Tirosint

• Thyroid hormones, including TIROSINT, either alone or with other therapeutic agents, should not be used for the treatment of obesity or for weight loss.
• In euthyroid patients, doses within the range of daily hormonal requirements are ineffective for weight reduction.
• Larger doses may produce serious or even life threatening manifestations of toxicity, particularly when given in association with sympathomimetic amines such as those used for their anorectic effects
  

  [see
  

  6 ADVERSE REACTIONS

  Adverse reactions associated with TIROSINT therapy are primarily those of hyperthyroidism due to therapeutic overdosage

  [see Warnings and Precautions (5)and Overdosage (10)].

  They include the following:

  • General:
    fatigue, increased appetite, weight loss, heat intolerance, fever, excessive sweating
  • Central nervous system:
    headache, hyperactivity, nervousness, anxiety, irritability, emotional lability, insomnia
  • Musculoskeletal:
    tremors, muscle weakness, muscle spasm
  • Cardiovascular:
    palpitations, tachycardia, arrhythmias, increased pulse and blood pressure, heart failure, angina, myocardial infarction, cardiac arrest
  • Respiratory
    : dyspnea
  • Gastrointestinal (GI):
    diarrhea, vomiting, abdominal cramps, elevations in liver function tests
  • Dermatologic:
    hair loss, flushing, rash
  • Endocrine:
    decreased bone mineral density
  • Reproductive:
    menstrual irregularities, impaired fertility

  Seizures have been reported rarely with the institution of levothyroxine therapy.

  Adverse reactions associated with TIROSINT are primarily those of hyperthyroidism due to therapeutic overdosage including: arrhythmias, myocardial infarction, dyspnea, muscle spasm, headache, nervousness, irritability, insomnia, tremors, muscle weakness, increased appetite, weight loss, diarrhea, heat intolerance, menstrual irregularities, and skin rash

  
  
  

  To report SUSPECTED ADVERSE REACTIONS, contact IBSA Pharma Inc. at 1-800-587-3513, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

  .

  Adverse Reactions in Children

  Pseudotumor cerebri and slipped capital femoral epiphysis have been reported in children receiving levothyroxine therapy. Overtreatment may result in craniosynostosis in infants and premature closure of the epiphyses in children 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.

  ,
  

  7.7 Sympathomimetics

  Concurrent use of sympathomimetics and TIROSINT 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.

  , and
  

  10 OVERDOSAGE

  The signs and symptoms of overdosage are those of hyperthyroidism

  [see Warnings and Precautions (5)and Adverse Reactions (6)].

  In addition, confusion and disorientation may occur. Cerebral embolism, shock, coma, and death have been reported. Seizures occurred in a 3-year-old child ingesting 3.6 mg of levothyroxine. Symptoms may not necessarily be evident or may not appear until several days after ingestion of levothyroxine sodium.

  Reduce the TIROSINT dose or discontinue temporarily if signs or symptoms of overdosage occur. Initiate appropriate supportive treatment as dictated by the patient's medical status.

  For current information on the management of poisoning or overdosage, contact the National Poison Control Center at 1-800-222-1222 or www.poison.org.

  ].
  

TIROSINT is L-thyroxine (T4) indicated for adults and pediatric patients 6 years and older with:

• Hypothyroidism - As replacement therapy in primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) congenital or acquired hypothyroidism (
  
  
  
  1 INDICATION AND USAGE

  TIROSINT is L-thyroxine (T4) indicated for adults and pediatric patients 6 years and older with:

  • Hypothyroidism - As replacement therapy in primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) congenital or acquired hypothyroidism
  • Pituitary Thyrotropin (Thyroid-Stimulating Hormone, TSH) Suppression - As an adjunct to surgery and radioiodine therapy in the management of thyrotropin-dependent well-differentiated thyroid cancer

  Limitations of Use:

  • Not indicated for suppression of benign thyroid nodules and nontoxic diffuse goiter in iodine-sufficient patients
  • Not indicated for treatment of transient hypothyroidism during the recovery phase of subacute thyroiditis

  Hypothyroidism

  TIROSINT is indicated as a replacement therapy in adults and pediatric patients 6 years and older with primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) congenital or acquired hypothyroidism.

  Pituitary Thyrotropin (Thyroid-Stimulating Hormone, TSH) Suppression

  TIROSINT is indicated as an adjunct to surgery and radioiodine therapy in the management of adults and pediatric patients 6 years and older with thyrotropin-dependent well-differentiated thyroid cancer.

  Limitations of Use:

  • TIROSINT 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 may induce hyperthyroidism
    [see Warnings and Precautions (5.4)].
  • TIROSINT is not indicated for treatment of transient hypothyroidism during the recovery phase of subacute thyroiditis.
  )
  
  
• Pituitary Thyrotropin (Thyroid-Stimulating Hormone, TSH) Suppression - As an adjunct to surgery and radioiodine therapy in the management of thyrotropin-dependent well-differentiated thyroid cancer (
  
  
  
  1 INDICATION AND USAGE

  TIROSINT is L-thyroxine (T4) indicated for adults and pediatric patients 6 years and older with:

  • Hypothyroidism - As replacement therapy in primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) congenital or acquired hypothyroidism
  • Pituitary Thyrotropin (Thyroid-Stimulating Hormone, TSH) Suppression - As an adjunct to surgery and radioiodine therapy in the management of thyrotropin-dependent well-differentiated thyroid cancer

  Limitations of Use:

  • Not indicated for suppression of benign thyroid nodules and nontoxic diffuse goiter in iodine-sufficient patients
  • Not indicated for treatment of transient hypothyroidism during the recovery phase of subacute thyroiditis

  Hypothyroidism

  TIROSINT is indicated as a replacement therapy in adults and pediatric patients 6 years and older with primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) congenital or acquired hypothyroidism.

  Pituitary Thyrotropin (Thyroid-Stimulating Hormone, TSH) Suppression

  TIROSINT is indicated as an adjunct to surgery and radioiodine therapy in the management of adults and pediatric patients 6 years and older with thyrotropin-dependent well-differentiated thyroid cancer.

  Limitations of Use:

  • TIROSINT 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 may induce hyperthyroidism
    [see Warnings and Precautions (5.4)].
  • TIROSINT is not indicated for treatment of transient hypothyroidism during the recovery phase of subacute thyroiditis.
  )
  
  

• Not indicated for suppression of benign thyroid nodules and nontoxic diffuse goiter in iodine-sufficient patients (
  
  
  
  1 INDICATION AND USAGE

  TIROSINT is L-thyroxine (T4) indicated for adults and pediatric patients 6 years and older with:

  • Hypothyroidism - As replacement therapy in primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) congenital or acquired hypothyroidism
  • Pituitary Thyrotropin (Thyroid-Stimulating Hormone, TSH) Suppression - As an adjunct to surgery and radioiodine therapy in the management of thyrotropin-dependent well-differentiated thyroid cancer

  Limitations of Use:

  • Not indicated for suppression of benign thyroid nodules and nontoxic diffuse goiter in iodine-sufficient patients
  • Not indicated for treatment of transient hypothyroidism during the recovery phase of subacute thyroiditis

  Hypothyroidism

  TIROSINT is indicated as a replacement therapy in adults and pediatric patients 6 years and older with primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) congenital or acquired hypothyroidism.

  Pituitary Thyrotropin (Thyroid-Stimulating Hormone, TSH) Suppression

  TIROSINT is indicated as an adjunct to surgery and radioiodine therapy in the management of adults and pediatric patients 6 years and older with thyrotropin-dependent well-differentiated thyroid cancer.

  Limitations of Use:

  • TIROSINT 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 may induce hyperthyroidism
    [see Warnings and Precautions (5.4)].
  • TIROSINT is not indicated for treatment of transient hypothyroidism during the recovery phase of subacute thyroiditis.
  )
  
  
• Not indicated for treatment of transient hypothyroidism during the recovery phase of subacute thyroiditis (
  
  
  
  1 INDICATION AND USAGE

  TIROSINT is L-thyroxine (T4) indicated for adults and pediatric patients 6 years and older with:

  • Hypothyroidism - As replacement therapy in primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) congenital or acquired hypothyroidism
  • Pituitary Thyrotropin (Thyroid-Stimulating Hormone, TSH) Suppression - As an adjunct to surgery and radioiodine therapy in the management of thyrotropin-dependent well-differentiated thyroid cancer

  Limitations of Use:

  • Not indicated for suppression of benign thyroid nodules and nontoxic diffuse goiter in iodine-sufficient patients
  • Not indicated for treatment of transient hypothyroidism during the recovery phase of subacute thyroiditis

  Hypothyroidism

  TIROSINT is indicated as a replacement therapy in adults and pediatric patients 6 years and older with primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) congenital or acquired hypothyroidism.

  Pituitary Thyrotropin (Thyroid-Stimulating Hormone, TSH) Suppression

  TIROSINT is indicated as an adjunct to surgery and radioiodine therapy in the management of adults and pediatric patients 6 years and older with thyrotropin-dependent well-differentiated thyroid cancer.

  Limitations of Use:

  • TIROSINT 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 may induce hyperthyroidism
    [see Warnings and Precautions (5.4)].
  • TIROSINT is not indicated for treatment of transient hypothyroidism during the recovery phase of subacute thyroiditis.
  )
  
  

• Administer once daily, on an empty stomach, one-half to one hour before breakfast (
  
  
  
  2.1 General Administration Information

  Administer TIROSINT as a single daily oral dose, on an empty stomach, one-half to one hour before breakfast.

  Administer TIROSINT at least 4 hours before or after drugs known to interfere with TIROSINT 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 absorption

  [see Drug Interactions (7.9)and Clinical Pharmacology (12.3)].

  Swallow TIROSINT capsules whole, do not cut, crush, or chew.
  )
  
  
• Administer at least 4 hours before or after drugs that are known to interfere with absorption (
  
  
  
  2.1 General Administration Information

  Administer TIROSINT as a single daily oral dose, on an empty stomach, one-half to one hour before breakfast.

  Administer TIROSINT at least 4 hours before or after drugs known to interfere with TIROSINT 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 absorption

  [see Drug Interactions (7.9)and Clinical Pharmacology (12.3)].

  Swallow TIROSINT capsules whole, do not cut, crush, or chew.
  )
  
  
• Evaluate the need for dose adjustments when regularly administering within an hour of certain foods that may affect TIROSINT absorption (
  
  
  
  2.1 General Administration Information

  Administer TIROSINT as a single daily oral dose, on an empty stomach, one-half to one hour before breakfast.

  Administer TIROSINT at least 4 hours before or after drugs known to interfere with TIROSINT 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 absorption

  [see Drug Interactions (7.9)and Clinical Pharmacology (12.3)].

  Swallow TIROSINT capsules whole, do not cut, crush, or chew.
  )
  
  
• Swallow TIROSINT capsules whole, do not cut, crush, or chew (
  
  
  
  2.1 General Administration Information

  Administer TIROSINT as a single daily oral dose, on an empty stomach, one-half to one hour before breakfast.

  Administer TIROSINT at least 4 hours before or after drugs known to interfere with TIROSINT 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 absorption

  [see Drug Interactions (7.9)and Clinical Pharmacology (12.3)].

  Swallow TIROSINT capsules whole, do not cut, crush, or chew.
  )
  
  
• Starting dose depends on a variety of factors, including age, body weight, cardiovascular status, concomitant medical conditions (including pregnancy), concomitant medications, co-administered food, and the specific nature of the condition being treated. Peak therapeutic effect may not be attained for 4-6 weeks (
  
  
  
  2.2 General Principles of Dosing

  The dose of TIROSINT 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 dose adjustments made based on periodic assessment of the patient's clinical response and laboratory parameters

  [see Dosage and Administration (2.4)].

  The peak therapeutic effect of a given dose of TIROSINT may not be attained for 4 to 6 weeks.
  )
  
  
• See full prescribing information for dosing in specific patient populations (
  
  
  
  2.3 Dosing In Specific Patient Populations

  Primary Hypothyroidism in Adults and in Adolescents in Whom Growth and Puberty are Complete

  Start TIROSINT at the full replacement dose in otherwise healthy, non-elderly individuals who have been hypothyroid for only a short time (such as a few months).The average full replacement dose of TIROSINT is approximately 1.6 mcg per kg per day (for example: 100-125 mcg per day for a 70 kg adult).

  Adjust the dose by 12.5 to 25 mcg increments every 4 to 6 weeks until the patient is clinically euthyroid and the serum TSH returns to normal. Doses greater than 200 mcg per day are seldom required. An inadequate response to daily doses greater than 300 mcg per day is rare and may indicate poor compliance, malabsorption, drug interactions, or a combination of these factors.

  For elderly patients or patients with underlying cardiovascular disease, start with a dose of 12.5 to 25 mcg per day. Increase the dose every 6 to 8 weeks, as needed, until the patient is clinically euthyroid and the serum TSH returns to normal. The full replacement dose of TIROSINT may be less than 1 mcg per kg per day in elderly patients.

  In patients with severe longstanding hypothyroidism, start with a dose of 12.5 to 25 mcg per day. Adjust the dose in 12.5 to 25 mcg increments every 2 to 4 weeks until the patient is clinically euthyroid and the serum TSH level is normalized.

  Secondary or Tertiary Hypothyroidism

  Start TIROSINT at the full replacement dose in otherwise healthy, non-elderly individuals. Start with a lower dose in elderly patients with underlying cardiovascular disease or patients with severe longstanding hypothyroidism as described above. Serum TSH is not a reliable measure of TIROSINT dose adequacy in patients with secondary or tertiary hypothyroidism, and should not be used to monitor therapy. Use the serum free-T4 level to monitor adequacy of therapy in this patient population. Titrate TIROSINT dosing per above instructions until the patient is clinically euthyroid and the serum free-T4 level is restored to the upper half of the normal range.

  Pediatric Dosage - Congenital or Acquired Hypothyroidism

  Only administer TIROSINT to pediatric patients 6 years and older who are able to swallow an intact capsule

  .

  The recommended daily dose of TIROSINT in pediatric patients with hypothyroidism is based on body weight and changes with age as described in Table 1. Start TIROSINT at the full daily dose in most pediatric patients. Start at a lower dose in children at risk for hyperactivity (see below). Monitor for clinical and laboratory response

  [see Dosage and Administration (2.4)]

  .

  Table 1: TIROSINT Dosing Guidelines for Pediatric Hypothyroidism

  Age	Daily Dose Per Kg Body WeightThe dose should be adjusted based on clinical response and laboratory parameters [see Dosage and Administration (2.4) and Use in Specific Populations (8.4)] .
  6-12 years	4-5 mcg/kg/day
  Greater than 12 years but growth and puberty incomplete	2-3 mcg/kg/day
  Growth and puberty complete	1.6 mcg/kg/day

  Children at risk for hyperactivity

  : To minimize the risk of hyperactivity in children, start at one-fourth the recommended full replacement dose, and increase on a weekly basis by one-fourth the full-recommended replacement dose until the full recommended replacement dose is reached.

  Pregnancy

  Preexisting Hypothyroidism:

  TIROSINT dose requirements may increase during pregnancy

  .

  Measure serum TSH and free-T4 as soon as pregnancy is confirmed and, at a minimum, during each trimester of pregnancy. In patients with primary hypothyroidism, maintain serum TSH in the trimester-specific reference range. For patients with serum TSH above the normal trimester specific range, increase the dose of TIROSINT by 12.5 to 25 mcg per day and measure TSH every four weeks until a stable TIROSINT dose is reached and serum TSH is within the normal trimester specific range. Reduce TIROSINT dosage to pre-pregnancy levels immediately after delivery and measure serum TSH levels 4 to 8 weeks postpartum to ensure the TIROSINT dose is appropriate.

  New Onset Hypothyroidism:

  Normalize thyroid function as rapidly as possible. In patients with moderate to severe signs and symptoms of hypothyroidism, start TIROSINT at the full replacement dose (1.6 mcg per kg body weight per day). In patients with mild hypothyroidism (TSH < 10 mIU per Liter), start TIROSINT at 1.0 mcg per kg body weight per day. Evaluate serum TSH every 4 weeks and adjust TIROSINT dosage until serum TSH is within the normal trimester specific range

  [see Use in Specific Populations (8.1)].

  TSH Suppression in Well-Differentiated Thyroid Cancer

  Generally, TSH is suppressed to below 0.1 mIU per Liter, and this usually requires a TIROSINT dose of greater than 2 mcg per kg per day. However, in patients with high-risk tumors, the target level for TSH suppression may be lower.
  )
  
  
• Adequacy of therapy determined with periodic monitoring of TSH and/or T4 as well as clinical status (
  
  
  
  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 may be evidence of inadequate absorption, poor compliance, drug interactions, or a combination of these factors.

  Adults

  In adult patients with primary hypothyroidism, monitor serum TSH levels after an interval of 6 to 8 weeks after any change in dose. In patients on a stable and appropriate replacement dose, evaluate clinical and biochemical response every 6 to 12 months and whenever there is a change in the patient's clinical status.

  Pediatrics

  In patients with congenital hypothyroidism, assess the adequacy of replacement therapy by measuring both serum TSH and total or free-T4. Monitor TSH and total or free-T4 in children is as follows: at 2 and 4 weeks after the initiation of treatment 2 weeks after any change in dosage, and then every 3 to 12 months thereafter following dose stabilization until growth is completed. Poor compliance or abnormal values may necessitate more frequent monitoring. Perform routine clinical examination, including assessment of mental and physical growth and development, and bone maturation at regular intervals.

  While the general aim of therapy is to normalize the serum TSH level, TSH may not normalize in some patients due to

  in utero

  hypothyroidism causing a resetting of the pituitary-thyroid feedback. Failure of the serum T4 to increase into the upper half of the normal range within 2 weeks of initiation of TIROSINT therapy and/or of the serum TSH to decrease below 20 mIU per Liter within 4 weeks may indicate the child is not receiving adequate therapy. Assess compliance, dose of medication administered, and method of administration prior to increasing the dose of TIROSINT

  [see Warnings and Precautions (5.4)and Use in Specific Populations (8.4)]

  .

  Secondary (Pituitary) and Tertiary (Hypothalamic) Hypothyroidism

  Monitor serum free-T4 levels maintain in the upper half of the normal range in these patients.
  )
  
  

TIROSINT capsules are amber-colored, round/biconvex capsules, imprinted with a dosage strength specific letter on one side and containing a viscous amber-colored liquid and are available as follows:

Pregnancy may require the use of higher doses of TIROSINT (