1. Name of the medicinal product

Levothyroxine Sodium for Injection USP 100mcg/Vial Taj Pharma
Levothyroxine Sodium for Injection USP 200mcg/Vial Taj Pharma
Levothyroxine Sodium for Injection USP 500mcg/Vial Taj Pharma

  1. Qualitative and quantitative composition

a) Levothyroxine Sodium for Injection USP 100mcg/Vial Taj Pharma
Each Vial contains:
Levothyroxine Sodium USP 100mcg
Excipients: Q.S.

b) Levothyroxine Sodium for Injection USP 200mcg/Vial Taj Pharma
Each Vial contains:
Levothyroxine Sodium USP 200mcg
Excipients: Q.S.

c) Levothyroxine Sodium for Injection USP 500mcg/Vial Taj Pharma
Each Vial contains:
Levothyroxine Sodium USP 500mcg
Excipients: Q.S.

3. Pharmaceutical form

Lyophilized Powder for Injection

PART I: HEALTH PROFESSIONAL INFORMATION 

SUMMARY PRODUCT INFORMATION 

Route of Administration Dosage Form/ Strength Clinically Relevant Nonmedicinal Ingredients
Injection (intravenous or intramuscular) Lyophilized Powder100mcg/vial 200mcg/vial, 500mcg/vial Mannitol, dibasic sodium phosphate heptahydrate, and sodium hydroxide.

INDICATIONS AND CLINICAL USE 

Levothyroxine Taj Pharma Sodium for Injection is indicated for: 

  • Replacement or supplemental therapy in congenital or acquired hypothyroidism of any etiology, except transient hypothyroidism during the recovery phase of subacute thyroiditis. Specific indications include: primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) hypothyroidism. Primary hypothyroidism may result from functional deficiency, primary atrophy, partial or total congenital absence of the thyroid gland, or from the effects of surgery, radiation, or drugs, with or without the presence of goiter.

Pediatrics: Levothyroxine Taj Pharma Sodium for Injection is approved for use in the pediatric population. However, dosing and monitoring considerations apply (see DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment, Pediatric Dosage).

Geriatrics: Levothyroxine Taj Pharma Sodium for Injection is approved for use in the geriatric population. However, dosing precautions apply (see DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment, Geriatric Dosage). 

CONTRAINDICATIONS 

  • Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see DOSAGE FORMS, COMPOSITION AND PACKAGING.
  • Patients with untreated subclinical (suppressed serum TSH level with normal T3 and T4 levels) or overt thyrotoxicosis of any etiology.
  • Patients with acute myocardial infarction, acute myocarditis, or acute pancarditis.
  • Patients with uncorrected adrenal insufficiency since thyroid hormones may precipitate an acute adrenal crisis by increasing the metabolic clearance of glucocorticoids (see WARNINGS AND PRECAUTIONS, Immune, Autoimmune Polyglandular Syndrome).
  • Combination therapy of Levothyroxine Taj Pharma Sodium for Injection and an antithyroid agent for hyperthyroidism during pregnancy (see WARNINGS AND PRECAUTIONS, Special Populations, Pregnant Women).

WARNINGS AND PRECAUTIONS 

Serious Warnings and Precautions Thyroid hormones, including Levothyroxine Taj Pharma, 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.

General

Levothyroxine Taj Pharma has a narrow therapeutic index. Regardless of the indication for use, careful dosage titration is necessary to avoid the consequences of over- or undertreatment. 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 Taj Pharma sodium, necessitating adjustments in dosing to maintain therapeutic response (see DRUG INTERACTIONS, Drug-Drug Interactions).

Before starting therapy with thyroid hormones or before performing a thyroid suppression test, the following diseases or medical conditions must be excluded or treated: coronary failure, angina pectoris, arteriosclerosis, hypertension, pituitary insufficiency, or adrenal insufficiency. Thyroid autonomy should also be excluded or treated before starting therapy with thyroid hormones.

The etiology of secondary hypothyroidism must be determined before thyroid hormone replacement therapy is given. If necessary, replacement treatment of a compensated adrenal insufficiency must be commenced.

Levothyroxine Taj Pharma Sodium for Injection therapy for patients with previously undiagnosed endocrine disorders, including adrenal insufficiency, hypopituitarism, and diabetes insipidus, may worsen symptoms of these endocrinopathies.

Seizures have been reported rarely in association with the initiation of Levothyroxine Taj Pharma sodium therapy, and may be related to the effect of thyroid hormone on seizure threshold.

Carcinogenesis and Mutagenesis
Although animal studies to determine the mutagenic or carcinogenic potential of thyroid hormones have not been performed, synthetic T4 is identical to that produced by the human thyroid gland. A reported association between prolonged thyroid hormone therapy and breast cancer has not been confirmed and patients receiving Levothyroxine Taj Pharma for established indications should not discontinue therapy.

Cardiovascular
Overtreatment with Levothyroxine Taj Pharma 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. If cardiac symptoms develop or worsen, the Levothyroxine Taj Pharma dose should be reduced. Patients with coronary artery disease who are receiving Levothyroxine Taj Pharma therapy should be monitored closely during surgical procedures, since the possibility of precipitating cardiac arrhythmias may be greater in those treated with Levothyroxine Taj Pharma. Concomitant administration of Levothyroxine Taj Pharma and sympathomimetic agents to patients with coronary artery disease may precipitate coronary insufficiency. Hence, frequent checks of thyroid hormone parameters must be performed in these cases.

Exercise caution when administering Levothyroxine Taj Pharma to patients with cardiovascular disorders and to the elderly in whom there is an increased risk of occult cardiac disease. In these patients, Levothyroxine Taj Pharma therapy should be initiated at lower doses than those recommended in younger individuals or in patients without cardiac disease (see WARNINGS AND PRECAUTIONS, Special Populations, Geriatric Use and DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment, Geriatric Dosage).

Endocrine and Metabolism
Hypothalamic/Pituitary Hormone Deficiencies: In patients with secondary or tertiary hypothyroidism, additional hypothalamic/pituitary hormone deficiencies should be considered, and, if diagnosed, treated for adrenal insufficiency (see WARNINGS AND PRECAUTIONS, Immune, Autoimmune Polyglandular Syndrome). 

Levothyroxine Taj Pharma sodium is not recommended in hyperthyroid metabolic states. An exception is the concomitant supplementation during anti-thyroid drug treatment of hyperthyroidism.

Bone Mineral Density: In women, long-term Levothyroxine Taj Pharma 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 Taj Pharma sodium. In postmenopausal women with hypothyroidism and an increased risk of osteoporosis supra-physiological serum levels of Levothyroxine Taj Pharma sodium have to be avoided and close monitoring of the thyroid function is recommended. Therefore, it is recommended that patients receiving Levothyroxine Taj Pharma sodium be given the minimum dose necessary to achieve the desired clinical and biochemical response.

Immune
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 Taj Pharma 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 Taj Pharma (see DRUG INTERACTIONS, Drug- Drug Interactions).

Hematologic
T4 enhances the response to anticoagulant therapy. Prothrombin time should be closely monitored in patients taking both Levothyroxine Taj Pharma and oral anticoagulants, and the dosage of anticoagulant adjusted accordingly (see DRUG INTERACTIONS, Drug-Drug Interactions).

Psychiatric
When initiating Levothyroxine Taj Pharma therapy in patients at risk of psychotic disorders, it is recommended to start at a low Levothyroxine Taj Pharma dose and to slowly increase the dosage at the beginning of the therapy. Monitoring of the patient is advised. If signs of psychotic disorders occur, adjustment of the dose of Levothyroxine Taj Pharma should be considered.

Sexual Function/Reproduction
Levothyroxine Taj Pharma sodium should not be used in the treatment of male or female infertility unless this condition is associated with hypothyroidism. Animal studies have not been performed to evaluate the effects of Levothyroxine Taj Pharma on fertility.

Special Populations
Pregnant Women:
Studies in women taking Levothyroxine Taj Pharma sodium during pregnancy have not shown an increased risk of congenital abnormalities. Levothyroxine Taj Pharma 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 Taj Pharma should have their TSH measured during each trimester. An elevated serum TSH level should be corrected by an increase in the dose of Levothyroxine Taj Pharma. Since postpartum TSH levels are similar to preconception values, the Levothyroxine Taj Pharma 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.

Combination therapy of Levothyroxine Taj Pharma and an antithyroid agent for hyperthyroidism is contraindicated during pregnancy (see CONTRAINDICATIONS). Such combination would require higher doses of anti-thyroid agents, which are known to pass the placenta and to induce hypothyroidism in the infant.

Nursing Women: Adequate replacement doses of Levothyroxine Taj Pharma are generally needed to maintain normal lactation. Although thyroid hormones are excreted only minimally in human milk, caution should be exercised when Levothyroxine Taj Pharma is administered to a nursing woman.

Pediatrics: The presence of concomitant medical conditions should be considered in certain clinical circumstances and, if present, appropriately treated (see WARNINGS AND PRECAUTIONS, General).

The patient should be monitored closely to avoid undertreatment or overtreatment. Undertreatment may have deleterious effects on intellectual development, concentration and 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.

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.

Congenital Hypothyroidism
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.

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 Taj Pharma therapy should be initiated immediately upon diagnosis and is generally continued for life.

During the first 2 weeks of Levothyroxine Taj Pharma therapy, infants should be closely monitored for cardiac overload, arrhythmias, and aspiration from avid suckling.

Acquired Hypothyroidism in Pediatric Patients
If transient hypothyroidism is suspected, hypothyroidism permanence may be assessed after the child reaches 3 years of age. Levothyroxine Taj Pharma therapy may be interrupted for 30 days and serum T4 and TSH measured. Low T4 and elevated TSH confirm permanent hypothyroidism; therapy should be re-instituted. If T4 and TSH remain in the normal range, a presumptive diagnosis of transient hypothyroidism can be made. In this instance, continued clinical monitoring and periodic thyroid function test re-evaluation may be warranted.

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 Taj Pharma 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 Taj Pharma treatment should be discontinued for another 30-day trial period followed by repeat serum T4 and TSH testing.

Geriatric Use:
Because of the increased prevalence of cardiovascular disease among the elderly, Levothyroxine Taj Pharma therapy should not be initiated at the full replacement dose. Atrial fibrillation is a common side effect associated with Levothyroxine Taj Pharma treatment in the elderly (see WARNINGS  AND PRECAUTIONS, Cardiovascular, and DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment, Geriatric Dosage).

Monitoring and Laboratory Tests
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 (see DRUG INTERACTIONS, Drug-Drug Interactions and Drug-Laboratory Interactions). Persistent clinical and laboratory evidence of hypothyroidism despite an apparent adequate replacement dose of Levothyroxine Taj Pharma may be evidence of inadequate absorption, poor compliance, drug interactions, or decreased T4 potency of the drug product.

Where thyroid autonomy is suspected, a Thyroid Releasing Hormone (TRH) test or a suppression scintigram is recommended before initiation of treatment.

Adequacy of Levothyroxine Taj Pharma sodium therapy for hypothyroidism of pituitary or hypothalamic origin should be assessed by measuring free T4, which should be maintained in the upper half of the normal range. Measurement of TSH is not a reliable indicator of response to therapy for this condition.

Adults:
In adult patients with primary (thyroidal) hypothyroidism, serum TSH levels alone may be used to monitor therapy. The frequency of TSH monitoring during Levothyroxine Taj Pharma dose titration depends on the clinical situation but it is generally recommended at 6 – 8 week intervals until normalization. For patients who have recently initiated Levothyroxine Taj Pharma therapy and whose serum TSH has normalized, or in patients who have had their dosage of Levothyroxine Taj Pharma changed, the serum TSH concentration should be measured after 8 – 12 weeks. When the optimum replacement dose has been attained, clinical (physical examination) and biochemical monitoring may be performed every 6 – 12 months, depending on the clinical situation, and whenever there is a change in the patient’s status

Pediatrics:
Congenital Hypothyroidism: Adequacy of replacement therapy should be assessed by measuring both serum TSH 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 Taj Pharma therapy and/or of the serum TSH to decrease below 20 mIU/L within 4 weeks should alert the physician to the possibility that the child is not receiving adequate therapy.

The recommended frequency of monitoring of TSH and total- or free-T4 in children is as follows: at 2 and 4 weeks after the initiation of treatment; every 1 – 2 months during the first year of life; every 2 – 3 months between 1 and 3 years of age; and every 3 – 12 months thereafter until growth is completed. More frequent intervals of monitoring may be necessary if 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 Taj Pharma dosage. Routine clinical examination, including assessment of mental and physical growth and development, and bone maturation, should be performed at regular intervals (see DOSAGE AND ADMINISTRATION, Dosing Considerations).

Secondary (Pituitary) and Tertiary (Hypothalamic) Hypothyroidism: Adequacy of therapy should be assessed by measuring serum free-T4 levels, which should be maintained in the upper half of the normal range in these patients. Measurement of TSH is not a reliable indicator of response to therapy for this condition

ADVERSE REACTIONS 

Adverse Drug Reaction Overview 

Adverse reactions associated with Levothyroxine Taj Pharma therapy are primarily those of hyperthyroidism due to therapeutic overdosage.

Nervous system:
headache, hyperactivity, nervousness, restlessness, anxiety, irritability, emotional lability, insomnia, pseudotumour cerebri, seizures;

Musculoskeletal:  tremors, muscle weakness, cramps, slipped capital femoral epiphysis, craniosynostosis (with reduced adult height);

Cardiovascular: palpitations, tachycardia, cardiac arrhythmias (e.g., atrial fibrillation and extrasystoles), increased pulse and blood pressure, heart failure, angina pectoris, myocardial infarction, cardiac arrest;

Respiratory: dyspnea;

Gastrointestinal:
diarrhea, vomiting, abdominal cramps and elevations in liver function tests;

Dermatologic: hair loss, flushing; Endocrine: decreased bone mineral density;

Reproductive:  menstrual irregularities, impaired fertility;
Immune: hypersensitivity reactions (urticaria, pruritus, skin rash, flushing, angioedema, various abdominal pain, nausea, vomiting and diarrhea, fever, arthralgia, serum sickness and wheezing).
Other: fatigue, increased appetite, weight loss, heat intolerance, fever, excessive sweating, exophthalmic goiter, pseudotumor cerebri (in children).

Clinical signs of hyperthyroidism may occur in case of overdose, if the individual tolerance limit for Levothyroxine Taj Pharma sodium is exceeded, or if the dose is increased too fast at the start of treatment. In such cases the daily dose has to be reduced or the medication withdrawn for several days. Therapy may carefully be resumed once the adverse reactions have disappeared (see OVERDOSAGE).

DRUG INTERACTIONS

Overview
Many drugs affect thyroid hormone pharmacokinetics and metabolism (e.g., absorption, synthesis, secretion, catabolism, protein binding, and target tissue response) and may alter the therapeutic response to Levothyroxine Taj Pharma. In addition, thyroid hormones and thyroid status have varied effects on the pharmacokinetics and actions of other drugs. A listing of drug-thyroidal axis interactions is contained in Table 1.

Drug-Drug Interactions
The list of drug-thyroidal axis interactions in Table 1 may not be comprehensive due to the introduction of new drugs that interact with the thyroidal axis or the discovery of previously unknown interactions.

Table 1: Established or Potential Drug-Drug Interactions 

Drug or Drug Class Ref Effect Clinical Comment 
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine

Agonists Glucocorticoids Octreotide

CT Use of these agents may result in a transient reduction in TSH secretion. Reduction when administered at the following doses: Dopamine (≥ 1mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide CT Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents.
Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients.
The fetus, neonate, elderly and

euthyroid patients with

underlying thyroid disease (e.g.,

Hashimoto’s thyroiditis or with

Graves’ disease previously

treated with radioiodine or

surgery) are among those

individuals who are particularly susceptible to iodine-induced hypothyroidism.

Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing radiographic contrast agents) Sertraline Chloroquinone Proguanil CT Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Graves’ disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma).
Sertraline, Chloroquinone / Proguanil decrease the efficacy of Levothyroxine Taj Pharma sodium and increase the serum TSH level.
Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may alter T4 and T3 serum transport – but FT4 concentration remains normal; therefore, the patient remains euthyroid
Clofibrate Estrogen-containing oral  contraceptives Estrogens (oral) Heroin/Methadone 5-Fluorouracil Mitotane Tamoxifen Increase serum TBG concentration N/A
Androgens/Anabolic Steroids Asparaginase Glucocorticoids Slow-release Nicotinic Acid Decrease serum TBG concentration N/A
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg i.v.) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs – Fenamates Phenylbutazone Salicylates (> 2 g/day) Dicumarol Furosemide in high doses (250mg) Clofibrate Administration of these agents with Levothyroxine Taj Pharma results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total- T4 levels may decrease by as much 30%.
Drugs that may alter T4 and T3 metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins (e.g. Phenytoin) Barbiturates (e.g. Phenobarbital) Rifampin CT Stimulation of hepatic microsomal drug-metabolizing enzyme activity by drugs like phenytoin may cause increased hepatic degradation/ clearance of Levothyroxine Taj Pharma, resulting in increased Levothyroxine Taj Pharma requirements. On the other hand, phenytoin may influence the effect of Levothyroxine Taj Pharma sodium by displacing Levothyroxine Taj Pharma sodium from plasma proteins resulting in an elevated fT4 and fT3 fraction. Carbamazepine reduces serum protein binding of Levothyroxine Taj Pharma, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. N/A

 

Drugs that may decrease T4 5’-deiodinase activity
Iodine containing contrast media Amiodarone

Beta adrenergic antagonists/ beta sympatholytics

– (e.g., Propranolol > 160 mg/day) Glucocorticoids

– (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)

CT Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid.
Due to its high iodine content amiodarone can trigger hyperthyroidism as well as hypothyroidism.
It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased decreased TTBG 3 and production T4 levels due (see to above).

In Levothyroxine Taj Pharma patients with concomitant use of Amiodarone, particular caution is advised in the case of nodular goiter with possibly unrecognised autonomy.

 

Miscellaneous
Anticoagulants (oral)

– Coumarin Derivatives

– Indandione Derivatives

CT Levothyroxine Taj Pharma sodium may intensify the effect of anticoagulants by displacing them from plasma protein bounds which may increase the risk of haemorrhage, e.g. CNS or gastrointestinal bleeding, especially in elderly patients. Thyroid hormones appear to increase the catabolism of vitamin K- dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Check the coagulation parameters regularly at the start of and during concomitant therapy. Prothrombin time can be carefully monitored in patients taking Levothyroxine Taj Pharma and if necessary, the anticoagulant dose has to be altered.

 

Antidepressants

– Tricyclics (e.g., Amitriptyline) – Tetracyclics (e.g., Maprotiline)
– Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline, chloroquine/proguanil)

CT Concurrent use of tri/tetracyclic antidepressants and Levothyroxine Taj Pharma 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 CNS stimulation; onset of action of tricyclics may be accelerated.

Sertraline, chloroquine/proguanil: these substances decrease the efficacy of Levothyroxine Taj Pharma sodium and increase the serum TSH level.

Antidiabetic Agents

– Biguanides – Meglitinides – Sulfonylureas – Thiazolidediones – Insulin

CT Levothyroxine Taj Pharma sodium may reduce the effect of anti-diabetics. If necessary, the anti-diabetic dose has to be adjusted. It is necessary to check blood glucose levels frequently at the start of thyroid hormone therapy or when thyroid hormone therapy is changed or discontinued.

 

Digitalis Glycosides CT Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state necessitating an increase in the dose of digitalis glycosides. Therapeutic effect of digitalis glycosides may be reduced by Levothyroxine Taj Pharma sodium.
Cytokines CT Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients, and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones – Somatrem – Somatropin CT Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. Untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine CT Concurrent use may produce marked hypertension and tachycardia. Cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine

Bronchodilators – (e.g., Theophylline)

CT CT Decreased theophylline clearance may occur in hypothyroid patients. Clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents CT Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. N/A
Estrogens CT Women using estrogen-containing contraceptives or postmenopausal women under hormone -replacement therapy may have an increased need for Levothyroxine Taj Pharma sodium. N/A
Protease inhibitors CT Protease indinavir, inhibitors lopinavir) (e.g. may ritonavir, influence the effect of Levothyroxine Taj Pharma sodium. Close monitoring of thyroid hormone parameters is recommended. If necessary, the Levothyroxine Taj Pharma sodium dose has to be adjusted.
Proton Pump Inhibitors T Plasma concentration of Levothyroxine Taj Pharma (thyroxine) is possibly reduced by Proton Pump Inhibitors. Monitoring of TSH plasma level is recommended.
Sympathomimetics CT Concurrent use 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.
Tyrosine-kinase inhibitors CT Tyrosine-kinase imatinib, sunitinib) inhibitors may decrease (e.g.  The efficacy of Levothyroxine Taj Pharma sodium. Therefore, it is recommended that patients are monitored for changes in thyroid function at the start or end of concomitant treatment. If necessary, the Levothyroxine Taj Pharma sodium dose has to be adjusted.
Orlistat n/a Hypothyroidism and / or reduced control of hypothyroidism may occur when orlistat and Levothyroxine Taj Pharma are co-administered Patients taking orlistat with Levothyroxine Taj Pharma should take the drugs at separate times. Thyroid hormone levels should be monitored more closely as the dose may need to be adjusted
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics CT These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. N/A

Legend: C = Case Study; CT = Clinical Trial; T = Theoretical

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Interactions A number of drugs or moieties are known to alter serum levels of TSH, T4 and T3 and may thereby influence the interpretation of laboratory tests of thyroid function (see Table 1).

Changes in Thyroid-Binding Globule (TBG) concentration must be considered when interpreting T4 and T3 values, which necessitates measurement and evaluation of unbound (free) hormone and/or determination of the free-T4 index (FT4I). Pregnancy, infectious hepatitis, estrogens, estrogen-containing oral contraceptives, and acute intermittent porphyria increase TBG concentrations. Decreases in TBG concentrations are observed in nephrosis, severe hypoproteinemia, severe liver disease, acromegaly, and after androgen or glucocorticoid therapy (see Table 1).

DOSAGE AND ADMINISTRATION 

Dosing Considerations
The goal of replacement therapy is to achieve and maintain a clinical and biochemical euthyroid state.

The dose of Levothyroxine Taj Pharma that is adequate to achieve these goals depends on a variety of factors including the patient’s age, body weight, cardiovascular status, concomitant medical conditions, including pregnancy, concomitant medications, and the specific nature of the condition being treated . Dosing must be individualized and adjustments made based on periodic assessment of the patient’s clinical response and laboratory parameters (see WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests, General).

Recommended Dose and Dosage Adjustment

The initial parenteral dosage should be approximately one-half the previously established oral dosage of Levothyroxine Taj Pharma sodium tablets.

Clinical and laboratory evaluations should generally be performed at 6 to 8 week intervals (2 to 4 weeks in severely hypothyroid patients), and the dosage adjusted, if necessary, until the serum TSH concentration is normalized and signs and symptoms resolve (see WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests, ).

If cardiac symptoms develop or worsen, the cardiac disease should be evaluated and the dose of Levothyroxine Taj Pharma reduced (see WARNINGS AND PRECAUTIONS, Cardiovascular). Rarely, worsening angina or other signs of cardiac ischemia may prevent achieving a TSH in the normal range.

In the elderly, the full replacement dose may be altered by decreases in T4 metabolism.

Pediatric Dosage – Congenital or Acquired Hypothyroidism The aim of therapy is to achieve and maintain normal growth and development. Delays in diagnosis and institution of therapy may have deleterious effects on the child’s intellectual and physical growth and development. During the first three years of life, serum T4 concentrations should be maintained in the upper half of the normal range and, if possible, serum TSH should be normalized. Undertreatment and overtreatment should be avoided. (See WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests, Pediatrics.). 

Geriatric Dosage
Because of the increased prevalence of cardiovascular disease among the elderly, Levothyroxine Taj Pharma therapy should not be initiated at the full replacement dose (see WARNINGS AND PRECAUTIONS, Cardiovascular).

Pregnancy

Treatment with thyroid hormones is given consistently during pregnancy. . Pregnancy may increase Levothyroxine Taj Pharma sodium requirements (see WARNINGS AND PRECAUTIONS, Special Populations, Pregnant Women)

There is no evidence of drug-induced teratogenicity and/or feto-toxicity in humans at the recommended therapeutic dose level. Excessively high dose levels of Levothyroxine Taj Pharma sodium during pregnancy may have a negative effect on fetal and postnatal development.

Lactation Adequate replacement doses of Levothyroxine Taj Pharma are generally needed to maintain normal lactation. Treatment with thyroid hormones is given consistently during lactation. Levothyroxine Taj Pharma sodium is secreted into breast milk during lactation but the concentrations achieved at the recommended therapeutic dose level are not sufficient to cause development of hyperthyroidism or suppression of TSH secretion in the infant.

Myxedema Coma

Myxedema coma represents the extreme expression of severe hypothyroidism and is considered a life-threatening medical emergency. It is characterized by hypothermia, hypotension, hypoventilation, hyponatremia, and bradycardia. In addition to restoration of normal thyroid hormone levels, therapy should be directed at the correction of electrolyte disturbances and possible infection. Because the mortality rate of patients with untreated myxedema coma is high, treatment must be started immediately, and should include appropriate supportive therapy and corticosteroids to prevent adrenal insufficiency. Possible precipitating factors should also be identified and treated.

A bolus dose of Levothyroxine Taj Pharma sodium is given immediately to replete the peripheral pool of T4, usually 300 to 500mcg. Although such a dose is usually well tolerated even in the elderly, the rapid intravenous administration of large doses of Levothyroxine Taj Pharma sodium to patients with cardiovascular disease is not without risks. Under such circumstances, intravenous therapy should not be undertaken without weighing the alternate risks of myxedema coma and the cardiovascular disease. Clinical judgment in this situation may dictate smaller intravenous doses of Levothyroxine Taj Pharma sodium. The initial dose is followed by daily intravenous doses of 75 to 100mcg until the patient is stable and oral administration is feasible. Normal T4 levels are usually achieved in 24 hours, followed by progressive increases in T3. Improvement in cardiac output, blood pressure, temperature, and mental status generally occur within 24 hours, with improvement in many manifestations of hypothyroidism in 4 to 7 days.

Administration

Levothyroxine Taj Pharma Sodium for Injection can be used intravenously in place of the oral dosage form when rapid repletion is required. It can also be used intravenously or intramuscularly when oral administration is precluded.

Administration of Levothyroxine Taj Pharma Sodium for Injection by the subcutaneous route is not recommended as studies have shown that the influx of T4 from the subcutaneous site is very slow, and depends on many factors such as volume of injection, the anatomic site of injection, ambient temperature, and presence of vasospasm.

Due to the long half-life of Levothyroxine Taj Pharma, the peak therapeutic effect at a given dose of Levothyroxine Taj Pharma sodium may not be attained for 4 – 6 weeks.

Caution should be exercised when administering Levothyroxine Taj Pharma to patients with underlying cardiovascular disease, to the elderly, and to those with concomitant adrenal insufficiency (see WARNINGS AND PRECAUTIONS, Cardiovascular). 

Reconstitution

Reconstitute the lyophilized Levothyroxine Taj Pharma sodium by aseptically adding 5 mL of 0.9% Sodium Chloride Injection, USP only. Do not use Bacteriostatic Sodium Chloride Injection, USP, as the bacteriostatic agent may interfere with complete reconstitution. Shake vial to ensure complete mixing. Use immediately after reconstitution. Do not add to other intravenous fluids.

Levothyroxine Taj Pharma Sodium for Injection comes in a single-dose vial, and any unused portion should be discarded.

As with all parenteral products, intravenous admixtures should be inspected for clarity of solutions, particulate matter, precipitate, discolouration, and leakage prior to administration whenever solution and container permit. Solutions showing haziness, particulate matter, precipitate, discolouration or leakage should not be used.

Missed Dose

The missed dose should be administered as soon as possible. If it is almost time for the next dose, the missed dose should not be taken. Instead, the next regularly scheduled dose should be administered. Doses should not be doubled.

OVERDOSAGE

The signs and symptoms of overdosage are those of hyperthyroidism (see ADVERSE REACTIONS, Adverse Drug Reaction Overview). Overdose may cause symptoms of a significant increase in the metabolic rate. In addition, confusion and disorientation may occur. Cerebral embolism, shock, coma, and death have been reported. Levothyroxine Taj Pharma overdose may also lead to symptoms of acute psychosis, especially in patients at risk of psychotic disorders .Symptoms may appear several days after the overdose of Levothyroxine Taj Pharma sodium. Several cases of sudden cardiac death have also been reported in patients with many years of Levothyroxine Taj Pharma sodium abuse.

An elevated T3 level is a reliable indicator of overdose, more so than elevated T4 or f T4 levels.

Depending on the extent of the overdose it is recommended that treatment is interrupted and that thyroid hormone monitored.

For management of a suspected drug overdose contact your regional Poison Control Centre. 


Acute Massive Overdosage:

This may be a life-threatening emergency; therefore, symptomatic and supportive therapy should be instituted immediately. Beta-sympathomimetic effects or central and peripheral increased sympathetic activity such as tachycardia, anxiety, agitation or hyperkinesia may be treated by administering betablockers, e.g., propranolol, provided that there are no medical contraindications to their use. Provide respiratory support as needed; control congestive heart failure and arrhythmia; control fever, hypoglycemia, and fluid loss as necessary. Large doses of antithyroid drugs (e.g., methimazole or propylthiouracil) followed in one to two hours by large doses of iodine may be given to inhibit synthesis and release of thyroid hormones. Glucocorticoids may be given to inhibit the conversion of T4 to T3. Plasmapheresis, charcoal hemoperfusion and exchange transfusion have been reserved for cases in which continued clinical deterioration occurs despite conventional therapy. Due to its high protein binding, Levothyroxine Taj Pharma sodium cannot be eliminated via hemodialysis or hemoperfusion.

ACTION AND CLINICAL PHARMACOLOGY 

Pharmacodynamics

Levothyroxine Taj Pharma Sodium for Injection contains synthetic crystalline L-3,3’,5,5’-tetraiodothyronine sodium salt [Levothyroxine Taj Pharma (T4) sodium]. Synthetic T4 is identical to that produced in the human thyroid gland.

Thyroid hormone synthesis and secretion is regulated by the hypothalamic-pituitary-thyroid axis. Thyrotropin-releasing hormone (TRH) released from the hypothalamus stimulates secretion of thyrotropin-stimulating hormone, TSH, from the anterior pituitary. TSH, in turn, is the physiologic stimulus for the synthesis and secretion of thyroid hormones, L-thyroxine (T4) and L-triiodothyronine (T3), by the thyroid gland. Circulating serum T3 and T4 levels exert a feedback effect on both TRH and TSH secretions. When serum T3 and T4 levels increase, TRH and TSH secretions decrease. When thyroid hormone levels decrease, TRH and TSH secretions increase.

The mechanisms by which thyroid hormones exert their physiologic actions are not completely understood, but it is thought that their principal effects are exerted through control of DNA transcription and protein synthesis. T3 and 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.

Thyroid hormones regulate multiple metabolic processes and play an essential role in normal growth and development, and normal maturation of the central nervous system and bone. The metabolic actions of thyroid hormones include augmentation of cellular respiration and thermogenesis, as well as metabolism of proteins, carbohydrates and lipids. The protein anabolic effects of thyroid hormones are essential to normal growth and development.

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. Levothyroxine Taj Pharma, at doses individualized according to patient response, is effective as replacement or supplemental therapy in hypothyroidism of any etiology, except transient hypothyroidism during the recovery phase of subacute thyroiditis.

Pharmacokinetics

Distribution: Circulating thyroid hormones are greater than 99% bound to plasma proteins, including thyroxine-binding globulin (TBG), thyroxine-binding pre-albumin (TBPA), and albumin (TBA), whose capacities and affinities vary for each hormone. The higher affinity of both TBG and TBPA for T4 partially explains the higher serum levels, slower metabolic clearance, and longer half-life of T4 compared to T3. 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 affect the binding of thyroid hormones to serum proteins (see DRUG INTERACTIONS, Drug-Drug Interactions and Drug-Laboratory Interactions). Thyroid hormones do not readily cross the placental barrier (see WARNINGS AND PRECAUTIONS, Special Populations, Pregnant Women). 

Metabolism: T4 is slowly eliminated (see Table 2). The major pathway of thyroid hormone metabolism is through sequential deiodination. Approximately 80% of circulating T3 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 (rT3). T3 and rT3 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.

Excretion: 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 T4 is eliminated in the stool. Urinary excretion of T4 decreases with age.

Table 2: Pharmacokinetic Parameters of Thyroid Hormones in Euthyroid Patients

Hormone Ratio in Thyroglobulin Biologic Potency t1⁄2 (days) Protein Binding  (%)2
Levothyroxine Taj Pharma (T4) Liothyronine (T3) 10-20

1

1

4

6-7

≤2

99.96

99.5

 

STORAGE AND STABILITY

Store at controlled room temperature between 15 and 30°C, protected from light. Single-dose vial. Use immediately after reconstitution. Discard any unused portion. Keep in a safe place out of the reach of children.

DOSAGE FORMS, COMPOSITION AND PACKAGING 

Composition

Medicinal Ingredients: synthetic crystalline Levothyroxine Taj Pharma sodium, USP

Non-medicinal Ingredients: mannitol, dibasic sodium phosphate heptahydrate and sodium hydroxide.

Dosage Forms

Levothyroxine Taj Pharma Sodium for Injection is a sterile lyophilized powder for reconstitution. It is supplied in 5 to 10mL single-dose vials:
Levothyroxine Taj Pharma 100mcg Levothyroxine Taj Pharma sodium, USP in 5 to 10 mL vials packaged individually. Levothyroxine Taj Pharma 200mcg Levothyroxine Taj Pharma sodium, USP in 5 to 10 mL vials packaged individually.
Levothyroxine Taj Pharma 500mcg Levothyroxine Taj Pharma sodium, USP in 5 to 10 mL vials packaged individually.

Not all pack sizes may be marketed.

Manufactured in India by:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825) Monday through Saturday 9:00 a.m. to 7:00 p.m. EST E-mail: tajgroup@tajpharma.com

PART II: SCIENTIFIC INFORMATION 

PHARMACEUTICAL INFORMATION 

Drug Substance

Sodium Levothyroxine Taj Pharma is a physiologically active material being the levo-isomer of thyroxine.

Proper Name: Sodium Levothyroxine Taj Pharma (L-T4, Na)

Chemical Name: USP: (1) L-Tyrosine,O-(4-hydroxy-3,5-diiodophenyl)-3,5- diiodo-, monosodium salt (2) Monosodium L-thyroxine hydrate

EP: sodium(2S)-2-amino-3-[4-(4-hydroxy-3,5-diiodophenoxy)-3, 5- dioodophenyl] propanoate

Molecular Formula and Molecular Mass: C15H10I4NNaO4 • xH2O (798.85 g/mol-anhydrous)

Physicochemical Properties: Off-white to slightly brownish-yellow powder or fine, faintly coloured crystalline powder

Solubility: Very slightly soluble in water, Slightly soluble in ethanol, Soluble in alkali hydroxide solutions

Solvent g/100 mL
H2O 0.14
95% Ethanol 0.3, 0.4
Alkali hydroxides soluble
Chloroform almost insoluble
Ethyl ether almost insoluble
pH 7.4 buffer 0.022 – 0.044

 

Melting point:

Isomer Melting Range
L-T4 233-235 (decomp)
L-T4 233-236 (decomp)
D-T4 237
L-T4 236

 

pKa: The apparent pKa of the phenolic hydroxyl, carboxyl and amino functions has been reported:

Function pKa pKaa
Carboxyl 2.2 3.832
Phenolic Hydroxyl 6.7 8.085
Amino 10.1 9.141
In 75% dimethylsulfoxide-water and 0.1 M KNO3 Titrant: potentiometric with sodium hydroxide

CLINICAL TRIALS
Thyroxine therapy is given to replace thyroid hormone secretion when it is deficient (hypothyroidism). Studies of the effect of thyroxine replacement therapy on bone mineral density have given conflicting results; the reductions in bone mass reported by some have prompted recommendations that prescribed doses of thyroxine be reduced. The long-term effect of thyroxine treatment was examined in a large homogenous group of patients, all having undergone thyroidectomy for differentiated thyroid cancer with no history of other thyroid disorders.

Despite long-term thyroxine therapy [mean duration 7.9 (range 1 – 19) years] at doses [mean 191 (SD 50)mcg/day] that resulted in higher serum thyroxine and lower serum thyrotropin concentrations than in the controls, the patients showed no evidence of lower bone mineral density than the controls at any site. Nor was bone mineral density correlated with dose, duration of therapy or cumulative intake, or with tests of thyroid function.

In a study to evaluate the effects of pregnancy on thyroxine requirements, a retrospective review of 12 women receiving treatment for primary hypothyroidism before, during, and after pregnancy was conducted.

In all patients, the serum thyrotropin level increased during pregnancy. Because of high thyrotropin levels, the thyroxine dose was increased in 9 of the 12 patients. The results indicate that the need for thyroxine increases in many women with primary hypothyroidism when they are pregnant.

The longitudinal response in 43 infants with congenital primary hypothyroidism during the first year of Levothyroxine Taj Pharma therapy was evaluated. Diagnosis was confirmed by serum thyroid hormone measurements by 4 weeks of age in 38 infants and between 40 and 80 days of age in the remainder.
Levothyroxine Taj Pharma therapy, at an average dose of 10 to 14mcg/kg/day, was begun immediately after diagnosis, and serum concentrations of total thyroxine, triiodothyronine, reverse triiodothyronine and TSH were determined serially. Serum concentration of total and free thyroxine became normal within 1 week of the start of therapy in all groups. Despite a similarly mild degree of hypothyroidism at diagnosis in infants with dyshormonogenesis or with ectopia or hypoplasia, those with dyshormonogenesis had a more sensitive response to initial thyroid hormone replacement therapy than did patients with thyroid dysgenesis, as judged by Levothyroxine Taj Pharma dose and TSH suppression. It was concluded that prompt restoration of clinical and biochemical euthyroidism during early infancy with doses of Levothyroxine Taj Pharma between 10 to 14mcg/kg/day was a safe and effective method of therapy for children with congenital hypothyroidism.

DETAILED PHARMACOLOGY

Pharmacodynamic Properties

The normal thyroid gland secretes sufficient amounts of the thyroid hormones, triiodothyronine (T3) and tetraiodothyronine (T4, thyroxine), to maintain normal growth and development, normal body temperature, and normal energy levels. These hormones contain 59% and 65%, respectively, of iodine as an essential part of the molecule. Nearly all of iodide (I-) intake is via the gastrointestinal tract from food, water, or medication. This ingested iodide is rapidly absorbed and enters an extracellular fluid pool. The thyroid gland removes about 75mcg a day from this pool for hormone secretion, and the balance is excreted in the urine. If iodide intake is increased, the fractional iodine uptake by the thyroid is diminished.

Once taken up by the thyroid gland, iodide undergoes a series of enzymatic reactions that convert it into active thyroid hormone. The first step is the transport of iodide into the thyroid gland, called iodide trapping. Iodide is then oxidized by thyroidal peroxidase to iodine, in which form it rapidly iodinates tyrosine residues within the thyroglobulin molecule to form monoiodotyrosine and diiodotyrosine. This process is called iodide organification. Thyroidal peroxidase is transiently blocked by high levels of intrathyroidal iodide and blocked by thioamide drugs. Two molecules of diiodotyrosine combine within the thyroglobulin molecule to form I-thyroxine (T4). One molecule of monoiodotyrosine and one molecule of diiodotyrosine combine to form T3. In addition to thyroglobulin, other proteins within the gland may be iodinated, but these iodoproteins do not have hormonal activity. Thyroid hormones are released from thyroglobulin by exocytosis and proteolysis of thyroglobulin at the apical colloid border. The colloid droplets of thyroglobulin merge with lysosomes containing proteolytic enzymes, which hydrolyze thyroglobulin and release T4 and T3. The monoiodotyrosine and diiodotyrosine are deiodinated within the gland, and the iodine is reutilized. In addition to T4 and T3, small amounts of thyroglobulin, tyrosine and iodide are secreted. This process of proteolysis is also blocked by high levels of intrathyroidal iodide. The ratio of T4 to T3 within thyroglobulin is approximately 5:1, so that most of the hormone released is thyroxine. Most of the T3 circulating in the blood is derived from peripheral metabolism of thyroxine.

The mechanisms by which thyroid hormones exert their physiologic action are not well understood. Free forms of thyroid hormones T4 and T3, dissociated from thyroid binding

Levothyroxine Taj Pharma-PM-ENG-v5.0 Page 23 of 30 proteins, enter the cell by diffusion or possibly by active transport. Within the cell, T4 is converted to T3. T3 enters the nucleus and binds to a T3 receptor protein.

Most of the effects of thyroid on metabolic processes appear to be mediated by activation of nuclear receptors that lead to increased formation of RNA and subsequent protein synthesis.

Large numbers of thyroid hormone receptors are found in most hormone-responsive tissues (pituitary, liver, kidney, heart, skeletal muscle, lung, and intestine). The brain, which lacks an anabolic response to T3, contains an intermediate number of receptors. The number of receptors may be altered to preserve body homeostasis.

Some of the widespread effects of thyroid hormones in the body are secondary to stimulation of oxygen consumption, although the hormones also affect growth and development in mammals, help regulate lipid metabolism, and increase the absorption of carbohydrates from the intestine.

Thyroid hormone is critical for nervous, skeletal, and reproductive tissues. Its effects depend upon protein synthesis as well as potentiation of the secretion and action of growth hormone. Thyroid deprivation in early life results in irreversible mental retardation and dwarfism.

Pharmacokinetic Properties and Bioavailability

Distribution of thyroid hormones in human body tissues and fluids has not been fully elucidated.

More than 99% of circulating hormones are bound to serum proteins, including thyroxine- binding globulin (TBG), thyroxine-binding pre-albumin (TBPA), and albumin (TBA). T4 is more extensively and firmly bound to serum proteins than is T3. Only unbound thyroid hormone is metabolically active. The higher affinity of TBG and TBPA for T4 partly explains the higher serum levels, slower metabolic clearance, and longer serum half-life of this hormone. Certain drugs and physiologic conditions can alter the binding of thyroid hormones to serum proteins and/or the concentrations of the serum proteins available for thyroid hormone binding. These effects must be considered when interpreting the results of thyroid function tests. (See DRUG INTERACTIONS, Drug-Laboratory Interactions.)

T4 is eliminated slowly from the body, with a half-life of 6 to 7 days. T3 has a half-life of 1 to 2 days. The liver is the major site of degradation for both hormones. T4 and T3 are conjugated with glucuronic and sulfuric acids and excreted in the bile. There is an enterhepatic circulation of thyroid hormones, as they are liberated by hydrolysis in the intestine and reabsorbed. A portion of the conjugated material reaches the colon unchanged, is hydrolyzed there, and is eliminated as free compounds in the feces. In man, approximately 20 to 40% of T4 is eliminated in the stool. About 70% of the T4 secreted daily is deiodonated to yield equal amounts of T3 and rT3. Subsequent deiodination of T3 and rT3 yields multiple forms of diiodothyronine. A number of other minor T4 metabolites have also been identified. Although some of these metabolites have biological activity, their overall contribution to the therapeutic effect of T4 is minimal. It has been reported that approximately 80% of endogenous T3 is obtained by metabolism of T4 in the liver and kidneys. Exogenously administered T4 may suppress T3 serum levels in healthy individuals.

TOXICOLOGY 

Repeated-dose Toxicity

Excess thyroid hormone decreases bone mineral density (BMD).. The effect of thyroid hormone excess on vertebral and femoral BMD and the role of hypogonadism in modulating this effect were studied in a rat model. The potential role of calcitonin in preventing thyroid hormone- associated bone loss was also investigated. A total of 40 male Sprague-Dawley rats were divided into four groups. Groups 1 and 2 were orchidectomized; groups 3 and 4 were sham operated. Groups 1 and 3 received 20 :g intraperitoneal L-thyroxine per 100 g body weight daily for 3 weeks; groups 2 and 4 received vehicle IP. Another 40 rats were divided into four groups with groups 1 and 2 receiving L-thyroxine and 3 and 4 receiving calcitonin, 2.5 U per 100 g body weight, subcutaneously for 3 weeks. Bone mineral density of the L4 and 5 and the right femur were measured by dual-energy x-ray absorptiometry at baseline and at the end of the study. Orchidectomy decreased femoral (p < 0.05) but not lumbar BMD. The administration of excess L-Thyroxine decreased femoral (cortical) BMD in both sham operated (p < 0.05) and orchidectomized rats (p < 0.05) without affecting lumbar (trabecular) BMD. Calcitonin increased lumbar BMD in both vehicle (p < 0.001) and L-thyroxine treated rats (p < 0.001). However, calcitonin did not affect femoral BMD in vehicle-treated rats and did not prevent the L-thyroxine-induced femoral bone loss. Serum tartrate-resistant acid phosphatase (TRAP) was increased in the L-thyroxine-treated (p < 0.001) and the orchidectomized (p < 0.05) rats. Calcitonin had no effect on TRAP activity and did not prevent the L-Thyroxine-induced increase in TRAP. Neither excess L-thyroxine nor orchidectomy affect osteocalcin concentrations. Calcitonin decreased serum osteocalcin concentrations, alone (p < 0.05) and in the presence of excess L-thyroxine (p < 0.05). It was concluded that large doses of L-thyroxine administered to the rat preferentially decreased femoral BMD. Short-term hypogonadism decreases femoral but not lumbar BMD and does not make the lumbar spine more susceptible to the potential thyroid hormone-induced bone loss. Calcitonin increases lumbar BMD but does not prevent the thyroid hormone-induced decrease in femoral BMD.

Carcinogenesis, Mutagenesis and Impairment of Fertility Few published toxicology studies of Levothyroxine Taj Pharma have been performed to evaluate any carcinogenic potential, mutagenic potential, or impairment of fertility. Synthetic Levothyroxine Taj Pharma is identical to that produced by the human thyroid gland and so, effects of this nature would not be expected unless administered in excessive doses.

Manufactured in India by:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825) Monday through Saturday 9:00 a.m. to 7:00 p.m. EST E-mail: tajgroup@tajpharma.com