Levothyroxine precautions

List of precautions
General Associated endocrine disorders Other associated medical conditions Lab tests Carcinogenesis Mutagenesis Impairment of fertility Pregnancy Nursing mothers Pediatric use Geriatric use
 * Effects on bone mineral density
 * Patients with underlying cardiovascular disease
 * Patients with nontoxic diffuse goiter/nodular thyroid disease
 * Hypothalamic/pituitary hormone deficiencies
 * Autoimmune polyglandular syndrome
 * General
 * Adults
 * Pediatrics
 * Secondary (pituitary)/tertiary (hypothalamic) hypothyroidism
 * General
 * Congenital hypothyroidism
 * Acquired hypothyroidism

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. Many drugs interact with Levothyroxine sodium necessitating adjustments in dosing to maintain therapeutic response. Return to top

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. Return to top

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. 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. Return to top

Patients with nontoxic diffuse goiter/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. If the serum TSH is already suppressed, Levothyroxine sodium should not be administered. Return to top

Hypothalamic/pituitary hormone deficiencies
In patients with secondary or tertiary hypothyroidism, additional hypothalamic/pituitary hormone deficiencies should be considered, and, if diagnosed, treated. Return to top

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. Return to top

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. Return to top

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. Persistent clinical and laboratory evidence of hypothyroidism despite an apparent adequate replacement dose of Levothyroxine sodium may be evidence of inadequate absorption, poor compliance, drug interactions, or decreased T4 potency of the drug product. Return to top

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 to 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 to 12 weeks. When the optimum replacement dose has been attained, clinical (physical examination) and biochemical monitoring may be performed every 6 to 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 Levothyroxine sodium. Return to top

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 Levothyroxine sodium 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 Levothyroxine sodium. 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 to 2 months during the first year of life; every 2 to 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 Levothyroxine sodium dosage. Routine clinical examination, including assessment of mental and physical growth and development, and bone maturation, should be performed at regular intervals. Return to top

Secondary (pituitary)/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. Return to top

Carcinogenesis
Animal studies have not been performed to evaluate the carcinogenic potential of Levothyroxine. The synthetic T4 in Levothyroxine sodium 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 Levothyroxine sodium for appropriate clinical indications should be titrated to the lowest effective replacement dose. Return to top

Mutagenesis
Animal studies have not been performed to evaluate the mutagenic potential of Levothyroxine. The synthetic T4 in Levothyroxine sodium is identical to that produced naturally by the human thyroid gland. Patients receiving Levothyroxine sodium for appropriate clinical indications should be titrated to the lowest effective replacement dose. Return to top

Impairment of fertility
Animal studies have not been performed to evaluate the effects on fertility of Levothyroxine. The synthetic T4 in Levothyroxine sodium is identical to that produced naturally by the human thyroid gland. Patients receiving Levothyroxine sodium for appropriate clinical indications should be titrated to the lowest effective replacement dose. Return to top

Pregnancy
Teratogenic Effects 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. Levothyroxine sodium 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 Levothyroxine sodium should have their TSH measured during each trimester. An elevated serum TSH level should be corrected by an increase in the dose of Levothyroxine sodium. Since postpartum TSH levels are similar to preconception values, the Levothyroxine sodium dosage should return to the pre-pregnancy dose immediately after delivery. A serum TSH level should be obtained 6 to 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. Return to top
 * Pregnancy category A

Nursing mothers
Although thyroid hormones are excreted only minimally in human milk, caution should be exercised when Levothyroxine sodium is administered to a nursing woman. However, adequate replacement doses of Levothyroxine are generally needed to maintain normal lactation. Return to top

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. 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.Return to top

Congenital hypothyroidism
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, Levothyroxine sodium therapy should be initiated immediately upon diagnosis and is generally continued for life. During the first 2 weeks of Levothyroxine sodium 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. Return to top

Acquired hypothyroidism
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. Return to top

Geriatric use
Because of the increased prevalence of cardiovascular disease among the elderly, Levothyroxine therapy should not be initiated at the full replacement dose. Return to top