Hypothyroidism

TIROSINT-SOL is indicated in adult and pediatric patients, including neonates, as a replacement therapy in primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) congenital or acquired hypothyroidism.

Pituitary Thyrotropin (Thyroid-Stimulating Hormone, TSH) Suppression

TIROSINT-SOL is indicated in adult and pediatric patients, including neonates, as an adjunct to surgery and radioiodine therapy in the management of thyrotropin-dependent well-differentiated thyroid cancer.

Limitations of Use

• Tirosint-SOL is not indicated for suppression of benign thyroid nodules and nontoxic diffuse goiter in iodine-sufficient patients as there are no clinical benefits and overtreatment with TIROSINT-SOL may induce hyperthyroidism [see Warnings and Precautions (5.1)] .
• Tirosint-SOL is not indicated for treatment of transient hypothyroidism during the recovery phase of subacute thyroiditis.

2.1 General Administration Information

Administer TIROSINT-SOL as a single daily oral dose, on an empty stomach,15 minutes before breakfast.

Administer TIROSINT-SOL at least 4 hours before or after drugs known to interfere with TIROSINT-SOL absorption [see Drug Interactions (7.1)] .

Evaluate the need for dose adjustments when regularly administering within an hour of certain foods that may affect TIROSINT-SOL absorption [see Dosage and Administration (2.2 and 2.3), Drug Interactions (7.9) and Clinical Pharmacology (12.3)] .

TIROSINT-SOL may be administered in water or directly into the mouth:

• To administer TIROSINT-SOL in water, squeeze the contents of one single unit-dose ampule into a glass or cup containing water. Stir the diluted TIROSINT-SOL and drink all of it immediately. Rinse the glass or cup with additional water and drink the contents to ensure that the total dose is taken. Do not dilute TIROSINT-SOL in a medium other than water. Open the ampule and prepare the solution immediately before intake.
• To administer TIROSINT-SOL directly (without water), either squeeze it into the mouth OR onto a spoon and immediately consume.

2.2 Important Considerations for Dosing

The dosage of TIROSINT-SOL for hypothyroidism or pituitary TSH suppression depends on a variety of factors including: the patient's age, body weight, cardiovascular status, concomitant medical conditions (including pregnancy), concomitant medications, co-administered food, and the specific nature of the condition being treated [see Dosage and Administration (2.3), Warnings and Precautions (5), and Drug Interactions (7)] . Dosing must be individualized to account for these factors and dosage adjustments made based on periodic assessment of the patient's clinical response and laboratory parameters [see Dosage and Administration (2.4)] .

For adult patients with primary hypothyroidism, titrate until the patient is clinically euthyroid and the serum TSH returns to normal [see Dosage and Administration (2.3)].

For secondary or tertiary hypothyroidism, serum TSH is not a reliable measure of TIROSINT-SOL dosage adequacy and should not be used to monitor therapy. Use the serum free-T4 level to titrate TIROSINT-SOL dosing until the patient is clinically euthyroid and the serum free-T4 level is restored to the upper half of the normal range [see Dosage and Administration (2.3)].

The peak therapeutic effect of a given dose of TIROSINT-SOL may not be attained for 4 to 6 weeks.

2.3 Recommended Dosage and Titration

Primary, Secondary, and Tertiary Hypothyroidism in Adults

2.4 Monitoring TSH and/or Thyroxine (T4) Levels

Assess the adequacy of therapy by periodic assessment of laboratory tests and clinical evaluation. Persistent clinical and laboratory evidence of hypothyroidism, despite an apparent adequate replacement dose of TIROSINT-SOL, may be evidence of inadequate absorption, poor compliance, drug interactions, or a combination of these factors.

5.1 Serious Risks Related to Overtreatment or Undertreatment with TIROSINT-SOL

TIROSINT-SOL has a narrow therapeutic index. Overtreatment or undertreatment with TIROSINT-SOL may have negative effects on growth and development, cardiovascular function, bone metabolism, reproductive function, cognitive function, gastrointestinal function, and glucose and lipid metabolism in adult or pediatric patients.

In pediatric patients with congenital and acquired hypothyroidism, undertreatment may adversely affect cognitive development and linear growth, and overtreatment is associated with craniosynostosis and acceleration of bone age [see Use in Specific Populations (8.4)].

Titrate the dose of TIROSINT-SOL carefully and monitor response to titration to avoid these effects [see Dosage and Administration (2.4)]. Consider the potential for food or drug interactions and adjust the administration or dosage of TIROSINT-SOL as needed [see Dosage and Administration (2.4), Drug Interactions (7.1), and Clinical Pharmacology (12.3)].

5.2 Cardiac Adverse Reactions in the Elderly and in Patients with Underlying Cardiovascular Disease

Overtreatment with levothyroxine may cause an increase in heart rate, cardiac wall thickness, and cardiac contractility, and may precipitate angina or arrhythmias, particularly in patients with cardiovascular disease and in elderly patients. Initiate TIROSINT-SOL therapy in this population at lower doses than those recommended in younger individuals or in patients without cardiac disease [see Dosage and Administration (2.3) and Use in Specific Populations (8.5)].

Monitor for cardiac arrhythmias during surgical procedures in patients with coronary artery disease receiving suppressive TIROSINT-SOL therapy. Monitor patients receiving concomitant TIROSINT-SOL and sympathomimetic agents for signs and symptoms of coronary insufficiency . If cardiac symptoms develop or worsen, reduce the TIROSINT-SOL dose or withhold it for one week and restart at a lower dose.

5.3 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. Use of oral thyroid hormone drug products is not recommended to treat myxedema coma. Administer thyroid hormone products formulated for intravenous administration to treat myxedema coma.

5.4 Acute Adrenal Crisis in Patients with Concomitant Adrenal Insufficiency

Thyroid hormone increases metabolic clearance of glucocorticoids. Initiation of thyroid hormone therapy prior to initiating glucocorticoid therapy may precipitate an acute adrenal crisis in patients with adrenal insufficiency. Treat patients with adrenal insufficiency with replacement glucocorticoids prior to initiating treatment with TIROSINT-SOL [see Contraindications (4)].

5.5 Worsening of Diabetic Control

Addition of levothyroxine therapy in patients with diabetes mellitus may worsen glycemic control and result in increased antidiabetic agent or insulin requirements. Carefully monitor glycemic control after starting, changing, or discontinuing TIROSINT-SOL [see Drug Interactions (7.2)] .

5.6 Decreased Bone Mineral Density Associated with Thyroid Hormone Over-Replacement

Increased bone resorption and decreased bone mineral density may occur as a result of levothyroxine over-replacement, particularly in post-menopausal women. 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. Administer the minimum dose of TIROSINT-SOL that achieves the desired clinical and biochemical response to mitigate this risk.

Adverse Reactions in Pediatric Patients

Pseudotumor cerebri and slipped capital femoral epiphysis have been reported in pediatric patients receiving levothyroxine therapy. Overtreatment may result in craniosynostosis in infants who have not undergone closure of the fontanelles, and in premature closure of the epiphyses in pediatric patients still experiencing growth with resultant compromised adult height.

Hypersensitivity Reactions

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.

7.1 Drugs Known to Affect Thyroid Hormone Pharmacokinetics

Many drugs can exert effects on thyroid hormone pharmacokinetics and metabolism (e.g., absorption, synthesis, secretion, catabolism, protein binding, and target tissue response) and may alter the therapeutic response to TIROSINT-SOL (Tables 5 to 8).

Table 5. Drugs That May Decrease T4 Absorption (Hypothyroidism)

Table 6. Drugs That May Alter T4 and Triiodothyronine (T3) Serum Transport Without Affecting Free Thyroxine (FT4) Concentration (Euthyroidism)

Table 7. Drugs That May Alter Hepatic Metabolism of T4 (Hypothyroidism)

Table 8.Drugs That May Decrease Conversion of T4 to T3

7.2 Antidiabetic Therapy

Addition of TIROSINT-SOL therapy in patients with diabetes mellitus may worsen glycemic control and result in increased antidiabetic agent or insulin requirements. Carefully monitor glycemic control, especially when thyroid therapy is started, changed, or discontinued [see Warnings and Precautions (5.5)] .

7.3 Oral Anticoagulants

TIROSINT-SOL 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 TIROSINT-SOL dose is increased. Closely monitor coagulation tests to permit appropriate and timely dosage adjustments.

7.4 Digitalis Glycosides

TIROSINT-SOL may reduce the therapeutic effects of digitalis glycosides. Serum digitalis glycoside levels may decrease when a hypothyroid patient becomes euthyroid, necessitating an increase in the dose of digitalis glycosides.

7.5 Antidepressant Therapy

Concurrent use of tricyclic (e.g., amitriptyline) or tetracyclic (e.g., maprotiline) antidepressants and TIROSINT-SOL 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 central nervous system stimulation. TIROSINT-SOL may accelerate the onset of action of tricyclics. Administration of sertraline in patients stabilized on TIROSINT-SOL may result in increased TIROSINT-SOL requirements.

7.6 Ketamine

Concurrent use of ketamine and TIROSINT-SOL may produce marked hypertension and tachycardia. Closely monitor blood pressure and heart rate in these patients.

7.7 Sympathomimetics

Concurrent use of sympathomimetics and TIROSINT-SOL 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.

7.8 Tyrosine-Kinase Inhibitors

Concurrent use of tyrosine-kinase inhibitors such as imatinib may cause hypothyroidism. Closely monitor TSH levels in such patients.

7.9 Drug-Food Interactions

Consumption of certain foods may affect TIROSINT-SOL absorption thereby necessitating adjustments in dosing [see Dosage and Administration (2.1)] . Soybean flour (infant formula), cottonseed meal, walnuts, and dietary fiber may bind and decrease the absorption of TIROSINT-SOL from the gastrointestinal tract. Grapefruit juice may delay the absorption of levothyroxine and reduce its bioavailability.

7.10 Drug-Laboratory Test Interactions

Consider changes in TBG concentration when interpreting T4 and T3 values. Measure and evaluate unbound (free) hormone and/or determine the free-T4 index (FT4I) in this circumstance. Pregnancy, infectious hepatitis, estrogens, estrogen-containing oral contraceptives, and acute intermittent porphyria increase TBG concentrations. Nephrosis, severe hypoproteinemia, severe liver disease, acromegaly, androgens and corticosteroids decrease TBG concentration. Familial hyper- or hypo-thyroxine binding globulinemias have been described, with the incidence of TBG deficiency approximating 1 in 9000.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

TIROSINT-SOL is indicated in patients from birth to less than 17 years of age:

• As a replacement therapy in primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) congenital or acquired hypothyroidism
• As an adjunct to surgery and radioiodine therapy in the management of thyrotropin-dependent well-differentiated thyroid cancer

Rapid restoration of normal serum T4 concentrations is essential for preventing the adverse effects of congenital hypothyroidism on cognitive development as well as on overall physical growth and maturation. Therefore, initiate TIROSINT-SOL therapy immediately upon diagnosis. Levothyroxine is generally continued for life in these patients [see Warnings and Precautions (5.1)].

Closely monitor infants during the first two weeks of TIROSINT-SOL therapy for cardiac overload and arrhythmias.

8.5 Geriatric Use

Because of the increased prevalence of cardiovascular disease among the elderly, initiate TIROSINT-SOL at less than the full replacement dose [ see Dosage and Administration (2.3) and Warnings and Precautions (5.1)]. Atrial arrhythmias can occur in elderly patients. Atrial fibrillation is the most common of the arrhythmias observed with levothyroxine overtreatment in the elderly .

12.1 Mechanism of Action

Thyroid hormones exert their physiologic actions through control of DNA transcription and protein synthesis. Triiodothyronine (T3) and L-thyroxine (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.

The physiological actions of thyroid hormones are produced predominantly by T3, the majority of which (approximately 80%) is derived from T4 by deiodination in peripheral tissues.

12.2 Pharmacodynamics

Oral levothyroxine sodium is a synthetic T4 hormone that exerts the same physiologic effect as endogenous T4, thereby maintaining normal T4 levels when a deficiency is present.

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term carcinogenicity studies in animals to evaluate the carcinogenic potential of levothyroxine have not been performed. Studies to evaluate mutagenic potential and animal fertility have not been performed.

How Supplied

TIROSINT-SOL (levothyroxine sodium) oral solution is a clear, colorless to slightly yellow solution supplied in a 1 mL white, non-transparent, unit-dose ampule. The dosage strength is identified on the box and the pouch, and is associated with a distinct color. Each ampule bears a colored label with the dosage strength and the product name (TIROSINT-SOL) (Table 10).

Storage and Handling

Store TIROSINT-SOL in the original container (closed pouch) at 20°C to 25°C (68°F to 77°F); excursions permitted to 15° to 30°C (59°F to 86°F) [See USP Controlled Room Temperature].

Use TIROSINT-SOL oral solution within three (3) months after opening the pouch. Keep the ampules in the pouch until ready to use as important information may be lost (i.e., manufacturer/distributor names and distributor contact phone number).

Dosing and Administration

• Instruct patients to take TIROSINT-SOL only as directed by their healthcare provider.
• Instruct patients to take TIROSINT-SOL 15 minutes before breakfast.
• Instruct patients about the TIROSINT-SOL dosing instructions.
• Inform patients that agents such as iron and calcium supplements and antacids can decrease the absorption of levothyroxine. Instruct patients not to take TIROSINT-SOL within 4 hours of these agents.
• Instruct patients to notify their healthcare provider should they become pregnant or are thinking of becoming pregnant while taking TIROSINT-SOL.

Important Information

• Inform patients that it may take several weeks before they notice an improvement in symptoms.
• Inform patients that the levothyroxine in TIROSINT-SOL is intended to replace a hormone that is normally produced by the thyroid gland. Generally, replacement therapy is to be taken for life.
• Inform patients that TIROSINT-SOL should not be used as a primary or adjunctive therapy in a weight control program.
• Instruct patients to notify their healthcare provider if they are taking any other medications, including prescription and over-the-counter preparations.
• Instruct patients to notify their healthcare provider of any other medical conditions, particularly heart disease, diabetes, clotting disorders, and adrenal or pituitary gland problems, as the dose of medications used to control these other conditions may need to be adjusted while taking TIROSINT-SOL. If they have diabetes, instruct patients to monitor their blood and/or urinary glucose levels as directed by their physician and immediately report any changes to their physician. If patients are taking anticoagulants, their clotting status should be checked frequently.
• Instruct patients to notify their physician or dentist that they are taking TIROSINT-SOL prior to any surgery.

Adverse Reactions

• Instruct patients to notify their healthcare provider if they 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 loss, vomiting, diarrhea, excessive sweating, heat intolerance, fever, changes in menstrual periods, hives or skin rash, or any other unusual medical event.
• Inform patients that partial hair loss may occur rarely during the first few months of TIROSINT-SOL therapy, but this is usually temporary.