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. Many drugs interact with levothyroxine sodium,
necessitating adjustments in dosing to maintain therapeutic response (see DRUG
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 Disease
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 Harmone 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
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 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 NOVOTHYROX (levothyroxine sodium tablets) may be evidence of inadequate absorption, poor
compliance, drug interactions, or decreased T4 potency of the drug
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 NOVOTHYROX (see WARNINGS,
PRECAUTIONS, and DOSAGE AND ADMINISTRATION).
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 NOVOTHYROX (levothyroxine sodium tablets) 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 NOVOTHYROX (levothyroxine sodium tablets) .
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 NOVOTHYROX (levothyroxine sodium tablets) 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
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 NOVOTHYROX (levothyroxine sodium tablets) 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 NOVOTHYROX (levothyroxine sodium tablets) 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. NOVOTHYROX (levothyroxine sodium tablets) 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 NOVOTHYROX (levothyroxine sodium tablets) should have their TSH measured during each trimester. An elevated serum TSH level should be corrected by an increase in the dose of NOVOTHYROX (levothyroxine sodium tablets) . Since postpartum TSH levels are similar to preconception values, the NOVOTHYROX (levothyroxine sodium tablets) 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 athyreotic 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 NOVOTHYROX (levothyroxine sodium tablets) 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,
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 testing.
The presence of concomitant medical conditions should be considered in certain
clinical circumstances and, if present, appropriately treated (see PRECAUTIONS).
(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, NOVOTHYROX (levothyroxine sodium tablets) therapy should be initiated immediately upon diagnosis and is generally continued for life.
During the first 2 weeks of NOVOTHYROX (levothyroxine sodium tablets) 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 AND ADMINISTRATION).