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Tirosint.com

HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use TIROSINT safely and effectively.
• Patients unable to swallow a capsule, including young children (generally under 6 years of age) (4) See full prescribing information for TIROSINT.
• Acute myocardial infarction (4) TIROSINT (levothyroxine sodium) capsules, for oral use
• Uncorrected adrenal insufficiency (4) Initial U.S. Approval: 2000
WARNINGS AND PRECAUTIONS
WARNING: NOT FOR TREATMENT OF OBESITY OR FOR WEIGHT LOSS
• Proper dose titration is critical to prevent the persistence of hypothyroidism or the development of See full prescribing information for complete boxed warning
hyperthyroidism (5.1) • Thyroid hormones, including TIROSINT, should not be used for the treatment of obesity or for
• Elderly and patients with cardiovascular disease: Initiate levothyroxine at less than the full replacement weight loss.
dose because of the increased risk of cardiac adverse reactions, including atrial fibrillation (2.3, 5.2, 8.5) • Doses beyond the range of daily hormonal requirements may produce serious or even life
• Suppression of thyroid nodules with levothyroxine is generally not recommended (5.3) threatening manifestations of toxicity (6, 10).
• Patients with concomitant adrenal insufficiency: Treat with replacement glucocorticoids prior to initiation of treatment with levothyroxine (5.4) INDICATIONS AND USAGE
• Long-term levothyroxine therapy can decrease bone mineral density. Give the lowest effective dose, particularly in patients with compromised bone mineral density (5.5) Levothyroxine sodium is L-thyroxine (T4) and is indicated for: • Hypothyroidism - As replacement or supplemental therapy in congenital or acquired hypothyroidism of
any etiology, except transient hypothyroidism during the recovery phase of subacute thyroiditis (1.1) Common adverse reactions for levothyroxine are primarily those of hyperthyroidism due to therapeutic • Pituitary Thyrotropin-Stimulating Hormone (TSH) Suppression - As an adjunct to surgery and radioio-
overdosage including: irregular heartbeat, chest pain, shortness of breath, leg cramps, headache, dine therapy in the management of thyrotropin-dependent well-differentiated thyroid cancer (1.2) nervousness, irritability, insomnia, tremors, muscle weakness, change in appetite, weight change, DOSAGE AND ADMINISTRATION
diarrhea, heat intolerance, changes in menstrual periods, and skin rash (6) • Do not cut or crush TIROSINT capsules (2.1)
To report SUSPECTED ADVERSE REACTIONS, contact Akrimax Pharmaceuticals at 1-888-383-1733,
• Administer once daily, one-half to one hour before breakfast (2.1) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
• Administer at least 4 hours before or after drugs and foods that are known to interfere with absorption • Starting dose depends on a variety of factors, including age, body weight, cardiovascular status, Many drugs affect thyroid hormone pharmacokinetics and metabolism (e.g., absorption, synthesis, pregnancy, and concomitant medications (2.2, 2.3) secretion, catabolism, protein binding, and target tissue response) and may alter the therapeutic response • The peak therapeutic effect may not be attained for 4-6 weeks (2.2) • Maintenance dose: Determined with periodic monitoring of TSH and/or T4 as well as clinical status (2.4) USE IN SPECIFIC POPULATIONS
DOSAGE FORMS AND STRENGTHS
Pregnancy may require the use of higher doses of levothyroxine (2.3, 8.1) Capsules: 13 mcg, 25 mcg, 50 mcg, 75 mcg, 88 mcg, 100 mcg, 112 mcg, 125 mcg, 137 mcg, 150 mcg (3) See 17 for PATIENT COUNSELING INFORMATION.
Revised: [March 2012]
FULL PRESCRIBING INFORMATION: CONTENTS*
7.5 Antidepressant Therapy WARNING: NOT FOR TREATMENT OF OBESITY OR FOR WEIGHT LOSS
7.7 Sympathomimetics 1 INDICATIONS AND USAGE
7.8 Tyrosine-Kinase Inhibitors 1.1 Hypothyroidism 7.9 Drug-Food Interactions 1.2 Pituitary TSH Suppression 7.10 Drug-Laboratory Test Interactions 2 DOSAGE AND ADMINISTRATION
8 USE IN SPECIFIC POPULATIONS
2.1 Important Information Before Use 2.2 Principles of Dosing 8.3 Nursing Mothers 2.3 Dosing in Specific Patient Populations 8.4 Pediatric Use 2.4 Monitoring TSH and/or Thyroxine (T4) Levels 8.5 Geriatric Use 3 DOSAGE FORMS AND STRENGTHS
5 WARNINGS AND PRECAUTIONS
12 CLINICAL PHARMACOLOGY
5.1 Importance of Proper Dose Titration to Prevent Hyperthyroidism or Incomplete Treatment of 12.1 Mechanism of Action 12.2 Pharmacodynamics 5.2 Risk of Cardiac Adverse Reactions in the Elderly and in Patients with Underlying Cardiovascular 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY
5.3 Patients with Nontoxic Diffuse Goiter or Nodular Thyroid Disease 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 5.4 Patients with Concomitant Adrenal Insufficiency 13.2 Animal Toxicology and/or Pharmacology 5.5 Thyroid Hormone Over-replacement Associated with Decreased Bone Mineral Density 16 HOW SUPPLIED/STORAGE AND HANDLING
6 ADVERSE REACTIONS
17 PATIENT COUNSELING INFORMATION
7 DRUG INTERACTIONS
17.1 Dosing and Administration 7.1 Drugs Known to Affect Thyroid Hormone Pharmacokinetics 17.2 Important Information 7.2 Antidiabetic Therapy 17.3 Adverse Reactions 7.3 Oral Anticoagulants 7.4 Digitalis Glycosides *Sections or subsections omitted from the full prescribing information are not listed.
FULL PRESCRIBING INFORMATION
Due to the long half-life of levothyroxine, the peak therapeutic effect at a given dose of levothyroxine sodium may not be attained for 4-6 weeks. WARNING: NOT FOR TREATMENT OF OBESITY OR FOR WEIGHT LOSS
• Thyroid hormones, including TIROSINT, either alone or with other therapeutic agents, should
2.3 Dosing In Specific Patient Populations
not be used for the treatment of obesity or for weight loss.
Hypothyroidism in Adults and in Adolescents in Whom Growth and Puberty are Complete • In euthyroid patients, doses within the range of daily hormonal requirements are ineffective
The average full replacement dose of levothyroxine sodium is approximately 1.7 mcg per kg per day (e.g., for weight reduction.
100-125 mcg per day for a 70 kg adult). Elderly patients may require less than 1 mcg per kg per day. • Larger doses may produce serious or even life threatening manifestations of toxicity,
The initial levothyroxine dosage is based on the age, weight, and cardiac status of the patient as well as particularly when given in association with sympathomimetic amines such as those used
the severity and duration of the hypothyroidism. Therapy may generally begin at full replacement doses for their anorectic effects [See Adverse Reactions (6), Drug Interactions (7.7), and
in otherwise non-elderly, healthy individuals. For elderly patients or those with underlying cardiovascular disease, a starting dose of levothyroxine sodium as low as 12.5 mcg per day may be appropriate, with gradual increments in dose at 6-8 week INDICATION AND USAGE
intervals, as needed [See Warnings and Precautions (5.2)]. More frequent monitoring is recommended for patients with more severe hypothyroidism.
1.1 Hypothyroidism
In general, levothyroxine sodium doses greater than 200 mcg per day are seldom required. An TIROSINT is indicated as a replacement or supplemental therapy in congenital or acquired inadequate response to daily doses greater than 300 mcg per day is rare and may indicate poor hypothyroidism of any etiology, except transient hypothyroidism during the recovery phase of compliance, malabsorption, and/or drug interactions.
subacute thyroiditis. Specific indications include: primary (thyroidal), secondary (pituitary), and tertiary Secondary or Tertiary Hypothyroidism (hypothalamic) hypothyroidism. Primary hypothyroidism may result from functional deficiency, primary In patients with secondary (pituitary) or tertiary (hypothalamic) hypothyroidism, the levothyroxine atrophy, partial or total congenital absence of the thyroid gland, or from the effects of surgery, sodium dose should be titrated until the patient is clinically euthyroid and the serum free thyroxine radiation, or drugs, with or without the presence of goiter. (FT4) level is restored to the upper half of the normal range.
Hypothyroidism (Congenital or Acquired) in the Pediatric Population 1.2 Pituitary Thyrotropin-Stimulating Hormone (TSH) Suppression
Only administer TIROSINT to children who are able to swal ow an intact capsule [See Contraindications (4)].
TIROSINT is indicated as an adjunct to surgery and radioiodine therapy in the management of In general, levothyroxine therapy should be instituted at full replacement doses as soon as possible. thyrotropin-dependent well-differentiated thyroid cancer.
Delays in diagnosis and institution of therapy may have deleterious effects on the child's intellectual DOSAGE AND ADMINISTRATION
and physical growth and development. Undertreatment and overtreatment should be avoided [See Warnings and Precautions (5.1) and Use in Specific Populations (8.4)].
2.1 Important Information Before Use
Levothyroxine therapy is usually initiated at full replacement doses, with the recommended dose per Do not cut or crush TIROSINT capsules; capsules should be swallowed whole.
body weight changing with age (Table 1).
Administer TIROSINT as a single daily dose, preferably one-half to one hour before breakfast. Administer at least 4 hours before or after drugs and foods that are known to interfere with TIROSINT Table 1: Levothyroxine Sodium Dosing Guidelines for Pediatric Hypothyroidism
absorption [See Drug Interactions (7.1, 7.9) and Clinical Pharmacology (12.3)]. Daily Dose Per Kg Body Weight1
2.2 Principles of Dosing
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 TIROSINT that is adequate to achieve these goals depends on a variety of factors including the >12 years but growth and puberty incomplete patient's age, body weight, cardiovascular status, concomitant medical conditions, pregnancy status, Growth and puberty complete concomitant medications, and the specific nature of the condition being treated. Hence, the following recommendations serve only as dosing guidelines. Dosing must be individualized 1 The dose should be adjusted based on clinical response and laboratory parameters. and adjustments made based on periodic assessment of the patient's clinical response and laboratory [See Warnings and Precautions (5.1) and Use in Specific Populations (8.4)] parameters. Inadequate levothyroxine dosage will fail to ameliorate the signs and symptoms of hypothyroidism [See Warnings and Precautions (5.1)].
In children with chronic or severe hypothyroidism, a lower initial dose of 25 mcg per day of potential associated adverse cardiovascular signs and symptoms of hyperthyroidism.
levothyroxine sodium is recommended with increasing increments of 25 mcg every 2-4 weeks until the desired effect is achieved.
5.4 Patients with Concomitant Adrenal Insufficiency
Hyperactivity in an older child can be minimized if the starting dose is one-fourth of the recommended Occasionally, chronic autoimmune thyroiditis may occur in association with other autoimmune disorders full replacement dose, and the dose is then increased on a weekly basis by an amount equal to one- such as adrenal insufficiency, pernicious anemia, and insulin-dependent diabetes mellitus. Patients with fourth the full-recommended replacement dose until the full recommended replacement dose is concomitant adrenal insufficiency should be treated with replacement glucocorticoids prior to initiation of treatment with levothyroxine sodium [See Contraindications (4)]. Failure to do so may precipitate an Pregnancy acute adrenal crisis when thyroid hormone therapy is initiated, due to increased metabolic clearance of Pregnancy may increase levothyroxine requirements. [See Use in Specific Populations (8.1)] glucocorticoids by thyroid hormone. Thyrotropin-Stimulating Hormone (TSH) Suppression in Well-Differentiated Thyroid Cancer 5.5 Thyroid Hormone Over-replacement Associated with Decreased Bone Mineral Density
In the treatment of well-differentiated (papillary and follicular) thyroid cancer, levothyroxine is used as Over-replacement with levothyroxine therapy has been associated with decreased bone mineral an adjunct to surgery and radioiodine therapy. Generally, TSH is suppressed to less than 0.1 mU per L, density, especially in post-menopausal women. The increased bone resorption may be associated with and this usually requires a levothyroxine sodium dose of greater than 2 mcg per kg per day. However, in increased serum levels and urinary excretion of calcium and phosphorous, elevations in bone alkaline patients with high-risk tumors, the target level for TSH suppression may be less than 0.01 mU per L. phosphatase, and suppressed serum parathyroid hormone levels. Therefore, it is recommended that Myxedema Coma patients receiving levothyroxine sodium be given the minimum dose necessary to achieve the desired Myxedema coma is a life-threatening emergency characterized by poor circulation and clinical and biochemical response, unless TSH suppression is the goal of therapy, as in patients with hypometabolism, and may result in unpredictable absorption of levothyroxine sodium from the well-differentiated thyroid cancer.
gastrointestinal tract. Therefore, thyroid hormone administered intravenously is the recommended route of administration in this rare condition. 2.4 Monitoring TSH and/or Thyroxine (T4) Levels
Common adverse reactions with levothyroxine therapy are primarily those of hyperthyroidism due to The adequacy of therapy is determined by periodic assessment of appropriate laboratory tests and therapeutic overdosage [See Overdosage (10)]. They include the following: clinical evaluation. The choice of laboratory tests depends on various factors including the etiology of • General: fatigue, increased appetite, weight loss, heat intolerance, fever, excessive sweating the underlying thyroid disease, the presence of concomitant medical conditions, including pregnancy, • Central nervous system: headache, hyperactivity, nervousness, anxiety, irritability, emotional lability, and the use of concomitant medications. Persistent clinical and laboratory evidence of hypothyroidism despite an apparent adequate replacement dose of TIROSINT may be evidence of inadequate • Musculoskeletal: tremors, muscle weakness absorption, poor compliance, drug interactions, or decreased T4 potency of the drug product.
• Cardiovascular: palpitations, tachycardia, arrhythmias, increased pulse and blood pressure, heart failure, angina, myocardial infarction, cardiac arrest In adult patients with primary (thyroidal) hypothyroidism, serum TSH levels alone may be used to • Respiratory: dyspnea monitor therapy. The frequency of TSH monitoring during levothyroxine dose titration depends • Gastrointestinal (GI): diarrhea, vomiting, abdominal cramps, elevations in liver function tests on the clinical situation but reassessment and titration should be done after an interval of at least 6 • Dermatologic: hair loss, flushing weeks after any change in dose. When the optimum replacement dose has been attained, clinical • Endocrine: decreased bone mineral density (physical examination) and biochemical monitoring may be performed every 6-12 months, depending • Reproductive: menstrual irregularities, impaired fertility on the clinical situation, and whenever there is a change in the patient's status. It is recommended Adverse Reactions in Children that a physical examination and a serum TSH measurement be performed at least annually in patients Pseudotumor cerebri and slipped capital femoral epiphysis have been reported in children receiving receiving TIROSINT.
levothyroxine therapy. Overtreatment may result in craniosynostosis in infants and premature closure of Pediatrics the epiphyses in children with resultant compromised adult height. Seizures have been reported rarely In patients with congenital hypothyroidism, the adequacy of replacement therapy should be assessed with the institution of levothyroxine therapy.
by measuring both serum TSH and total or FT4. While the aim of therapy is to also normalize the Hypersensitivity Reactions serum TSH level, this is not always possible in a small percentage of patients, particularly in the first Hypersensitivity reactions to inactive ingredients (in this product or other levothyroxine products) have few months of therapy. TSH may not normalize due to a resetting of the pituitary-thyroid feedback occurred in patients treated with thyroid hormone products. These include urticaria, pruritus, skin rash, threshold as a result of in utero hypothyroidism. Failure of the serum T4 to increase into the upper flushing, angioedema, various GI symptoms (abdominal pain, nausea, vomiting and diarrhea), fever, half of the normal range within 2 weeks of initiation of TIROSINT therapy and/or of the serum TSH to arthralgia, serum sickness and wheezing. Hypersensitivity to levothyroxine itself is not known to occur.
decrease below 20 mU per 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 increasing the dose of TIROSINT.
7.1 Drugs Known to Affect Thyroid Hormone Pharmacokinetics
The recommended frequency of monitoring of TSH and total or FT4 in children is as follows: at 2 and 4 Many drugs affect thyroid hormone pharmacokinetics (e.g., absorption, synthesis, secretion, weeks after the initiation of treatment and following dose stabilization every 3 to 12 months thereafter catabolism, protein binding, and target tissue response) and may alter the therapeutic response to until growth is completed. More frequent intervals of monitoring may be necessary if poor compliance TIROSINT. In addition, thyroid hormones and thyroid status have varied effects on the pharmacokinetics is suspected or abnormal values are obtained. It is recommended that TSH and T4 levels, and a physical and actions of other drugs. examination, if indicated, be performed 2 weeks after any change in TIROSINT dosage. Routine clinical examination, including assessment of mental and physical growth and development, and bone A listing of drug interactions with L-thyroxine (T4) is provided in the following tables. These tables maturation, should be performed at regular intervals [See Warnings and Precautions (5.1), and Use in should not be seen as comprehensive due to the introduction of new drugs that interact with the Specific Populations (8.4)]. thyroidal axis or the discovery of previously unknown interactions. The prescriber should be aware Secondary (Pituitary) and Tertiary (Hypothalamic) Hypothyroidism of this fact and should consult appropriate reference sources (e.g., prescribing information of Adequacy of therapy should be assessed by measuring serum FT newly approved drugs, medical literature) for additional information if a drug-drug interaction with 4 levels, which should be maintained in the upper half of the normal range in these patients.
levothyroxine is suspected.
DOSAGE FORMS AND STRENGTHS
Table 2: Drugs That May Decrease T4 Absorption (Hypothyroidism)
TIROSINT Capsules: 13 mcg, 25 mcg, 50 mcg, 75 mcg, 88 mcg, 100 mcg, 112 mcg, 125 mcg, 137 mcg, Potential impact: Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism.
TIROSINT Capsules are amber-colored, round/biconvex capsules that contain a viscous amber-colored Drug or Drug Class
Calcium carbonate may form an insoluble chelate with levothyroxine, Calcium Carbonate and ferrous sulfate likely forms a ferric-thyroxine complex. Administer • Do not give TIROSINT to anyone who may be unable to swallow a capsule, including young children levothyroxine at least 4 hours apart from these agents.
(generally under 6 years of age) because of the risk of aspiration. Patients treated concomitantly with orlistat and levothyroxine should be • Levothyroxine is also contraindicated in patients with: monitored for changes in thyroid function.
• Acute myocardial infarction: administration of levothyroxine in this setting can exacerbate angina and increase the risk of arrhythmia.
Bile Acid Sequestrants Bile acid sequestrants and ion exchange resins are known to decrease • Uncorrected adrenal insufficiency since thyroid hormones may precipitate an acute adrenal levothyroxine absorption. Administer levothyroxine at least 4 hours prior crisis by increasing the metabolic clearance of glucocorticoid [See Warnings and Precautions to these drugs or monitor thyrotropin-stimulating hormone (TSH) levels. WARNINGS AND PRECAUTIONS
Ion Exchange Resins 5.1 Importance of Proper Dose Titration to Prevent Hyperthyroidism or Incomplete Treatment
of Hypothyroidism
Levothyroxine has a narrow therapeutic index. Regardless of the indication for use, careful dosage titration is necessary to avoid hyperthyroidism or incomplete treatment of hypothyroidism. These consequences include, among others, adverse effects on cardiovascular function, growth and development, bone metabolism, reproductive function, cognitive function, emotional state, gastrointestinal function, and on glucose and lipid metabolism. Periodic clinical and thyroid function monitoring is recommended [See Dosage and Administration (2.4)]. In addition, many drugs interact with levothyroxine sodium necessitating adjustments in dosing to maintain therapeutic response [See Drug Interactions (7)].
5.2 Risk of Cardiac Adverse Reactions in the Elderly and in Patients with Underlying
Table 3: Drugs That May Alter T
Cardiovascular Disease
4 and Triiodothyronine (T3) Serum Transport Without Effecting
Free Thyroxine (FT
In the elderly and in patients with cardiovascular disorders, levothyroxine therapy should be initiated 4) Concentration (Euthyroidism)
at lower doses than those recommended in younger individuals or in patients without cardiac disease Drugs That May Increase Serum Thyroxine-
Drugs That May Decrease Serum
and it should be noted that unlike levothyroxine sodium tablets, TIROSINT capsules cannot be cut in Binding Globulin (TBG) Concentration
half [See Dosage and Administration (2.3) and Use in Specific Populations (8.5)]. If cardiac symptoms develop or worsen, the levothyroxine sodium dose should be reduced or withheld for one week Androgens / Anabolic Steroids and then cautiously restarted at a lower dose. Overtreatment with levothyroxine sodium may have Estrogen-containing oral contraceptives 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 Heroin / Methadone Slow-Release Nicotinic Acid receiving levothyroxine therapy should be monitored closely during surgical procedures because of the possibility of precipitating cardiac arrhythmias, including atrial fibrillation. Concomitant administration of levothyroxine and sympathomimetic agents to patients with coronary artery disease may precipitate coronary insufficiency [See Drug Interactions (7.7)].
Drugs That May Cause Protein-Binding Site Displacement
5.3 Patients with Nontoxic Diffuse Goiter or Nodular Thyroid Disease
Potential impact: Administration of these agents with levothyroxine results in an initial transient Suppression of thyroid nodules with levothyroxine is a controversial issue. Routine suppression of increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH benign thyroid nodules is generally not recommended in iodine-sufficient patients. If the serum concentrations, and patients are likely clinically euthyroid.
thyrotropin-stimulating hormone (TSH) is already suppressed, levothyroxine sodium should not be administered. If the serum TSH level is not suppressed, TIROSINT should not be used without frequent laboratory monitoring of thyroid function for evidence of hyperthyroidism and clinical monitoring for are observed in nephrosis, severe hypoproteinemia, severe liver disease, acromegaly, and after Table 3: Drugs That May Alter T4 and Triiodothyronine (T3) Serum Transport Without Effecting
androgen or corticosteroid therapy. Familial hyper- or hypo-thyroxine binding globulinemias have been Free Thyroxine (FT4) Concentration (Euthyroidism)
described, with the incidence of TBG deficiency approximating 1 in 9000.
Salicylates (> 2 g/day) Salicylates inhibit binding of T4 and T3 to TBG 8 USE IN SPECIFIC POPULATIONS
and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels 8.1 Pregnancy
with sustained therapeutic serum salicylate Pregnancy category A. Levothyroxine should not be discontinued during pregnancy and concentrations, although total T4 levels may hypothyroidism diagnosed during pregnancy should be promptly treated. Hypothyroidism during decrease by as much as 30%.
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. Furosemide (> 80 mg IV) During pregnancy, serum thyroxine (T4) levels may decrease and serum thyrotropin-stimulating hormone (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 TIROSINT should have their TSH measured Non-Steroidal Anti-inflammatory Drugs during each trimester. An elevated serum TSH level should be corrected by an increase in the dose of TIROSINT. Since postpartum TSH levels are similar to preconception values, the TIROSINT 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.
Table 4: Drugs That May Alter Hepatic Metabolism of T4 (Hypothyroidism)
Potential impact: Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause 8.3 Nursing Mothers
increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements.
Thyroid hormones are excreted only minimally in human milk. Adequate replacement doses of levothyroxine are generally needed to maintain normal lactation. Drug or Drug
8.4 Pediatric Use
The goal of treatment in pediatric patients with hypothyroidism is to achieve and maintain normal Phenytoin and carbamazepine reduce serum protein binding of intellectual and physical growth and development.
levothyroxine, and total and FT4 may be reduced by 20% to 40%, The initial dose of levothyroxine varies with age and body weight [See Dosage and Administration but most patients have normal serum TSH levels and are clinically euthyroid. (2.2)]. Dosing adjustments are based on an assessment of the individual patient's clinical and laboratory Close monitoring of thyroid hormone parameters is recommended.
parameters [See Warnings and Precautions (5.1)] In children in whom a diagnosis of permanent hypothyroidism has not been established, it is recommended that at an appropriate age levothyroxine be discontinued for a trial period. Serum T and TSH levels should be obtained at the end of the trial period, and laboratory test results and clinical assessments should then guide diagnosis and treatment, if warranted. 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 Table 5: Drugs That May Decrease Conversion of T4 to T3
maturation. Therefore, levothyroxine therapy should be initiated immediately upon diagnosis and is Potential impact: Administration of these enzyme inhibitors decreases the peripheral conversion generally continued for life.
of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may The patient should be monitored closely to avoid undertreatment and overtreatment. Undertreatment occasionally be slightly increased.
may result in poor school performance due to impaired concentration and slowed mentation and in Drug or Drug Class
reduced adult height. Overtreatment may accelerate the bone age and result in premature epiphyseal closure and compromised adult stature.
In patients treated with large doses of Treated children may manifest a period of catch-up growth, which may be adequate in some cases to (e.g., Propranolol > 160 mg/day) propranolol (> 160 mg/day), T normalize adult height. In children with severe or prolonged hypothyroidism, catch-up growth may not change slightly, TSH levels remain normal, be adequate to normalize adult height.
and patients are clinically euthyroid. It should 8.5 Geriatric Use
be noted that actions of particular beta- Because of the increased prevalence of cardiovascular disease among the elderly, levothyroxine adrenergic antagonists may be impaired when therapy should not be initiated at the full replacement dose. Atrial fibrillation is a common side effect the hypothyroid patient is converted to the associated with levothyroxine treatment in the elderly [See Dosage and Administration (2.3) and euthyroid state.
Warnings and Precautions (5.2)].
Short-term administration of large doses (e.g., Dexamethasone ≥ 4 mg/day) of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in The signs and symptoms of overdosage are those of hyperthyroidism. [See Warnings and Precautions serum T4 levels. However, long-term (5.1) and Adverse Reactions (6)]. In addition, confusion and disorientation may occur. Cerebral glucocorticoid therapy may result in slightly embolism, shock, coma, and death have been reported. Seizures have occurred in a 3-year-old child decreased T3 and T4 levels due to decreased ingesting 3.6 mg of levothyroxine. Symptoms may not necessarily be evident or may not appear until TBG production (See above).
several days after ingestion of levothyroxine sodium.
Treatment of Overdosage Levothyroxine sodium should be reduced in dose or temporarily discontinued if signs or symptoms of overdosage occur.
To obtain up-to-date information about the treatment of overdose, a good resource is the certified Regional Poison Control Center. In managing overdosage, consider the possibility of multiple drug 7.2 Antidiabetic Therapy
overdoses, interaction among drugs, and unusual drug kinetics in the patient.
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or In the event of an overdose, appropriate supportive treatment should be initiated as dictated by the insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid patient's medical status.
therapy is started, changed, or discontinued. 7.3 Oral Anticoagulants
TIROSINT (levothyroxine sodium) is L-thyroxine. The orally administered gelatin capsules contain Levothyroxine increases the response to oral anticoagulant therapy. Therefore, a decrease in the dose synthetic L-3,3',5,5'-tetraiodothyronine sodium salt [levothyroxine (T of anticoagulant may be warranted with correction of the hypothyroid state or when the TIROSINT dose 4) sodium]. Synthetic T4 is chemically identical to that produced in the human thyroid gland. Levothyroxine (T is increased. Coagulation tests should be closely monitored to permit appropriate and timely dosage an empirical formula of C 15H10I4NNaO4 • x H2O (where x = 5), molecular weight of 798.86 g/mol (anhydrous), and structural formula as shown: 7.4 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.
7.5 Antidepressant Therapy
Concurrent use of tricyclic (e.g., Amitriptyline) or tetracyclic (e.g., Maprotiline) 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 The inactive ingredients in TIROSINT are gelatin, glycerin and water.
and central nervous system stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
CLINICAL PHARMACOLOGY
7.6 Ketamine
12.1 Mechanism of Action
Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients Thyroid hormones exert their physiologic actions through control of DNA transcription and protein receiving thyroid hormone therapy is recommended.
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.
Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones The physiological actions of thyroid hormones are produced predominantly by T may increase the risk of coronary insufficiency when sympathomimetic agents are administered to 3, the majority of which (approximately 80%) is derived from T patients with coronary artery disease.
4 by deiodination in peripheral tissues. 12.2 Pharmacodynamics
7.8 Tyrosine-Kinase Inhibitors
Thyroid hormone synthesis and secretion is regulated by the hypothalamic-pituitary-thyroid axis. Concurrent use of tyrosine-kinase inhibitors such as imatinib may cause hypothyroidism. TSH levels Thyrotropin-releasing hormone (TRH) released from the hypothalamus stimulates secretion of should be closely monitored in such patients.
thyrotropin-stimulating hormone (TSH), from the anterior pituitary. TSH, in turn, is the physiologic Drug-Food Interactions
stimulus for the synthesis and secretion of thyroid hormones, T4 and T3, by the thyroid gland. Circulating Consumption of certain foods may affect levothyroxine sodium absorption thereby necessitating serum T3 and T4 levels exert a feedback effect on both TRH and TSH secretion. When serum T3 and T4 adjustments in dosing. Soybean flour, cotton seed meal, walnuts, and dietary fiber may bind and levels increase, TRH and TSH secretion decrease. When thyroid hormone levels decrease, TRH and TSH decrease the absorption of levothyroxine sodium from the GI tract.
secretion increase. TSH, along with T4 levels and other laboratory and clinical data, is primarily used for both the diagnosis 7.10 Drug-Laboratory Test Interactions
of hypothyroidism and evaluation of levothyroxine therapy adequacy [Dosage and Administration (2.4)]. Changes in TBG concentration must be considered when interpreting T4 and T3 values, which There are drugs known to affect thyroid hormones and TSH levels by various mechanisms. Some drugs necessitates measurement and evaluation of unbound (free) hormone and/or determination of the free may cause a transient decrease in TSH secretion without hypothyroidism: dopamine (≥ 1 mcg per kg T4 index (FT4I). Pregnancy, infectious hepatitis, estrogens, estrogen-containing oral contraceptives, per min), glucocorticoids (hydrocortisone ≥ 100 mg per day or equivalent) and octreotide (> 100 mcg and acute intermittent porphyria increase TBG concentrations. Decreases in TBG concentrations Thyroid hormones regulate multiple metabolic processes and play an essential role in normal growth • Instruct patients to notify their healthcare provider should they become pregnant or are thinking and development, and normal maturation of the central nervous system and bone. The metabolic of becoming pregnant while taking TIROSINT. It is likely that the dose of TIROSINT will need to be actions of thyroid hormones include augmentation of cellular respiration and thermogenesis, as well as increased during pregnancy.
metabolism of proteins, carbohydrates, and lipids. The protein anabolic effects of thyroid hormones are • To assist with identifying the name and strength of each TIROSINT capsule, instruct patients not to essential to normal growth and development.
remove capsules from the blisters in advance, particularly if they are taking multiple strengths.
12.3 Pharmacokinetics
17.2 Important Information
Absorption • Inform patients that it may take several weeks before they notice an improvement in symptoms. Absorption of orally administered T4 from the gastrointestinal (GI) tract ranges from 40% to 80%. • Inform patients that the levothyroxine in TIROSINT is intended to replace a hormone that is normally The majority of the levothyroxine dose is absorbed from the jejunum and upper ileum. The relative produced by the thyroid gland. Generally, replacement therapy is to be taken for life.
bioavailability of TIROSINT capsules compared to another marketed levothyroxine sodium tablet, is • Inform patients that TIROSINT should not be used as a primary or adjunctive therapy in a weight approximately 103%. T4 absorption is increased by fasting, and decreased in malabsorption syndromes control program.
and by certain foods such as soybeans. Dietary fiber decreases the bioavailability of T4. Absorption may • Instruct patients to notify their healthcare provider if they are taking any other medications, including also decrease with age. In addition, many drugs and foods affect T4 absorption [See Drug Interactions prescription and over-the-counter preparations.
(7)]. • Instruct patients to notify their healthcare provider of any other medical conditions, particularly Distribution heart disease, diabetes, clotting disorders, and adrenal or pituitary gland problems, as the dose of Circulating thyroid hormones are greater than 99% bound to plasma proteins, including thyroxine- medications used to control these other conditions may need to be adjusted while taking TIROSINT. If binding globulin (TBG), thyroxine-binding prealbumin (TBPA), and thyroxine-binding albumin (TBA), patients are taking anticoagulants (blood thinners), their clotting status should be checked frequently.
whose capacities and affinities vary for each hormone. The higher affinity of both TBG and TBPA for 17.3 Adverse Reactions
4 partially explains the higher serum levels, slower metabolic clearance, and longer half-life of T4 • Instruct patients to notify their healthcare provider if they experience any of the following symptoms: 3. Protein-bound thyroid hormones exist in reverse equilibrium with small amounts of free hormone. Only unbound hormone is metabolically active. Many drugs and physiologic conditions rapid or irregular heartbeat, chest pain, shortness of breath, leg cramps, headache, nervousness, affect the binding of thyroid hormones to serum proteins [See Drug Interactions (7)].
irritability, sleeplessness, tremors, change in appetite, weight gain or loss, vomiting, diarrhea, Thyroid hormones do not readily cross the placental barrier [See Use in Specific Populations (8.1)].
excessive sweating, heat intolerance, fever, changes in menstrual periods, hives or skin rash, or any Metabolism other unusual medical event.
• Inform patients that partial hair loss may occur rarely during the first few months of TIROSINT therapy; 4 is slowly eliminated. The major pathway of thyroid hormone metabolism is through sequential deiodination. Approximately 80% of circulating T this is usually temporary.
3 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 (r T3). T3 and r T3 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.
Manufactured for Akrimax Pharmaceuticals, LLC by:
Elimination IBSA Institut Biochimique SA 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 T 4 is eliminated in the stool. Urinary excretion of T4 decreases with age.
Akrimax Pharmaceuticals, LLC, Table 6: Pharmacokinetic Parameters of Thyroid Hormones in Euthyroid Patients
Cranford, NJ 07016 Protein Binding
Version April 2012 1047F003 Rev 04/12
4: Levothyroxine (L-thyroxine) T3: Liothyronine (Triiodothyronine) 1 3 – 4 days in hyperthyroidism, 9 – 10 days in hypothyroidism.
2 Includes TBG, TBPA and TBA.
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Animal studies have not been performed to evaluate the carcinogenic potential, mutagenic potential or effects on fertility of Levothyroxine Sodium. 13.2 Animal Toxicology and/or Pharmacology
No animal toxicology studies have been conducted with Levothyroxine Sodium. HOW SUPPLIED/STORAGE AND HANDLING
TIROSINT (levothyroxine sodium) capsules are amber-colored, round/biconvex capsules that contain a viscous amber-colored liquid. They are supplied as follows: Boxes of 28 capsules, consisting of 4 blisters with 7 capsules each. The dosage strength on each box is clearly identified in several locations, and is associated with a distinct color. The color of the circles on the blister is the same color as on the box. Each blister pack contains 7 capsules placed in individual cavities labeled with the dosage strength, the product name (TIROSINT), and an abbreviation for the day of the week on which the capsule is taken.
Do not separate the individual cavities containing the drug from the intact blister as important
information may be lost (i.e., manufacturer/distributor names, distributor contact phone number, lot number, and expiration date), and do not remove the individual capsules from blister packaging until
ready to use.
Table 7: TIROSINT Packaging Description
*Shown on box and blister packing, not on individual capsules.
Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [See USP Controlled Room Temperature]. TIROSINT capsules should be protected from heat, light and moisture.
PATIENT COUNSELING INFORMATION
Patients should be informed of the following information to aid in the safe and effective use of 17.1 Dosing and Administration
• Instruct patients that TIROSINT should only be taken as directed by their healthcare provider.
• Instruct patients to take TIROSINT one-half to one hour before breakfast.
• Instruct patients that TIROSINT capsules should never be crushed or cut.

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