levothyroxine is suspected.
Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class Effect
Drugs that may reduce TSH secretion –the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine / Dopamine Agonists
Glucocorticoids
Octreotide
Use of these agents may result in a transient reduction in TSH secretion when administered at
the following doses: Dopamine ( > 1 mg/kg/min); Glucocorticoids (hydrocortisone > 100
mg/day or equivalent); Octreotide ( > 100 mg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing
Radiographic contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU)
Sulfonamides
Tolbutamide
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical
or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and
euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with
Grave’s disease previously treated with radioiodine or surgery) are among those individuals who
are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents
and amiodarone are slowly excreted, producing more prolonged hypothyroidism than
parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy
may minimally decrease T4 and T3 levels and increase TSH, although all values remain within
normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone
Iodide (including iodine-containing
Radiographic contrast agents)
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in
euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in
euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning
thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for
several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by
causing thyroiditis.
Drugs that may decreaseT4 absorption, which may result in hypothyroidism
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Antacids
- Aluminum & Magnesium Hydroxides
- Simethicone
Bile Acid Sequestrants
- Cholestyramine
- Colestipol
Calcium Carbonate
Cation Exchange Resins
- Kayexalate
Ferrous Sulfate
Sucralfate
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or
preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form
an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine
complex. Administer levothyroxine at least 4 hours apart from these agents.
Drugs that may alter T4 and T3 serum transport (changes in total T4) - but FT4 concentrations remain normal; and,
therefore, hyperthyroidism does not occur
Drugs that may increase serum TBG concentration Drugs that may decrease serum TBG concentration
Clofibrate
Estrogen-containing oral contraceptives
Estrogens (oral)
Heroin / Methadone
5-Fluorouracil
Mitotane
Tamoxifen
Androgens / Anabolic Steroids
Asparaginase
Glucocorticoids
Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV)
Heparin
Hydantoins
Non Steroidal Anti-Inflammatory Drugs
- Fenamates
- Phenylbutazone
Salicylates ( > 2 g/day)
Administration of these agents with levothyroxine results in an initial transient increase in
FT4. Continued administration results in a decrease in serum T4, and normal FT4 and TSH
concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of
T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return
of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although
total-T4 levels may decrease by as much as 30%.
Drugs that may alter T4 and T3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased
hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements.
Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and
free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and
are clinically euthyroid.
Drugs that may decrease T4 5’-deiodinase activity
Amiodarone
Beta-adrenergic antagonists
- (e.g., Propranolol > 160 mg/day)
Glucocorticoids
- (e.g., Dexamethasone > 4 mg/day)
Propylthiouracil (PTU)
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3,
leading to decreased T3 levels. However, serum T4 levels are usually normal but may
occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160
mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are
clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists
may be impaired when the hypothyroid patient is converted to the euthyroid state. Shortterm
administration of large doses of glucocorticoids may decrease serum T3 concentrations
by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy
may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral)
- Coumarin Derivatives
- Indandione Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors,
thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these
agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time
should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the
dose of anticoagulant therapy adjusted accordingly.
Antidepressants
- Tricyclics (e.g., Amitriptyline)
- Tetracyclics (e.g., Maprotiline)
- Selective Serotonin Reuptake Inhibitors
(SSRIs; e.g., Sertraline)
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the
therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to
catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS
stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in
patients stabilized on levothyroxine may result in increased levothyroxine requirements.
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Antidiabetic Agents
- Biguanides
- Meglitinides
- Sulfonylureas
- Thiazolidediones
- Insulin
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased
antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is
recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid
patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be
reduced.
Cytokines
- Interferon-a
- Interleukin-2
Therapy with interferon-a has been associated with the development of antithyroid
microsomal antibodies in 20% of patients and some have transient hypothyroidism,
hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at
higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with
transient painless thyroiditis in 20% of patients. Interferon-b and -g have not been reported
to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure.
However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine Concurrent use may produce marked hypertension and tachycardia; cautious administration to
patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
- (e.g., Theophylline)
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to
normal when the euthyroid state is achieved.
Radiographic Agents Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc.
Sympathomimetics Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid
hormones may increase the risk of coronary insufficiency when sympathomimetic agents are
administered to patients with coronary artery disease.
Chloral Hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-Mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide Diuretics
These agents have been associated with thyroid hormone and / or TSH level alterations by
various mechanisms.
Oral anticoagulants- Levothyroxine increases the response to oral anticoagulant therapy. Therefore, a decrease in
the dose of anticoagulant may be warranted with correction of the hypothyroid state or when the UNITHROID dose
is increased. Prothrombin time should be closely monitored to permit appropriate and timely dosage adjustments (see
Table 2).
Digitalis glycosides- The therapeutic effects of digitalis glycosides may be reduced by levothyroxine. Serum digitalis
glycoside levels may be decreased when a hypothyroid patient becomes euthyroid, necessitating an increase in the
dose of digitalis glycosides (see Table 2).
Drug-Food Interactions – Consumption of certain foods may affect levothyroxine absorption thereby necessitating
adjustments in dosing. Soybean flour (infant formula), cotton seed meal, walnuts, and dietary fiber may bind and
decrease the absorption of levothyroxine sodium from the GI tract.
Drug-Laboratory Test Interactions – Changes in TBG concentration must be considered when interpreting T4 and
T3 values, which necessitates measurement and evaluation of unbound (free) hormone and/or determination of the
free T4 index (FT4I). Pregnancy, infectious hepatitis, estrogens, estrogen-containing oral contraceptives, and acute
Unithroid (levothyroxine sodium tablets, USP)
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intermittent porphyria increase TBG concentrations. Decreases in TBG concentrations are observed in nephrosis,
severe hypoproteinemia, severe liver disease, acromegaly, and after androgen or corticosteroid therapy (see also
Table 2). Familial hyper- or hypo-thyroxine binding globulinemias have been described, with the incidence of TBG
deficiency approximating 1 in 9000.
Carcinogenesis, Mutagenesis, and Impairment of Fertility – Animal studies have not been performed to evaluate
the carcinogenic potential, mutagenic potential or effects on fertility of levothyroxine. The synthetic T4 in
UNITHROID is identical to that produced naturally by the human thyroid gland. Although there has been a reported
association between prolonged thyroid hormone therapy and breast cancer, this has not been confirmed. Patients
receiving UNITHROID for appropriate clinical indications should be titrated to the lowest effective replacement dose.
Pregnancy – Category A – Studies in women taking levothyroxine sodium during pregnancy have not shown an
increased risk of congenital abnormalities. Therefore, the possibility of fetal harm appears remote. UNITHROID
should not be discontinued during pregnancy and hypothyroidism diagnosed during pregnancy should be promptly
treated.
Hypothyroidism during pregnancy is associated with a higher rate of complications, including spontaneous abortion,
pre-eclampsia, stillbirth and premature delivery. Maternal hypothyroidism may have an adverse effect on fetal and
childhood growth and development. During pregnancy, serum T4 levels may decrease and serum TSH levels increase
to values outside the normal range. Since elevations in serum TSH may occur as early as 4 weeks gestation, pregnant
women taking UNITHROID should have their TSH measured during each trimester. An elevated serum TSH level
should be corrected by an increase in the dose of UNITHROID. Since postpartum TSH levels are similar to
preconception values, the UNITHROID dosage should return to the pre-pregnancy dose immediately after delivery.
A serum TSH level should be obtained 6-8 weeks postpartum.
Thyroid hormones do not readily cross the placental barrier; however, some transfer does occur as evidenced by
levels in cord blood of athyroceotic fetuses being approximately one-third maternal levels. Transfer of thyroid
hormone from the mother to the fetus; however, may not be adequate to prevent in utero hypothyroidism.
Nursing Mothers – Although thyroid hormones are excreted only minimally in human milk, caution should be
exercised when UNITHROID is administered to a nursing woman. However, adequate replacement doses of
levothyroxine are generally needed to maintain normal lactation.
Pediatric Use
General
The goal of treatment in pediatric patients with hypothyroidism is to achieve and maintain normal intellectual and
physical growth and development.
The initial dose of levothyroxine varies with age and body weight (see DOSAGE AND ADMINISTRATION, Table
3). Dosing adjustments are based on an assessment of the individual patient’s clinical and laboratory parameters (see
PRECAUTIONS, Laboratory Tests).
In children in whom a diagnosis of permanent hypothyroidism has not been established, it is recommended that
levothyroxine administration be discontinued for a 30-day trial period, but only after the child is at least 3 years of
age. Serum T4 and TSH levels should then be obtained. If the T 4 is low and the TSH high, the diagnosis of
permanent hypothyroidism is established, and levothyroxine therapy should be reinstituted. If the T4 and TSH are
normal, euthyroidism may be assumed and, therefore, the hypothyroidism can be considered to have been transien t.
In this instance, however, the physician should carefully monitor the child and repeat the thyroid function tests if
any signs or symptoms of hypothyroidism develop. In this setting, the clinician should have a high index of
suspicion of relapse. If the results of the levothyroxine withdrawal test are inconclusive, careful follow-up and
subsequent testing will be necessary.
Unithroid (levothyroxine sodium tablets, USP)
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Since some more severely affected children may become clinically hypothyroid when treatment is discontinued for 30
days, an alternate approach is reduce the replacement dose of levothyroxine by half during the 30-day trial period. If,
after 30 days, the serum TSH is elevated above 20 mU/L, the diagnosis permanent hypothyroidism is confirmed and
full replacement therapy should be resumed. However, if the serum TSH has not risen to greater than 20mU/L,
levothyroxine treatment should be discontinued for another 30-day trial period followed by repeat serum T4 and TSH.
The presence of concomitant medical conditions should be considered in certain clinical circumstances and, if
present, appropriately treated (see PRECAUTIONS).
Congenital Hypothyroidism (see PRECAUTIONS, Laboratory Tests and DOSAGE and ADMINISTRATION)
Rapid restoration of normal serum T4 concentrations is essential for preventing the adverse effects of congenital
hypothyroidism on intellectual development as well as on overall physical growth and maturation. Therefore,
UNITHROID therapy should be initiated immediately upon diagnosis and is generally continued for life.
During the first 2 weeks of UNITHROID therapy, infants should be closely monitored for cardiac overload,
arrhythmias, and aspiration from avid suckling.
The patient should be monitored closely to avoid undertreatment or overtreatment. Undertreatment may have
deleterious effects on intellectual development and linear growth. Overtreatment has been associated with
craniosynostosis in infants, and may adversely affect the tempo of brain maturation and accelerate the bone age with
resultant premature closure of the epiphyses and compromised adult stature.
Acquired Hypothyroidism in Pediatric Patients
The patient should be monitored closely to avoid undertreatment and overtreatment. 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.
Geriatric Use
Because of the increased prevalence of cardiovascular disease among the elderly, levothyroxine therapy should not
be initiated at the full replacement dose (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).
ADVERSE REACTIONS
Adverse reactions associated with levothyroxine therapy are primarily those of hyperthyroidism due to therapeutic
overdosage. They include the following:
General: fatigue, increased appetite, weight loss, heat intolerance, fever, excessive sweating;
Central nervous system: headache, hyperactivity, nervousness, anxiety, irritability, emotional lability, insomnia;
Musculoskeletal: tremors, muscle weakness;
Cardiac: palpitations, tachycardia, arrhythmias, increased pulse and blood pressure, heart failure, angina, myocardial
infarction, cardiac arrest;
Pulmonary: dyspnea;
GI: diarrhea, vomiting, abdominal cramps;
Dermatologic: hair loss;
Reproductive: menstrual irregularities, infertility.
Pseudotumor cerebri has been reported in children receiving levothyroxine therapy.
Unithroid (levothyroxine sodium tablets, USP)
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Seizures have been reported rarely with the institution of levothyroxine therapy.
Inadequate levothyroxine dosage will produce or fail to ameliorate the signs and symptoms of hypothyroidism.
Hypersensitivity reactions to inactive ingredients have occurred in patients treated with thyroid hormone products.
These include urticaria, pruritus, skin rash, flushing, angioedema, various GI symptoms (abdominal pain, nausea,
vomiting and diarrhea), fever, arthralgia, serum sickness and wheezing. Hypersensitivity to levothyroxine itself is not
known to occur.
OVERDOSAGE
The signs and symptoms of overdosage are those of hyperthyroidism (see PRECAUTIONS and ADVERSE
REACTIONS). In addition, confusion and disorientation may occur. Cerebral embolism, shock, coma, and death
have been reported. Seizures have occurred in a child ingesting approximately 20 mg of levothyroxine. Symptoms
may not necessarily be evident or may not appear until several days after ingestion of levothyroxine sodium.
Acute Massive Overdosage – This may be a life-threatening emergency, therefore, symptomatic and supportive
therapy should be instituted immediately. If not contraindicated (e.g. by seizures, coma, or loss of the gag reflex), the
stomach should be emptied by emesis or gastric lavage to decrease gastrointestinal absorption. Activated charcoal
or cholestyramine may also be used to decrease absorption. Central and peripheral increased sympathetic activity
may be treated by administering B-receptor antagonists, e.g., propranolol (1 to 3 mg intravenously over a 10 minute
period, or orally, 80 to 160 mg/day). Provide respiratory support as needed; control congestive heart failure; control
fever, hypoglycemia, and fluid loss as necessary. Glucocorticoids may be given to inhibit the conversion of T4 to T3.
Because T4 is highly protein bound, very little drug will be removed by dialysis.
DOSAGE AND ADMINISTRATION
General Principles:
The goal of replacement therapy is to achieve and maintain a clinical and biochemical euthyroid state. The goal of
suppressive therapy is to inhibit growth and/or function of abnormal thyroid tissue. The dose of UNITHROID that is
adequate to achieve these goals depends on a variety of factors including the patient’s age, body weight,
cardiovascular status, concomitant medical conditions, including pregnancy, concomitant medications, and the
specific nature of the condition being treated (see PRECAUTIONS). Hence, the following recommendations serve
only as dosing guidelines. Dosing must be individualized and adjustments made based on periodic assessment of
the patient’s clinical response and laboratory parameters (see PRECAUTIONS, Laboratory Tests).
UNITHROID is administered as a single daily dose, preferably one-half to one-hour before breakfast. UNITHROID
should be taken at least 4 hours apart from drugs that are known to interfere with its absorption (see
PRECAUTIONS, Drug Interactions).
Due to the long half-life of levothyroxine, the peak therapeutic effect at a given dose of levothyroxine may not be
attained for 4-6 weeks.
Caution should be exercised when administering UNITHROID to patients with underlying cardiovascular disease, to
the elderly, and to those with concomitant adrenal insufficiency (see PRECAUTIONS).
Specific Patient Populations:
Hypothyroidism in Adults and in Children in Whom Growth and Puberty are Complete (see PRECAUTIONS,
Laboratory Tests)
Therapy may begin at full replacement doses in otherwise healthy individuals less than 50 years old and in those
older than 50 years who have been recently treated for hyperthyroidism or who have been hypothyroid for only a
short time (such as a few months). The average full replacement dose of levothyroxine is approximately 1.7
mcg/kg/day (e.g. 100-125 mcg/day for a 70 kg adult). Older patients may require less than 1 mcg/kg/day.
Levothyroxine doses greater than 200 mcg/day are seldom required. An inadequate response to daily doses > 300
mcg/day is rare and may indicate poor compliance, malabsorption, and/or drug interactions.
Unithroid (levothyroxine sodium tablets, USP)
Page 12
For most patients older than 50 years or for patients under 50 years of age with underlying cardiac disease, an initial
starting dose of 25-50 mcg/day of levothyroxine is recommended, with gradual increments in dose at 6-8 week
intervals. The recommended starting dose of levothyroxine in elderly patients with cardiac disease is 12.5-25
mcg/day, with gradual dose increments at 4-6 week intervals. The levothyroxine dose is generally adjusted in 12.5-25
mcg increments until the patient with primary hypothyroidism is clinically euthyroid and the serum TSH has
normalized.
In patients with severe hypothyroidism, the recommended initial levothyroxine dose is 12.5-25 mcg/day with
increases of 25 mcg/day every 2-4 weeks, accompanied by clinical and laboratory assessment, until the TSH level is
normalized.
In patients with secondary (pituitary) or tertiary (hypothalamic) hypothyroidism, the levothyroxine dose should be
titrated until the patient is clinically euthyroid and the serum free-T4 level is restored to the upper half of the normal
range.
Unithroid (levothyroxine sodium tablets, USP)
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Pediatric Dosage – Congenital or Acquired Hypothyroidism (see PRECAUTIONS, Laboratory Tests)
General Principles
In general, levothyroxine therapy should be instituted at full replacement doses as soon as possible. Delays in
diagnosis and institution of therapy may have deleterious effects on the child’s intellectual and physical growth and
development
Undertreatment and overtreatment should be avoided (see PRECAUTIONS, Pediatric Use).
UNITHROID may be administered to infants and children who cannot swallow intact tablets by crushing the tablet
and suspending the freshly crushed tablet in a small amount (5-10 ml or 1-2 teaspoons) of water. This suspension can
be administered by spoon or dropper. DO NOT STORE THE SUSPENSION. Foods that decrease absorption of
levothyroxine, such as soybean infant formula, should not be used for administering levothyroxine. (see
PRECAUTIONS , Drug-Food Interactions).
Newborns
The recommended starting dose of levothyroxine in newborn infants is 10-15 mcg/kg/day. A lower starting dose
(e.g., 25 mcg/day) should be considered in infants at risk for cardiac failure, and the dose should be increased in 4-6
weeks as needed based on clinical and laboratory response to treatment. In infants with very low (< 5 mcg/dl) or
undetectable serum T4 concentrations, the recommended initial starting dose is 50 mcg/day of levothyroxine.
Infants and Children
Levothyroxine therapy is usually initiated at full replacement doses, with the recommended dose per body weight
decreasing with age (see TABLE 3). However, in children with chronic or severe hypothyroidism, an initial dose of
25 mcg/day of levothyroxine is recommended with increments of 25 mcg every 2-4 weeks until the desired effect is
achieved.
Hyperactivity in an older child can be minimized if the starting dose is one-fourth of the recommended full
replacement dose, and the dose is then increased on a weekly basis by an amount equal to one-fourth the fullrecommended
replacement dose until the full recommended replacement dose is reached.
Table 3: Levothyroxine Dosing Guidelines for Pediatric Hypothyroidism
AGE Daily Dose Per Kg Body Weighta
0-3 months 10-15 mcg/kg/day
3-6 months 8-10 mcg/kg/day
6-12 months 6-8 mcg/kg/day
1-5 years 5-6 mcg/kg/day
6-12 years 4-5 mcg/kg/day
>12 years 2-3 mcg/kg/day
Growth and puberty complete 1.7 mcg/kg/day
a The dose should be adjusted based on clinical response and laboratory parameters (see PRECAUTIONS,
Laboratory Tests and Pediatric Use).
Pregnancy- Pregnancy may increase levothyroxine requirements (see PREGNANCY).
Subclinical Hypothyroidism- If this condition is treated, lower levothyroxine doses (e.g. 1 mcg/kg/day) than that
used for full replacement may be adequate to normalize the serum TSH level. Patients who are not treated should be
monitored yearly for changes in clinical status and thyroid laboratory parameters.
Unithroid (levothyroxine sodium tablets, USP)
Page 14
TSH Suppression in Well-differentiated Thyroid Cancer and Thyroid Nodules –Levothyroxine is used as an adjunct
to surgery and radioiodine therapy in the treatment of well-differentiated (papillary and follicular) thyroid cancer.
Generally, TSH is suppressed to <0.1 mU/L, and this usually requires a levothyroxine dose of greater than 2
mcg/kg/day.
In the treatment of benign nodules and nontoxic multinodular goiter, TSH is generally suppressed to a higher target
(0.1-0.3 mU/L) than that used for the treatment of thyroid cancer. Exercise caution when administering levothyroxine
to patients with autonomous thyroid tissue (see PRECAUTIONS).
Myxedema Coma – Myxedema coma is a life-threatening emergency characterized by poor circulation and
hypometabolism, and may result in unpredictable absorption of levothyroxine sodium from the gastrointestinal tract.
Therefore, oral levothyroxine is not recommended to treat this condition. Intravenous levothyroxine sodium should
be administered.
HOW SUPPLIED
---UNITHROID™ (levothyroxine sodium tablets, USP) are round, color coded, partial bisected tablets debossed with
JSP and ID number:
Strength (mcg) Color NDC # for bottles of 100 NDC # for bottles of 1000
25 Peach NDC 50564-513-01 NDC 50564-513-10
50 White NDC 50564-514-01 NDC 50564-514-10
75 Purple NDC 50564-515-01 NDC 50564-515-10
88 Olive NDC 50564-561-01 NDC 50564-561-10
100 Yellow NDC 50564-516-01 NDC 50564-516-10
112 Rose NDC 50564-562-01 NDC 50564-562-10
125 Tan NDC 50564-519-01 NDC 50564-519-10
150 Blue NDC 50564-520-01 NDC 50564-520-10
175 Lilac NDC 50564-563-01 NDC 50564-563-10
200 Pink NDC 50564-522-01 NDC 50564-522-10
300 Green NDC 50564-523-01 NDC 50564-523-10
STORAGE CONDITIONS
20-25°C (68-77°F) with excursions between 15-30°C (59-86°F)
Rx ONLY
MANUFACTURER
Jerome Stevens Pharmaceuticals, Inc.
Bohemia, NY 11716
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