Levothyroxine has a narrow therapeutic index. Regardless
of the indication for use, careful dosage titration is necessary to avoid the
consequences of over- or undertreatment. 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. Many drugs
interact with levothyroxine sodium necessitating adjustments in dosing to
maintain therapeutic response (see DRUG INTERACTIONS).
Effects On Bone Mineral Density
In women, long-term levothyroxine sodium therapy has been
associated with increased bone resorption, thereby decreasing bone mineral density,
especially in post-menopausal women on greater than replacement doses or in women
who are receiving suppressive doses of levothyroxine sodium. The increased bone
resorption may be associated with increased serum levels and urinary excretion of
calcium and phosphorous, elevations in bone alkaline phosphatase and suppressed
serum parathyroid hormone levels. 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 WARNINGS; 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 restarted 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 Nontoxic Diffuse Goiter Or Nodular Thyroid
Exercise caution when administering levothyroxine to
patients with nontoxic diffuse goiter or nodular thyroid disease in order to
prevent precipitation of thyrotoxicosis (see WARNINGS). If the serum TSH
is already suppressed, levothyroxine sodium should not be administered (see CONTRAINDICATIONS).
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.
The diagnosis of hypothyroidism is confirmed by measuring
TSH levels using a sensitive assay (second generation assay sensitivity ≤
0.1 mlU/L or third generation assay sensitivity ≤ 0.01 mlU/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.
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 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 WARNINGS, PRECAUTIONS and DOSAGE
In patients with congenital hypothyroidism, the adequacy
of replacement therapy should be assessed by measuring both serum TSH (using a
sensitive assay) and totalor 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 UNlTHROID.
The recommended frequency of monitoring of TSH and total
or free T4 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.
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.
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 cross the placental barrier to some
extent 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.
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.
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 T4 is low and the TSH high, the diagnosis of permanent hypothyroidism
is established, and levothyroxine therapy should be reinstituted. If the T4 and
TSH levels are normal, euthyroidism may be assumed and, therefore, the hypothyroidism
can be considered to have been transient. 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.
Since some more severely affected children may become
clinically hypothyroid when treatment is discontinued for 30 days, an alternate
approach is to 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 of permanent hypothyroidism is confirmed, and full
replacement therapy should be resumed. However, if the serum TSH has not risen
to greater than 20 mU/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.
Because of the increased prevalence of cardiovascular
disease among the elderly, levothyroxine therapy should not be initiated at the
full replacement dose (see WARNINGS, PRECAUTIONS and DOSAGE