Product Monograph. Finally.

Transcription

1 Product Monograph Finally.

2 TIROSINT Product Monograph 2

3 Table of Contents Finally. 1. EXECUTIVE SUMMARY...5 Table of Contents 2. DISEASE DESCRIPTION Epidemiology Pathophysiology Hashimoto s Disease Secondary/Central Hypothyroidism Nontoxic goiter Clinical Importance Treatment Goals Treatment Options PLACE IN THERAPY Narrow Therapeutic Index Bioequivalence Gastric ph: Significant Effect on Dissolution and Absorption Uniform Delivery With TIROSINT Gel Capsules PRODUCT DESCRIPTION Generic Name, Brand Name, and Therapeutic Class Dosage Forms and Package Sizes NDC for All Formulations WAC Cost Per Unit AHFS or Other Drug Classification FDA-Approved Indications Use in Special Populations Pharmacology Pharmacokinetics/Bioequivalence Manufacturing and Purification Contraindications Warnings/Precautions Adverse Events Drug/Food/Disease Interactions Dosing and Administration Specific Patient Populations Pediatric Dosage

4 TIROSINT Product Monograph Table of Contents (cont d) 5. OTHER STUDIED USES Subclinical Hypothyroidism REFERENCES

5 Executive Summary Finally. Summary In hypothyroidism, precise treatment with levothyroxine sodium (T4) to bring thyrotropin levels within the therapeutic range is clinically challenging but critical to quality patient care. The narrow therapeutic index associated with T4 therapy requires individualized titration and follow-up to adequately treat hypothyroidism, without overtreating to hyperthyroidism. Failure to maintain T4 levels within the therapeutic range can result in significant clinical consequences and higher health care costs. Levothyroxine sodium tablets, the current standard of care for management of hypothyroidism, have been prone to significant variance in bioavailability. In response, national medical organizations and patient advocacy continue to question bioequivalence between branded and generic T4 formulations. TIROSINT (levothyroxine sodium) capsules represent a change in levothyroxine formulation the first and only T4 therapy in a liquid gel cap form. TIROSINT also provides bioavailability comparable to Synthroid (levothyroxine sodium tablets). * TIROSINT manufacturing processes avoid excessive heat, preventing degradation of the levothyroxine molecule. Gel capsules protect T4 from degradation by light, air, humidity, and micro-contaminants. *Synthroid is a registered trademark of Abbott Laboratories. 5

6 TIROSINT Product Monograph Disease Description 2.1 Epidemiology Hypothyroidism is an endocrine disorder with numerous etiologies resulting in a deficiency in thyroid hormone (Table 1). About 2% of women and 0.1% of men have overt hypothyroidism, and as many as 10% have subclinical (mild) hypothyroidism. The condition is most common in women >40 years of age and in the elderly of both sexes. 1,2 In a population-based study, the mean average age at diagnosis was 58 to 59 years with the probability of developing hypothyroidism increasing with age. 3 Nearly 10% of women and 6% of men >65 years of age have hypothyroidism. 4 Primary hypothyroidism results from deterioration or destruction of the thyroid, most commonly from autoimmune thyroiditis, know as Hashimoto s disease. The development of Hashimoto s disease is most common in women during middle age. 5 Other causes include surgical removal of the thyroid, ablation with radioactive iodine (as in management of hyperthyroidism or goiter), irradiation, tumor (lymphoma), and drugs such as lithium, interferon, or amiodarone. 6,7 Central hypothyroidism, also known as secondary/tertiary hypothyroidism, involves disorders of the hypothalmic-pituitary axis that impair production of thyroid stimulating hormone (TSH). 4 Table 1: Causes of hypothyroidism 7 Chronic autoimmune thyroiditis (Hashimoto s disease) Radioactive iodine therapy Subtotal thyroidectomy Antithyroid drugs Head and neck surgery Radiation therapy to the head, neck, or chest Iodine deficiency Medications: lithium, iodine, amiodarone Secondary hypothyroidism (hypopituitarism) Idiopathic Congenital 2.2 Pathophysiology The principal thyroid hormones are thyroxine (T4) and triiodothyronine (T3). T4 is an endogenous prohormone that is converted in body tissue into the biologically active T3. These hormones are active in most cells of the body, affecting protein, lipid and carbohydrate metabolism, as well as growth and development. T3 and T4 promote oxygen consumption, resulting in increased energy expenditure and heat production. Cardiac effects are also attributed to the effects of thyroid hormones on the heart. 2,8 6

7 Disease Description (cont d) Finally. In the blood, T3 and T4 are almost entirely bound to protein, requiring analysis of free T4/T3 to determine circulating levels. 9 Their secretion is stimulated by the presence of iodine and is regulated by release of the thyroid-stimulating hormone (TSH) thyrotropin from the pituitary. TSH secretion is, in turn, dependent on release of thyroid-regulating hormone (TRH) secreted from the hypothalamus. These hormones interact in a feedback loop, so that decreases in thyroid hormones T4/T3 stimulate secretion of TRH and TSH (Figure 1). 9 Thus, TSH is an important marker for hypothyroidism. High levels of thyroid hormone signal a drop in TRH and TSH production and reduce further T3 and T4 release from the thyroid. 9 Disease Description Figure 1: Major steps in thyroid hormone regulation 9 Hypothalamus TRH Pituitary Gland TSH Thyroid T3, T4 in Blood and Tissue Hashimoto s Disease (Chronic Autoimmune Thyroiditis) Hashimoto s disease, the most common cause of hypothyroidism, is an autoimmune disorder characterized by chronic infiltration of the thyroid by plasma cells and lymphocytes. 5 Pathology of the disease stems from a complex process of immunologic events, resulting in destruction of thyroid tissue. 5,7 The condition is mediated by the presence of thyroid peroxidase enzyme (TPO) antibodies. TPO is a protein that liberates iodine for addition to tyrosine residues on thyroglobulin for the production of T3 and T4. TPO antibodies are present in >90% of cases and thus an important marker for the disease. 5,7 Hashimoto s disease is often associated with other autoimmune diseases, including vitiligo, rheumatoid arthritis, Addison s disease, diabetes mellitus, and pernicious anemia. 6 7

8 TIROSINT Product Monograph Disease Description (cont d) Secondary/Central Hypothyroidism Different profiles of hormonal changes occur with primary vs secondary hypothyroidism. Primary hypothyroidism results in elevated serum TSH levels and free T4 levels that are lower than the population reference range (Figure 2A). Secondary, also know as central, hypothyroidism is a dysfunction of pituitary origin characterized by low levels of TSH. In adults, central hypothyroidism (Figure 2B) is most often caused by tumors, inflammatory conditions, infiltrative diseases, infections, pituitary surgery, pituitary radiation therapy, and head trauma. 1 Figure 2A: Hormone changes occurring during the development of primary hypothyroidism 1 High Values Normal Range Low Values Set Key TSH T 3 T 4 Normal Mild Moderate Severe Severity of Hypothyroidism Figure 2B: Hormone changes occurring during the development of central hypothyroidism 1 High Values Normal Range Low Values Set Key TSH T 3 T 4 Normal Mild Moderate Severe Severity of Hypothyroidism 8

9 Disease Description (cont d) Finally Nontoxic Goiter Thyroid dysfunction is associated with other common conditions such as goiter. Known causes of simple nontoxic goiter include intrinsic thyroid hormone production defects and an iodine deficiency. 4 Other causes include the use of drugs that can decrease the synthesis of thyroid hormone (eg, amiodarone or other iodine-containing compounds, such as lithium). Goiter frequently occurs at puberty, during pregnancy, and at menopause; causes are not clearly understood. Overexpression of TSH, which may lead to goiter, can be suppressed by supplementation of thyroid hormone Clinical Importance Due to the ubiquitous presence of thyroid hormone throughout the body, inadequate levels cause serious general effects such as decreased oxygen consumption as well as defects in individual organs. 2 Hypothyroidism typically has a gradual course. Abnormal blood levels of the hormone may be present before symptoms become apparent; some patients with mild disease may not become aware of symptoms, such as fatigue, until hormone replacement treatment takes effect. 7 The signs and symptoms of hypothyroidism are nonspecific and may include fatigue, cold intolerance, coarse hair, dry skin, weight gain, delayed return phase of reflexes, and constipation. 7 Due to its vague clinical and physical manifestations, hypothyroidism is often overlooked or ignored. For this reason, clinicians are advised to utilize a low threshold for screening when patients present with symptoms suggestive of thyroid dysfunction. 7 Patients with more severe hypothyroidism (myxedema) may have distinct clinical characteristics including periorbital edema. 2,4 Untreated hypothyroidism carries the risk of myxedema coma, a life-threatening endocrine emergency. Multiple organ systems are affected, including pulmonary (respiratory failure), cardiac (bradycardia, hypotension, pericardial effusion), gastrointestinal (ileus), and renal (decreased renal perfusion). Hypothermia can be severe. 4 Elderly patients are especially vulnerable and may be difficult to diagnose, attributing symptoms to natural aging processes. Symptoms mimic nonspecific geriatric syndromes including anorexia, weight loss, falling, incontinence, arthralgias, muscle aches, decreased mobility, and confusion. In the elderly, hypothyroidism may mimic dementia or Parkinsonism. 4 Hypothyroidism during pregnancy is associated with increased maternal and fetal morbidity, including maternal hypertension, preeclampsia, anemia, postpartum hemorrhage, spontaneous abortion, fetal death, low birth weight, and abnormal brain development. T4 therapy is safe during pregnancy and recommended even in mild hypothyroidism. 6 Disease Description 9

10 TIROSINT Product Monograph Disease Description (cont d) Table 2: Clinical presentation of hypothyroidism 2 Affected body system Symptoms Signs General Cold intolerance Fatigue Mild weight gain Hypothermia Nervous system Lethargy Memory defects Poor attention span Personality change Somnolence Slow speech Psychopathology: myxedema madness Diminished hearing and taste Cerebellar ataxia Depression Neuromuscular system Gastrointestinal system Weakness Muscle cramps Joint pain Nausea Constipation Delayed relaxation of deep tendon reflexes Carpal tunnel syndrome Large tongue Ascites Cardiorespiratory system Decreased exercise tolerance Hoarse voice Bradycardia Mild hypertension Pericardial effusion Pleural effusion Hyperlipidemia Reproductive system Decreased libido Decreased fertility Menstrual disorders Heavier and/or more frequent menstrual periods Skin and appendages Rough, dry, itchy skin Puffy face Hair loss Brittle nails Edema of the hands, face, ankles Periorbital swelling Pallor Yelllowish skin Coarse hair Decreased sweating 10

11 Disease Description (cont d) Finally. 2.4 Treatment Goals The American Academy of Endocrinology (AACE) Guidelines for Clinical Practice for Evaluation and Treatment of Hypothyroidismcall for careful dose titration of oral levothyroxine to a target TSH level as the standard of care for hypothyroidism. 6 Careful titration and monitoring is necessary in order to maintain a euthyroid state, while avoiding adverse events (AEs) due to overtreatment. Target serum TSH levels in patients receiving T4 should be between 0.5 and 3.0 miu/l. 10 To achieve this goal, mean replacement dose of levothyroxine is 1.7 mcg/kg of body weight per day for patients <65 years of age typically, between 75 and 100 mcg per day in women and between 100 and 150 mcg per day in men. 10 In elderly patients without overt heart disease, levothyroxine should be initiated at 25 mcg per day, with 25-mcg increments at 8-week intervals, until serum TSH level returns to normal. 10 In secondary (central) hypothyroidism the goal of therapy is to maintain T4 levels within the mid- or upper-normal range. Dysfunction of the hypothalamus or pituitary affects TSH values and, therefore, they are not an accurate measure of thyroid hormone levels in secondary hypothyroidism Treatment Options According to AACE, all physicians should treat hypothyroidism with oral levothyroxine replacement therapy. 6 It is the treatment of choice supported by clinically demonstrated safety and efficacy. For the majority of patients with hypothyroidism, levothyroxine safely, effectively, and reliably relieves symptoms and normalizes laboratory test values. 1,12-14 Levothyroxine is available in multiple dosage strengths to allow for precise titration to achieve target TSH levels. 1 The 7-day half-life of levothyroxine permits once-a-day dosing and maintenance of a steady state, even with occasional missed doses. Steady-state levels in the blood are needed to assure conversion of biologically inactive T4 into adequate amounts of T3. 1 In a clinical study of 50 euthyroid patients who received levothyroxine therapy for thyroid hormone replacement after thyroidectomy, postsurgical serum T3 concentrations were comparable to values before surgery. This study demonstrated that T4 monotherapy leads to adequate serum concentrations of T3. 15 Long-term thyroid hormone replacement therapy with T3(liothyroxine sodium) is not recommended. This hormone is well absorbed, fast acting, and has a shorter half-life (1.5 days) than T4, leading to marked fluctuations in T3 levels. 4 These T3 peaks render patients receiving liothyroxine sodium chemically hyperthyroid for hours at a time, potentially increasing cardiac risks. 4 Disease Description According to the AACE, clinical evidence does not support the use of a combination of T4 and T3 or natural thyroid preparations. 6 A 1:1 fixed dose combination of T4 and T3 is available as liotrix tablets (Thyrolar ).* Results of a meta-analysis of 11 studies involving 1216 patients found no significant improvements in quality of life (QOL) parameters of combination therapy over monotherapy with T4. 16 Generic thyroid USP preparations of desiccated porcine thyroid tissue contain T4, T3, and primarily bound iodine. The ratio of T3 to T4 in porcine thyroid is not identical to that of humans and may result in higher than normal T3 concentrations. 11 * Thyrolar is a registered trademark of Forest Pharmaceuticals. 11

12 TIROSINT Product Monograph Place in Therapy T4 is the standard of care in the treatment of hypothyroidism. TIROSINT capsules are a unique T4 formulation the first and only levothyroxine (T4) therapy in a liquid gel cap form. TIROSINT was approved by the FDA on the basis of standard bioequivalence studies. The relative bioequivalence of TIROSINT to Synthroid was evaluated in a randomized, 2-way, crossover study (N=25). 17 Healthy volunteers were administered a 600-mcg oral dose of either drug under fasting conditions. There was a 35-day washout period between treatments. Pharmacokinetic parameters were adjusted for baseline levothyroxine levels. The pharmacokinetics of levothyroxine after TIROSINT administration was comparable to those following Synthroid administration in this one study. TIROSINT dose proportionality was demonstrated in a 3-way crossover study comparing a 600-mcg dose administered as 12 TIROSINT 50-mcg, 6 TIROSINT 100-mcg, and 4 TIROSINT 150-mcg capsules Narrow Therapeutic Index The narrow therapeutic index of thyroid replacement therapy with T4 is well recognized. Even small variations in the available amount of active T4 can affect both efficacy and safety, as they may result in clinical or subclinical hypothyroidism or hyperthyroidism. 6 Careful titration is required to adjust TSH levels to within normal limits for each individual. During therapy, many physiologic factors may necessitate dosage adjustment (Table 3) and numerous pharmacodynamic and behavioral factors affect drug absorption. 6,10 12

13 Place in Therapy (cont d) Table 3: Circumstances that may alter levothyroxine requirements 10,18,19 Increased levothyroxine requirements Malabsorption Gastrointestinal disorders Mucosal diseases of the small bowel (eg, sprue) After jejunoileal bypass and small-bowel resection Diabetic diarrhea Cirrhosis Pregnancy Increased gastric ph Decreased levothyroxine requirements Aging (65 years and older) Therapy with certain pharmacologic agents: Drugs that block absorption Cholestyramine Sucralfate Aluminum hydroxide Ferrous sulfate Lovastatin Proton pump inhibitors Drugs that increase nondeiodinative T4 clearance Rifampin Carbamazepine Phenytoin Drugs that block T4 to T3 conversion Amiodarone Selenium deficiency Finally. Place in Therapy Failure to maintain T4 levels within the therapeutic range can result in significant clinical consequences and higher healthcare costs. 6,20 With undertreatment, risks include suboptimal response and sequelae of ongoing hypothyroidism including myxedema coma, infertility, and higher rate of stillbirth. 4 Risks associated with overtreatment include cardiotoxic effects such as cardiac pain, palpitations, or cardiac arrhythmias. Excess T4 is particularly dangerous in patients with coronary heart disease (CHD). 8,10 T4 treatment to the point of hyperthyroidism is associated with increases in hepatic enzymes and risk of accelerated loss of bone mineral density (BMD) in pre- and post-menopausal women. 10 Increased health care costs are incurred with inaccurate hormone replacement due to the need for frequent patient visits and laboratory testing. 6 13

14 TIROSINT Product Monograph Place in Therapy (cont d) 3.2 Bioequivalence The narrow therapeutic ratio exhibited by T4 amplifies the need for consistent bioavailability, making it particularly important that the amount of available active agent is consistent for a given pharmaceutical dose. However, the bioavailability of T4 tablets has been repeatedly questioned. Issues concerning the stability, potency, and therapeutic bioequivalence of past and current formulations have been raised for both branded and generic tablets. To better assure reliable stability of levothyroxine sodium formulation, the FDA required New Drug Applications (NDAs), with bioequivalance and bioavailability data, to be submitted and approved for all levothyroxine products marketed after August 14, Unpredictable potency of tablet formulations has been attributed to the instability of levothyroxine sodium and its vulnerability to pharmaceutical tablet manufacturing processes. 21 The FDA now requires manufacturers to meet a 95% to 105% potency specification. 20,22 In order to compensate for degradation, formulations have been manufactured with an excess of active ingredient, resulting in superpotency. Thus, as a result of stability problems and manufacturing practices used to compensate for instability of the drug, potency of each product may vary considerably between brands or even within the same brand. 3.3 Gastric ph: Significant Effect on Dissolution and Absorption The bioavailability and absorption of different formulations of T4 are affected by properties such as the rate of drug dissolution and rate of release. 23,24 Adequate absorption of T4 is critical to the effectiveness of therapy and is influenced by numerous factors including age, patient compliance and diet, absorption kinetics, malabsorption disorders, gastric ph, and the effects of other drugs. 10,18,19 Thyroxine is principally absorbed at the level of the jejunum and ileum. 18 The effect of gastric acidity on the absorption of T4 is of particular concern due to the many conditions that affect acid secretion and gastric ph. Absorption of approximately 62% to 82% of the ingested T4 dose is typical. 18 Clinical studies have demonstrated significant malabsorption of T4 in patients with altered gastric ph due to Helicobacter pylori infection, with chronic gastritis, and undergoing treatment with proton pump inhibitors (PPIs). 18,19 In one trial, patients with gastric abnormalities and those treated with omeprazole required doses that were 22% to 34% higher than those required by the control group patients to maintain a euthyroid state. 18 In a retrospective analysis, the initiation of PPI therapy with lansoprazole in euthyroid patients necessitated a statistically significant mean dose increase of 29% to maintain pretreatment TSH levels (P=.035). Changes in dose for a control group were not statistically significant

15 Place in Therapy (cont d) Finally. Recently, an in vitro study was conducted to compare the effect of ph on the dissolution rate of TIROSINT capsules. A highly sensitive analytic technique (inductively coupled plasma mass spectroscopy) was employed. 23 When measured at various ph levels, TIROSINT dissolution was 100% across ph 1-8, delivering rapid, consistent dissolution regardless of the level of gastric ph present (Figure 3). 23* Place in Therapy Figure 3: An in vitro dissolution study showed that Tirosint gel caps were unaffected by gastric ph 23 * T4 dissolved (%) ph 1.2 ph 2.4 ph 4.0 ph 5.0 ph 6.0 ph 7.0 ph Time (minutes) *In vitro data do not necessarily correlate with clinical outcomes. Numerous clinical circumstances may cause irregularity in the gastric ph leading to gastric hypoacidity and altered oral absorption of T4, including H pylori infection, chronic gastritis, and hypochlorhydria. 25 Gastric hypoacidity may also result from chronic acid suppression therapy with PPIs, antacids, and histamine H2 receptor antagonists used to treat gastroesophageal reflux disease (GERD), and other acid peptic disorders 26 that may affect between 20% to 25% of the patient population. 27 Gastric ph profile may change by as much as 2 to 3 ph units during these conditions or as a result of chronic acid suppression therapy. 25,28 Under these conditions, in which variations in gastric ph may reduce dissolution of T4 tablets and the absorption of T4, TIROSINT capsules offer greater reassurance that the patient will receive a consistent and reliable dose. 3.4 Uniform Delivery With TIROSINT Gel Capsules TIROSINT is the first and only FDA-approved T4 formulation that delivers levothyroxine (T4) in a glycerin solution via a soft gel capsule. Because the active drug is dissolved in a liquid phase, TIROSINT provides batch-to-batch consistency and uniform distribution. The process used to manufacture TIROSINT avoids excessive heat, preventing degradation of the molecule by heat-related deactivation of T4. The soft capsules have an outer shell to protect T4 from light, air, humidity, and micro-contaminants, which assures levothyroxine stability and consistency over time. No excessively high temperatures are used in manufacturing

16 TIROSINT Product Monograph Product Description 4.1 Generic Name, Brand Name, and Therapeutic Class TIROSINT (levothyroxine sodium) is a thyroid hormone replacement agent. 4.2 Dosage Forms and Package Sizes TIROSINT delivers levothyroxine in a glycerin solution via a soft gel tablet. The gel caps are easy to swallow, dye free, gluten free, alcohol free, lactose free, and sugar free. TIROSINT packaging is designed to facilitate customized dose titration for physicians and to simplify patient compliance. TIROSINT is available in 10 dosage strengths including the exclusive low, 13-mcg dose (Table 4). To reduce confusion, product boxes and blister packaging are color-coded for each individual dosage strength. To help reduce the potential for missed or forgotten doses, each blister pack contains 7 capsules labeled for days of the week. 4.3 NDC for All Formulations See Table 4 Table 4. TIROSINT product information Strength (mcg) Color NDC 13 Olive Orange White Purple Green Yellow Rose Brown Blue Turquoise WAC Cost Per Unit WAC cost per unit is $ AHFS or Other Drug Classification FDA-Approved Indications TIROSINT is indicated as a replacement or supplemental therapy in congenital or acquired hypothyroidism of any etiology. Specific indications include primary (thyroidal) hypothyroidism resulting from functional deficiency, primary atrophy, partial or total congenital absence of the thyroid gland or from the effects of surgery, radiation, or drugs. TIROSINT is appropriate for these conditions with or without the presence of goiter. 16

17 Product Description (cont d) Finally. TlROSINT therapy is not indicated for the treatment of transient hypothyroidism during the recovery phase of subacute thyroiditis. TIROSINT is also indicated for secondary (pituitary) hypothyroidism, tertiary (hypothalamic) hypothyroidism, and subclinical hypothyroidism. As a pituitary TSH suppressant, TIROSINT is indicated in the treatment or prevention of various types of euthyroid goiters, including thyroid nodules, subacute or chronic lymphocytic thyroiditis (Hashimoto s disease), multinodular goiter, and in conjunction with surgery and radioactive iodine therapy in the management of thyrotropindependent well-differentiated thyroid carcinoma. 4.7 Use in Special Populations See WARNINGS and PRECAUTIONS and DOSING and ADMINSTRATION for specific information about treating these and other patient populations with TIROSINT. 4.8 Pharmacology The principal pharmacologic effect of exogenous thyroid hormones is to increase the metabolic rate of body tissues. Thyroid hormones are also involved in the regulation of cell growth and differentiation. Although the precise mechanism of action (MOA) by which thyroid hormones affect metabolism and cellular growth and differentiation is not clearly established, it is known that these physiologic effects are mediated at the cellular level, principally via triiodothyronine or T3; a major portion of triiodothyronine is derived from thyroxine or T4 by deiodination in peripheral tissues. Thyroxine is the major component of normal secretions of the thyroid gland and is therefore the principal determinant of normal thyroid function. 4.9 Pharmacokinetics/Bioequivalence The relative bioavailability of TIROSINT to Synthroid was evaluated in a randomized, 2-way crossover study (N=25). 17 Healthy volunteers were administered a 600-mcg oral dose of either drug under fasting conditions. There was a 35-day washout period between treatments. Pharmacokinetic parameters were adjusted for baseline levothyroxine levels. The pharmacokinetics of levothyroxine after TIROSINT administration was comparable to those following Synthroid administration (Table 5). Table 5: Summary of levothyroxine pharmacokinetic parameters (adjusted for baseline T4 levels) 17 Product Description Parameter Ratio (%) (Test/Reference) 90% Confidence Interval AUC 0-t (n=24; adjusted with the baseline) C max (n=24; adjusted with the baseline)

18 TIROSINT Product Monograph Product Description (cont d) Dosage form proportionality was evaluated in a randomized, 600-mcg dose, 3-way crossover study in healthy volunteers under fasting conditions. Single oral doses of TIROSINT in 3 strengths (ie, 12 capsules of 50 mcg, 6 capsules of 100 mcg, and 4 capsules of 150 mcg) were administered in the study and the treatments were separated by at least a 35-day washout period. The study demonstrated that the 50 mcg, 100 mcg, and 150 mcg are dosage form equivalent (Table 6). 17 Table 6: Results of bioequivalence assessment using baseline-adjusted serum levothyroxine concentrations 17 Ratio (90% CI) Parameter 50 μg vs 100 μg 150 μg vs 100 μg AUC 0-t (ng h/ml; n=24) 97.3% ( ) 98.8 ( ) C max (ng/ml; n=24) 95.6 ( ) ( ) 4.10 Manufacturing and Purification TIROSINT is manufactured using a process called PEARLtec (Precision Encapsulation technology for the Application and Release of a Liquid formulation). This extremely precise and delicate technique saves the chemically unstable active ingredient (levothyroxine) from mechanical and thermal stress. The active ingredient does not need to be finely ground or heated, both of which occur during tablet manufacturing. The state-of-the-art manufacturing facility uses the most modern, advanced technology and equipment. In the PEARLtec manufacturing process, the dosage of the soft gel capsules is determined by the concentration of the levothyroxine sodium solution and by the volume of the injected solution. Since they are enclosed in an inert environment, the levothyroxine molecules remain protected from UV rays, as well as from oxygen and humidity. This avoids any decomposition reactions Contraindications Levothyroxine is contraindicated in patients with untreated subclinical (suppressed serum TSH level with normal T3 and T4 levels) or overt thyrotoxicosis of any etiology and in patients with acute myocardial infarction (AMI). Levothyroxine is contraindicated in patients with uncorrected adrenal insufficiency, since thyroid hormones may precipitate an acute adrenal crisis by increasing the metabolic clearance of glucocorticoids (see PRECAUTIONS). TIROSINT is contraindicated in patients with hypersensitivity to any of the inactive ingredients in TIROSINT capsules (See DESCRIPTION, Inactive Ingredients). 18

19 Product Description (cont d) Finally. TIROSINT is also contraindicated for anyone who may be unable to swallow a capsule (eg, infants, small children) Warnings/Precautions WARNING: 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 lifethreatening manifestations of toxicity, particularly when given in association with sympathomimetic amines such as those used for their anorectic effects. Levothyroxine sodium should not be used in the treatment of male or female infertility unless this condition is associated with hypothyroidism. In patients with nontoxic diffuse goiter or nodular thyroid disease, particularly the elderly or those with underlying cardiovascular disease, levothyroxine sodium therapy is contraindicated if the serum TSH level is already suppressed due to the risk of precipitating overt thyrotoxicosis (see CONTRAINDICATIONS). If the serum TSH level is not suppressed, TIROSINT should be used with caution in conjunction with careful monitoring of thyroid function for evidence of hyperthyroidism and clinical monitoring for potential associated adverse cardiovascular signs and symptoms of hyperthyroidism. General Levothyroxine has a narrow therapeutic index. Regardless of the indication for use, careful dosage titration is necessary to avoid the consequences of over- or undertreatment. These consequences include, among others, effects on growth and development, cardiovascular function, bone metabolism, reproductive function, cognitive function, emotional state, gastrointestinal function, and glucose and lipid metabolism. Many drugs interact with levothyroxine sodium, necessitating adjustments in dosing to maintain therapeutic response (see Drug Interactions). Effects on bone mineral density In women, long-term levothyroxine sodium therapy has been associated with increased bone resorption, thereby decreasing BMD, especially in post-menopausal women on greater than replacement doses or in women who are receiving suppressive doses of levothyroxine sodium. The increased bone resorption may be associated with increased serum levels and urinary excretion of calcium and phosphorous, elevations in bone alkaline phosphatase, and suppressed serum parathyroid hormone levels. Therefore, it is recommended that patients receiving levothyroxine sodium be given the minimum dose necessary to achieve the desired clinical and biochemical response. Product Description 19

20 TIROSINT Product Monograph Product Description (cont d) Patients with underlying cardiovascular disease Exercise caution when administering levothyroxine to patients with cardiovascular disorders and to the elderly in whom there is an increased risk of occult cardiac disease. In these patients, levothyroxine therapy should be initiated at lower doses than those recommended in younger individuals or in patients without cardiac disease. It should be noted that, unlike levothyroxine sodium tablets, TlROSINT capsules cannot be cut in half. (see WARNINGS; PRECAUTIONS, Geriatric Use; and DOSAGE AND ADMINISTRATION). If cardiac symptoms develop or worsen, the levothyroxine dose should be reduced or withheld for one week and then cautiously restarted at a lower dose. Overtreatment with levothyroxine sodium may have adverse cardiovascular effects such as an increase in heart rate, cardiac wall thickness, and cardiac contractility and may precipitate angina or arrhythmias. Patients with coronary artery disease who are receiving levothyroxine therapy should be monitored closely during surgical procedures, since the possibility of precipitating cardiac arrhythmias may be greater in those treated with levothyroxine. Concomitant administration of levothyroxine and sympathomimetic agents to patients with coronary artery disease may precipitate coronary insufficiency. Patients with nontoxic diffuse goiter or nodular thyroid disease Exercise caution when administering levothyroxine to patients with nontoxic diffuse goiter or nodular thyroid disease in order to prevent precipitation of thyrotoxicosis (see WARNINGS). If the serum TSH is already suppressed, levothyroxine sodium should not be administered (see CONTRAINDICATIONS). Associated Endocrine Disorders Hypothalamic pituitary hormone deficiencies In patients with secondary or tertiary hypothyroidism, additional hypothalamic/pituitary hormone deficiencies should be considered, and, if diagnosed, treated (see PRECAUTIONS, Autoimmune polyglandular syndrome for adrenal insufficiency). Autoimmune polyglandular syndrome Occasionally, chronic autoimmune thyroiditis may occur in association with other autoimmune disorders such as adrenal insufficiency, pernicious anemia, and insulin-dependent diabetes mellitus. Patients with concomitant adrenal insufficiency should be treated with replacement glucocorticoids prior to initiation of treatment with levothyroxine sodium. Failure to do so may precipitate an acute adrenal crisis when thyroid hormone therapy is initiated, due to increased metabolic clearance of glucocorticoids by thyroid hormone. Patients with diabetes mellitus may require upward adjustments of their antidiabetic therapeutic regimens when treated with levothyroxine (see PRECAUTIONS, Drug Interactions). Other associated medical conditions Infants with congenital hypothyroidism appear to be at increased risk for other congenital anomalies, with cardiovasc ular anomalies (pulmonary stenosis, atrial septal defect, and ventricular septal defect) being the most common association. 20

21 Product Description (cont d) LABORATORY TESTS Finally. 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 PRECAUTIONS, Drug Interactions and Drug-Laboratory Test Interactions). 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 decreased T4 potency of the drug product. Adults In adult patients with primary (thyroidal) hypothyroidism, serum TSH levels (using a sensitive assay) alone may be used to monitor therapy. The frequency of TSH monitoring during levothyroxine dose titration depends on the clinical situation but it is generally recommended at 6-8 week intervals until normalization. For patients who have recently initiated levothyroxine therapy and whose serum TSH has normalized or in patients who have had their dosage or brand of levothyroxine changed, the serum TSH concentration should be measured after 8-12 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. It is recommended that a physical examination and a serum TSH measurement be performed at least annually in patients receiving TIROSINT (see WARNINGS, PRECAUTIONS, and DOSAGE AND ADMINISTRATION). Pediatrics In patients with congenital hypothyroidism, the adequacy of replacement therapy should be assessed by measuring both serum TSH (using a sensitive assay) and total- or free- T4. During the first 3 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 TIROSINT 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. Careful inquiry should then be made regarding compliance, dose of medication administered, and method of administration prior to raising the dose of TIROSINT. 21 Product Description

22 TIROSINT Product Monograph Product Description (cont d) 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 to 12 months thereafter until growth is completed. More frequent intervals of monitoring may be necessary if poor compliance is suspected or abnormal values are obtained. It is recommended that TSH and T4 levels, and a physical examination, if indicated, be performed 2 weeks after any change in TIROSINT dosage. Routine clinical examination, including assessment of mental and physical growth and development, and bone maturation, should be performed at regular intervals (see PRECAUTIONS, Pediatric Use and DOSAGE AND ADMINISTRATION). 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. Geriatric Use Because of the increased prevalence of cardiovascular disease among the elderly, levothyroxine therapy should not be initiated at the full replacement dose Adverse Events ADVERSE REACTIONS Adverse reactions associated with levothyroxine therapy are primarily those of hyperthyroidism due to therapeutic overdosage (see PRECAUTIONS and OVERDOSAGE). 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; Cardiovascular: palpitations, tachycardia, arrhythmias, increased pulse and blood pressure, heart failure, angina, 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. 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. Seizures have been reported rarely with the institution of levothyroxine therapy. Inadequate levothyroxine dosage will produce or fail to ameliorate the signs and symptoms of hypothyroidism. 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, 22

23 Product Description (cont d) Finally. vomiting, and diarrhea), fever, arthralgia, serum sickness, and wheezing. Hypersensitivity to levothyroxine itself is not known to occur. Overdosage The signs and symptoms of overdosage are those of hyperthyroidism (see PRECAUTIONS and ADVERSE REACTIONS). In addition, confusion and disorientation may occur. Cerebral embolism, shock, coma, and death have been reported. Seizures have occurred in a child ingesting 18 mg of levothyroxine. Symptoms may not necessarily be evident or may not appear until several days after ingestion of levothyroxine sodium Drug/Food/Disease Interactions DRUG INTERACTIONS Many drugs affect thyroid hormone pharmacokinetics and metabolism (eg, absorption, synthesis, secretion, catabolism, protein binding, and target tissue response) and may alter the therapeutic response to TIROSINT. 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 7. The list of drug-thyroidal axis interactions in Table 7 may not be comprehensive due to the introduction of new drugs that interact with the thyroidal axis or the discovery of previously unknown interactions. The prescriber should be aware of this fact and should consult appropriate reference sources (eg, package inserts of newly approved drugs, medical literature) for additional information if a drug-drug interaction with levothyroxine is suspected. Table 7: Drug Thyroid axis interaction Product Description Drug or drug class Effect Drugs that may reduce TSH secretion the reduction is not sustained; therefore, hypothyroidism does not occur Dopamine/Dopamine agonists Glucocorticoids Octreotide Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( 1 mcg/kg/min); Glucocorticoids (hydrocortisone 100 mg/day or equivalent); Octreotide (>100 mcg/day). 23

24 TIROSINT Product Monograph Product Description (cont d) Table 7: Drug Thyroid axis interaction (cont d) Drugs that alter thyroid hormone secretion Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide 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. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (eg, Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. 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. Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism Amiodarone Iodide (including iodine-containing radiographic contrast agents) Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (eg, multinodular goiter or hyperfunctioning thyroid adenoma). 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 decrease T4 absorption, which may result in hypothyroidism Antacids - Aluminum and Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate - Ferrous Sulfate - Orlistat - Sucralfate Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Drugs that may alter T4 and T3 serum transport, but FT4 concentration remains normal; therefore, the patient remains euthyroid Drugs that may increase serum TBG concentrations Clofibrate Estrogen-containing Oral Contraceptives Estrogens (oral) Heroine/Methadone 5-fluorouracil Mitotane Tamoxifen Drugs that decrease serum TBG concentration Androgen/Anabolic Steroids Asparaginase Glucocorticoids Slow release nicotinic acid 24

25 Product Description (cont d) Table 7: Drug Thyroid axis interaction (cont d) Drugs that may cause protein-binding site displacement Finally. Product Description Furosemide (>80 mg IV) Heparin Hydantoins Nonsteroidal Anti-inflammatory Drugs - Fenamates - Phenylbutazone Salicyclate (>2 g/day) Administration of these agents with levothyroxine 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 FT4 and T3 to TBG arid 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 as 30%. Drugs that may alter T4 and T3 metabolism Drugs that may increase hepatic metabolism which may result in hypothyroidism Carbamazepine Hydantoins Phenobarbital Rifampin Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T4 may be reduced by 20% - 40%, but most patients have normal serum TSH levels and are clinically euthyroid. Drugs that may decrease T4 5'-deiodinase activity Amiodarone Beta-adrenergic antagonists (eg, propranolol >160 mg/day) Glucocorticoids (eg, dexamethasone 4 mg/day) Propylthioracil (PTU) 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. 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 glucocorticoids therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). Miscellaneous Anticoagulants - Coumarin derivatives - Indandione derivatives 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. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. 25

26 TIROSINT Product Monograph Table 7: Drug Thyroid axis interaction (cont d) Antidepressants - Tricyclics (eg, amitriptyline) - Tetracyclics (eg, maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; eg, sertraline) Antidiabetic Agents - Iguanides - Sulfonylureas - Thiazolidinediones - Insulin Cardiac Glycosides Cytokines - interferon-α - interleukin-2 Growth Hormones - Somatrem - Somatropin Ketamine Methylxanthine Bronchodilators (eg, theophylline) Radiographic Agents Sympathomimetics Chloral hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide diuretics Concurrent use of tri/tetracyclic 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 and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. 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. Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. Thyroid hormones may reduce the uptake of 123 I, 131 I, and 99 TC 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. These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. 26