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Product Monograph

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TIROSINT Product Monograph

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Table of Contents1. EXECUTIVE SUMMARY .................................................................................................................5

2. DISEASE DESCRIPTION ................................................................................................................62.1 Epidemiology ........................................................................................................................6 2.2 Pathophysiology ..................................................................................................................6

2.2.1 Hashimoto’s Disease .............................................................................................7 2.2.2 Secondary/Central Hypothyroidism ...............................................................82.2.3 Nontoxic goiter .......................................................................................................9

2.3 Clinical Importance .............................................................................................................92.4 Treatment Goals .................................................................................................................11 2.5 Treatment Options ............................................................................................................11

3. PLACE IN THERAPY .....................................................................................................................123.1 Narrow Therapeutic Index..............................................................................................123.2 Bioequivalence...................................................................................................................143.3 Gastric pH: Significant Effect on Dissolution and Absorption...........................143.4 Uniform Delivery With TIROSINT Gel Capsules .......................................................15

4. PRODUCT DESCRIPTION...........................................................................................................164.1 Generic Name, Brand Name, and Therapeutic Class.............................................164.2 Dosage Forms and Package Sizes................................................................................164.3 NDC for All Formulations ................................................................................................164.4 WAC Cost Per Unit .............................................................................................................164.5 AHFS or Other Drug Classification ..............................................................................164.6 FDA-Approved Indications.............................................................................................164.7 Use in Special Populations .............................................................................................174.8 Pharmacology.....................................................................................................................174.9 Pharmacokinetics/Bioequivalence..............................................................................174.10 Manufacturing and Purification.................................................................................184.11 Contraindications............................................................................................................184.12 Warnings/Precautions ...................................................................................................194.13 Adverse Events.................................................................................................................224.14 Drug/Food/Disease Interactions ...............................................................................234.15 Dosing and Administration .........................................................................................28

4.15.1 Specific Patient Populations..........................................................................284.15.2 Pediatric Dosage................................................................................................29

Table of Contents

Table of Contents (cont’d)5. OTHER STUDIED USES.............................................................................................................32

5.1 Subclinical Hypothyroidism ...........................................................................................32

6. REFERENCES ...............................................................................................................................33

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Finally.

Executive Summary

In hypothyroidism, precise treatment with levothyroxine sodium (T4) to bring thyrotropinlevels within the therapeutic range is clinically challenging but critical to quality patientcare. The narrow therapeutic index associated with T4 therapy requires individualizedtitration and follow-up to adequately treat hypothyroidism, without overtreating tohyperthyroidism. Failure to maintain T4 levels within the therapeutic range can result insignificant clinical consequences and higher health care costs. Levothyroxine sodiumtablets, the current standard of care for management of hypothyroidism, have beenprone to significant variance in bioavailability. In response, national medical organizationsand patient advocacy continue to question bioequivalence between branded andgeneric T4 formulations.

TIROSINT® (levothyroxine sodium) capsules represent a change in levothyroxineformulation—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.

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Summ

ary

Disease Description

2.1 EpidemiologyHypothyroidism is an endocrine disorder with numerous etiologies resulting in adeficiency in thyroid hormone (Table 1). About 2% of women and 0.1% of men haveovert hypothyroidism, and as many as 10% have subclinical (mild) hypothyroidism. Thecondition 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 withthe probability of developing hypothyroidism increasing with age.3 Nearly 10% ofwomen and 6% of men >65 years of age have hypothyroidism.4

Primary hypothyroidism results from deterioration or destruction of the thyroid, mostcommonly from autoimmune thyroiditis, know as Hashimoto’s disease. The developmentof Hashimoto’s disease is most common in women during middle age.5 Other causesinclude surgical removal of the thyroid, ablation with radioactive iodine (as inmanagement of hyperthyroidism or goiter), irradiation, tumor (lymphoma), and drugssuch as lithium, interferon, or amiodarone.6,7 Central hypothyroidism, also known assecondary/tertiary hypothyroidism, involves disorders of the hypothalmic-pituitary axisthat impair production of thyroid stimulating hormone (TSH).4

2.2 PathophysiologyThe principal thyroid hormones are thyroxine (T4) and triiodothyronine (T3). T4 is anendogenous “prohormone” that is converted in body tissue into the biologically activeT3. These hormones are active in most cells of the body, affecting protein, lipid andcarbohydrate metabolism, as well as growth and development. T3 and T4 promote oxygenconsumption, resulting in increased energy expenditure and heat production. Cardiaceffects are also attributed to the effects of thyroid hormones on the heart.2,8

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Chronic autoimmune thyroiditis (Hashimoto’s disease)Radioactive iodine therapySubtotal thyroidectomy Antithyroid drugsHead and neck surgeryRadiation therapy to the head, neck, or chestIodine deficiencyMedications: lithium, iodine, amiodaroneSecondary hypothyroidism (hypopituitarism)IdiopathicCongenital

Table 1: Causes of hypothyroidism7


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Disease D

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Disease Description (cont’d)In the blood, T3 and T4 are almost entirely bound to protein, requiring analysis of freeT4/T3 to determine circulating levels.9 Their secretion is stimulated by the presence ofiodine and is regulated by release of the thyroid-stimulating hormone (TSH) thyrotropinfrom the pituitary. TSH secretion is, in turn, dependent on release of thyroid-regulatinghormone (TRH) secreted from the hypothalamus. These hormones interact in a feedbackloop, 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 thyroidhormone signal a drop in TRH and TSH production and reduce further T3 and T4 releasefrom the thyroid.9

Figure 1: Major steps in thyroid hormone regulation9

2.2.1 Hashimoto’s Disease (Chronic Autoimmune Thyroiditis)Hashimoto’s disease, the most common cause of hypothyroidism, is an autoimmunedisorder characterized by chronic infiltration of the thyroid by plasma cells andlymphocytes.5 Pathology of the disease stems from a complex process of immunologicevents, resulting in destruction of thyroid tissue.5,7 The condition is mediated by thepresence of thyroid peroxidase enzyme (TPO) antibodies. TPO is a protein that liberatesiodine 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 thedisease.5,7 Hashimoto’s disease is often associated with other autoimmune diseases,including vitiligo, rheumatoid arthritis, Addison’s disease, diabetes mellitus, andpernicious anemia.6

Hypothalamus

Pituitary Gland

Thyroid

TRH

TSH

T3, T4 in Blood and Tissue

2.2.2 Secondary/Central HypothyroidismDifferent profiles of hormonal changes occur with primary vs secondary hypothyroidism.Primary hypothyroidism results in elevated serum TSH levels and free T4 levels that arelower 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, pituitaryradiation therapy, and head trauma.1

Figure 2A:Hormone changes occurring during the development of primary hypothyroidism1

Figure 2B:Hormone changes occurring during the development of central hypothyroidism1

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HighValues

Values

Normal

Set KeyTSHT3

T4

Severity of Hypothyroidism

Mild Moderate Severe

NormalRange

Low

HighValues

Values

Normal

Set KeyTSHT3

T4

Severity of Hypothyroidism

Mild Moderate Severe

NormalRange

Low

Disease Description (cont’d)

Disease D

escription

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Disease Description (cont’d)2.2.3 Nontoxic GoiterThyroid dysfunction is associated with other common conditions such as goiter. Knowncauses of simple nontoxic goiter include intrinsic thyroid hormone production defectsand an iodine deficiency.4 Other causes include the use of drugs that can decrease thesynthesis of thyroid hormone (eg, amiodarone or other iodine-containing compounds,such as lithium). Goiter frequently occurs at puberty, during pregnancy, and atmenopause; causes are not clearly understood. Overexpression of TSH, which may leadto goiter, can be suppressed by supplementation of thyroid hormone.4

2.3 Clinical ImportanceDue to the ubiquitous presence of thyroid hormone throughout the body, inadequatelevels cause serious general effects such as decreased oxygen consumption as well asdefects in individual organs.2 Hypothyroidism typically has a gradual course. Abnormalblood levels of the hormone may be present before symptoms become apparent; somepatients with mild disease may not become aware of symptoms, such as fatigue, untilhormone 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, andconstipation.7 Due to its vague clinical and physical manifestations, hypothyroidism isoften overlooked or ignored. For this reason, clinicians are advised to utilize a lowthreshold for screening when patients present with symptoms suggestive of thyroiddysfunction.7

Patients with more severe hypothyroidism (myxedema) may have distinct clinicalcharacteristics including periorbital edema.2,4 Untreated hypothyroidism carries the riskof myxedema coma, a life-threatening endocrine emergency. Multiple organ systemsare 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, attributingsymptoms to natural aging processes. Symptoms mimic nonspecific geriatric syndromesincluding anorexia, weight loss, falling, incontinence, arthralgias, muscle aches,decreased mobility, and confusion. In the elderly, hypothyroidism may mimic dementiaor Parkinsonism.4

Hypothyroidism during pregnancy is associated with increased maternal and fetalmorbidity, including maternal hypertension, preeclampsia, anemia, postpartumhemorrhage, spontaneous abortion, fetal death, low birth weight, and abnormal braindevelopment. T4 therapy is safe during pregnancy and recommended even in mildhypothyroidism.6

Table 2: Clinical presentation of hypothyroidism2

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Affected body system Symptoms Signs

GeneralCold intolerance FatigueMild weight gain

Hypothermia

Nervous system

LethargyMemory defectsPoor attention spanPersonality change

SomnolenceSlow speechPsychopathology: myxedemamadnessDiminished hearing and taste Cerebellar ataxiaDepression

Neuromuscular system WeaknessMuscle crampsJoint pain

Delayed relaxation of deeptendon reflexesCarpal tunnel syndrome

Gastrointestinal system NauseaConstipation

Large tongueAscites

Cardiorespiratory system Decreased exercise tolerance

Hoarse voiceBradycardiaMild hypertensionPericardial effusionPleural effusionHyperlipidemia

Reproductive systemDecreased libidoDecreased fertilityMenstrual disorders

Heavier and/or more frequentmenstrual periods

Skin and appendages

Rough, dry, itchy skinPuffy faceHair lossBrittle nails

Edema of the hands, face, anklesPeriorbital swellingPallorYelllowish skinCoarse hairDecreased sweating



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Disease D

escription2.4 Treatment Goals The American Academy of Endocrinology (AACE) Guidelines for Clinical Practice for Evaluation andTreatment of Hypothyroidism call for careful dose titration of oral levothyroxine to a target TSH levelas the standard of care for hypothyroidism.6 Careful titration and monitoring is necessary in orderto maintain a euthyroid state, while avoiding adverse events (AEs) due to overtreatment. Targetserum TSH levels in patients receiving T4 should be between 0.5 and 3.0 mIU/L.10 To achieve thisgoal, 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 and150 mcg per day in men.10 In elderly patients without overt heart disease, levothyroxine should beinitiated at 25 mcg per day, with 25-mcg increments at 8-week intervals, until serum TSH levelreturns to normal.10

In secondary (central) hypothyroidism the goal of therapy is to maintain T4 levels within the mid- orupper-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.11

2.5 Treatment OptionsAccording to AACE, all physicians should treat hypothyroidism with oral levothyroxine replacementtherapy.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 reliablyrelieves symptoms and normalizes laboratory test values.1,12-14

Levothyroxine is available in multiple dosage strengths to allow for precise titration to achievetarget TSH levels.1The 7-day half-life of levothyroxine permits once-a-day dosing and maintenanceof a steady state, even with occasional missed doses. Steady-state levels in the blood are neededto assure conversion of biologically inactive T4 into adequate amounts of T3.1 In a clinical study of50 euthyroid patients who received levothyroxine therapy for thyroid hormone replacement afterthyroidectomy, 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 tomarked fluctuations in T3 levels.4 These T3 peaks render patients receiving liothyroxine sodiumchemically hyperthyroid for hours at a time, potentially increasing cardiac risks.4

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 liotrixtablets (Thyrolar®).* Results of a meta-analysis of 11 studies involving 1216 patients found nosignificant improvements in quality of life (QOL) parameters of combination therapy overmonotherapy with T4.16 Generic thyroid USP preparations of desiccated porcine thyroid tissuecontain T4, T3, and primarily bound iodine. The ratio of T3 to T4 in porcine thyroid is not identical tothat of humans and may result in higher than normal T3 concentrations.11

* Thyrolar is a registered trademark of Forest Pharmaceuticals.


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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. Therelative 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 ofeither drug under fasting conditions. There was a 35-day washout period betweentreatments. Pharmacokinetic parameters were adjusted for baseline levothyroxine levels.The pharmacokinetics of levothyroxine after TIROSINT administration was comparable tothose following Synthroid administration in this one study. TIROSINT dose proportionalitywas demonstrated in a 3-way crossover study comparing a 600-mcg dose administeredas 12 TIROSINT 50-mcg, 6 TIROSINT 100-mcg, and 4 TIROSINT 150-mcg capsules.17

3.1 Narrow Therapeutic IndexThe 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 andsafety, 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

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Place in Therapy

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Table 3: Circumstances that may alter levothyroxine requirements10,18,19

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

Place in Therapy (cont’d)

Failure to maintain T4 levels within the therapeutic range can result in significant clinicalconsequences and higher healthcare costs.6,20 With undertreatment, risks includesuboptimal response and sequelae of ongoing hypothyroidism including myxedemacoma, infertility, and higher rate of stillbirth.4 Risks associated with overtreatment includecardiotoxic effects such as cardiac pain, palpitations, or cardiac arrhythmias. Excess T4 isparticularly dangerous in patients with coronary heart disease (CHD).8,10 T4 treatment tothe point of hyperthyroidism is associated with increases in hepatic enzymes and risk ofaccelerated 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 theneed for frequent patient visits and laboratory testing.6

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3.2 BioequivalenceThe narrow therapeutic ratio exhibited by T4 amplifies the need for consistentbioavailability, making it particularly important that the amount of available active agentis consistent for a given pharmaceutical dose. However, the bioavailability of T4 tabletshas been repeatedly questioned. Issues concerning the stability, potency, andtherapeutic bioequivalence of past and current formulations have been raised for bothbranded and generic tablets. To better assure reliable stability of levothyroxine sodiumformulation, the FDA required New Drug Applications (NDAs), with bioequivalance andbioavailability data, to be submitted and approved for all levothyroxine productsmarketed after August 14, 2000.20

Unpredictable potency of tablet formulations has been attributed to the instability oflevothyroxine sodium and its vulnerability to pharmaceutical tablet manufacturingprocesses.21 The FDA now requires manufacturers to meet a 95% to 105% potencyspecification.20,22 In order to compensate for degradation, formulations have beenmanufactured with an excess of active ingredient, resulting in superpotency. Thus, as aresult of stability problems and manufacturing practices used to compensate forinstability of the drug, potency of each product may vary considerably between brandsor even within the same brand.

3.3 Gastric pH: Significant Effect on Dissolution and AbsorptionThe bioavailability and absorption of different formulations of T4 are affected byproperties such as the rate of drug dissolution and rate of release.23,24 Adequateabsorption of T4 is critical to the effectiveness of therapy and is influenced by numerousfactors including age, patient compliance and diet, absorption kinetics, malabsorptiondisorders, gastric pH, and the effects of other drugs.10,18,19 Thyroxine is principallyabsorbed 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 themany conditions that affect acid secretion and gastric pH. Absorption of approximately62% to 82% of the ingested T4 dose is typical.18 Clinical studies have demonstratedsignificant malabsorption of T4 in patients with altered gastric pH due to Helicobacterpylori infection, with chronic gastritis, and undergoing treatment with proton pumpinhibitors (PPIs).18,19

In one trial, patients with gastric abnormalities and those treated with omeprazolerequired doses that were 22% to 34% higher than those required by the control grouppatients to maintain a euthyroid state.18 In a retrospective analysis, the initiation of PPItherapy with lansoprazole in euthyroid patients necessitated a statistically significantmean dose increase of 29% to maintain pretreatment TSH levels (P=.035). Changes indose for a control group were not statistically significant.19

Place in Therapy (cont’d)

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Place in Therapy

Finally.

Place in Therapy (cont’d)Recently, an in vitro study was conducted to compare the effect of pH on the dissolutionrate of TIROSINT capsules. A highly sensitive analytic technique (inductively coupledplasma mass spectroscopy) was employed.23 When measured at various pH levels,TIROSINT dissolution was 100% across pH 1-8, delivering rapid, consistent dissolutionregardless of the level of gastric pH present (Figure 3).23*

Figure 3: An in vitro dissolution study showed that Tirosint gel caps were unaffectedby gastric pH23*

*In vitro data do not necessarily correlate with clinical outcomes.

Numerous clinical circumstances may cause irregularity in the gastric pH leading togastric hypoacidity and altered oral absorption of T4, including H pylori infection, chronicgastritis, and hypochlorhydria.25 Gastric hypoacidity may also result from chronic acidsuppression therapy with PPIs, antacids, and histamine H2 receptor antagonists used totreat gastroesophageal reflux disease (GERD), and other acid peptic disorders26 that mayaffect between 20% to 25% of the patient population.27 Gastric pH profile may changeby as much as 2 to 3 pH units during these conditions or as a result of chronic acidsuppression therapy.25,28 Under these conditions, in which variations in gastric pH mayreduce dissolution of T4 tablets and the absorption of T4, TIROSINT capsules offer greaterreassurance 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 aliquid phase, TIROSINT provides batch-to-batch consistency and uniform distribution.The process used to manufacture TIROSINT avoids excessive heat, preventingdegradation of the molecule by heat-related deactivation of T4. The soft capsules have anouter shell to protect T4 from light, air, humidity, and micro-contaminants, which assureslevothyroxine stability and consistency over time. No excessively high temperatures areused in manufacturing.17

pH 1.2

pH 2.4

pH 4.0

pH 5.0

pH 6.0

pH 7.0

pH 8.0

0

20

40

60

80

100

120

0 20 40 60 80 100 120 140 160 180 200

Time (minutes)

T 4 di

ssolve

d (%

)

4.1 Generic Name, Brand Name, and Therapeutic ClassTIROSINT® (levothyroxine sodium) is a thyroid hormone replacement agent.

4.2 Dosage Forms and Package SizesTIROSINT delivers levothyroxine in a glycerin solution via a soft gel tablet. The gel capsare 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 andto simplify patient compliance. TIROSINT is available in 10 dosage strengths includingthe exclusive low, 13-mcg dose (Table 4). To reduce confusion, product boxes and blisterpackaging are color-coded for each individual dosage strength. To help reduce thepotential for missed or forgotten doses, each blister pack contains 7 capsules labeled fordays of the week.

4.3 NDC for All FormulationsSee Table 4

4.4 WAC Cost Per UnitWAC cost per unit is $17.36.

4.5 AHFS or Other Drug Classification68.36.04

4.6 FDA-Approved IndicationsTIROSINT is indicated as a replacement or supplemental therapy in congenital oracquired hypothyroidism of any etiology. Specific indications include primary (thyroidal)hypothyroidism resulting from functional deficiency, primary atrophy, partial or totalcongenital 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.

Product Description

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Table 4. TIROSINT product information

Strength (mcg) Color NDC13 Olive 24090-490-8425 Orange 24090-491-8450 White 24090-492-8475 Purple 24090-493-8488 Green 24090-494-84

100 Yellow 24090-495-84112 Rose 24090-496-84125 Brown 24090-497-84137 Blue 24090-498-84150 Turquoise 24090-499-84

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Product Description

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Product Description (cont’d)TlROSINT therapy is not indicated for the treatment of transient hypothyroidism duringthe recovery phase of subacute thyroiditis. TIROSINT is also indicated for secondary(pituitary) hypothyroidism, tertiary (hypothalamic) hypothyroidism, and subclinicalhypothyroidism.

As a pituitary TSH suppressant, TIROSINT is indicated in the treatment or prevention ofvarious types of euthyroid goiters, including thyroid nodules, subacute or chroniclymphocytic thyroiditis (Hashimoto’s disease), multinodular goiter, and in conjunctionwith surgery and radioactive iodine therapy in the management of thyrotropin-dependent well-differentiated thyroid carcinoma.

4.7 Use in Special PopulationsSee WARNINGS and PRECAUTIONS and DOSING and ADMINSTRATION for specificinformation about treating these and other patient populations with TIROSINT.

4.8 PharmacologyThe principal pharmacologic effect of exogenous thyroid hormones is to increase themetabolic rate of body tissues. Thyroid hormones are also involved in the regulation ofcell growth and differentiation. Although the precise mechanism of action (MOA) bywhich thyroid hormones affect metabolism and cellular growth and differentiation is notclearly established, it is known that these physiologic effects are mediated at the cellularlevel, principally via triiodothyronine or T3; a major portion of triiodothyronine is derivedfrom thyroxine or T4 by deiodination in peripheral tissues. Thyroxine is the majorcomponent of normal secretions of the thyroid gland and is therefore the principaldeterminant of normal thyroid function.

4.9 Pharmacokinetics/BioequivalenceThe 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 oraldose of either drug under fasting conditions. There was a 35-day washout periodbetween treatments. Pharmacokinetic parameters were adjusted for baselinelevothyroxine levels. The pharmacokinetics of levothyroxine after TIROSINTadministration was comparable to those following Synthroid administration (Table 5).

Table 5: Summary of levothyroxine pharmacokinetic parameters (adjusted for baseline T4 levels)17

Parameter

AUC0-t (n=24; adjusted with the baseline)

Cmax (n=24; adjusted with the baseline)

103.0 92.8-114.4

106.8 100.7-113.2

Ratio (%)

(Test/Reference)

90% Confidence

Interval

Dosage form proportionality was evaluated in a randomized, 600-mcg dose, 3-waycrossover study in healthy volunteers under fasting conditions. Single oral doses ofTIROSINT in 3 strengths (ie, 12 capsules of 50 mcg, 6 capsules of 100 mcg, and 4 capsulesof 150 mcg) were administered in the study and the treatments were separated by atleast a 35-day washout period. The study demonstrated that the 50 mcg, 100 mcg, and150 mcg are dosage form equivalent (Table 6).17

Table 6: Results of bioequivalence assessment using baseline-adjusted serum levothyroxine concentrations17

4.10 Manufacturing and Purification TIROSINT is manufactured using a process called PEARLtec™ (Precision Encapsulationtechnology for the Application and Release of a Liquid formulation). This extremelyprecise and delicate technique saves the chemically unstable active ingredient(levothyroxine) from mechanical and thermal stress. The active ingredient does not needto be finely ground or heated, both of which occur during tablet manufacturing. Thestate-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 determinedby the concentration of the levothyroxine sodium solution and by the volume of theinjected solution. Since they are enclosed in an inert environment, the levothyroxinemolecules remain protected from UV rays, as well as from oxygen and humidity. Thisavoids any decomposition reactions.

4.11 ContraindicationsLevothyroxine is contraindicated in patients with untreated subclinical (suppressedserum TSH level with normal T3 and T4 levels) or overt thyrotoxicosis of any etiology andin patients with acute myocardial infarction (AMI). Levothyroxine is contraindicated inpatients with uncorrected adrenal insufficiency, since thyroid hormones may precipitatean acute adrenal crisis by increasing the metabolic clearance of glucocorticoids (seePRECAUTIONS). TIROSINT is contraindicated in patients with hypersensitivity to any ofthe inactive ingredients in TIROSINT capsules (See DESCRIPTION, Inactive Ingredients).

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Ratio (90% CI)

Parameter

AUC0-t (ng h/mL; n=24) 97.3% (89.1-106.3) 98.8 (90.4-107.9)

Cmax (ng/mL; n=24) 95.6 (87.8-104.0) 103.0 (94.6-112.1)

50 μg vs 100 μg 150 μg vs 100 μg


Product Description (cont’d)

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Product Description

Finally.

Product Description (cont’d)TIROSINT is also contraindicated for anyone who may be unable to swallow a capsule(eg, infants, small children).

4.12 Warnings/PrecautionsWARNING: Thyroid hormones, including TIROSINT, either alone or with othertherapeutic 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 areineffective for weight reduction. Larger doses may produce serious or even life-threatening manifestations of toxicity, particularly when given in association withsympathomimetic amines such as those used for their anorectic effects.

Levothyroxine sodium should not be used in the treatment of male or female infertilityunless this condition is associated with hypothyroidism.

In patients with nontoxic diffuse goiter or nodular thyroid disease, particularly the elderlyor those with underlying cardiovascular disease, levothyroxine sodium therapy iscontraindicated if the serum TSH level is already suppressed due to the risk ofprecipitating overt thyrotoxicosis (see CONTRAINDICATIONS). If the serum TSH level isnot suppressed, TIROSINT should be used with caution in conjunction with carefulmonitoring of thyroid function for evidence of hyperthyroidism and clinical monitoringfor potential associated adverse cardiovascular signs and symptoms of hyperthyroidism.

GeneralLevothyroxine has a narrow therapeutic index. Regardless of the indication for use,careful dosage titration is necessary to avoid the consequences of over- or under-treatment. These consequences include, among others, effects on growth anddevelopment, cardiovascular function, bone metabolism, reproductive function,cognitive function, emotional state, gastrointestinal function, and glucose and lipidmetabolism. Many drugs interact with levothyroxine sodium, necessitating adjustmentsin dosing to maintain therapeutic response (see Drug Interactions).

Effects on bone mineral density – In women, long-term levothyroxine sodium therapyhas been associated with increased bone resorption, thereby decreasing BMD, especiallyin post-menopausal women on greater than replacement doses or in women who arereceiving suppressive doses of levothyroxine sodium. The increased bone resorption maybe associated with increased serum levels and urinary excretion of calcium andphosphorous, elevations in bone alkaline phosphatase, and suppressed serumparathyroid hormone levels. Therefore, it is recommended that patients receivinglevothyroxine sodium be given the minimum dose necessary to achieve the desiredclinical and biochemical response.

Patients with underlying cardiovascular disease – Exercise caution when administeringlevothyroxine to patients with cardiovascular disorders and to the elderly in whom thereis an increased risk of occult cardiac disease. In these patients, levothyroxine therapyshould be initiated at lower doses than those recommended in younger individuals or inpatients without cardiac disease. It should be noted that, unlike levothyroxine sodiumtablets, TlROSINT capsules cannot be cut in half. (see WARNINGS; PRECAUTIONS, GeriatricUse; and DOSAGE AND ADMINISTRATION). If cardiac symptoms develop or worsen, thelevothyroxine dose should be reduced or withheld for one week and then cautiouslyrestarted at a lower dose. Overtreatment with levothyroxine sodium may have adversecardiovascular effects such as an increase in heart rate, cardiac wall thickness, and cardiaccontractility and may precipitate angina or arrhythmias. Patients with coronary arterydisease who are receiving levothyroxine therapy should be monitored closely duringsurgical procedures, since the possibility of precipitating cardiac arrhythmias may begreater in those treated with levothyroxine. Concomitant administration of levothyroxineand sympathomimetic agents to patients with coronary artery disease may precipitatecoronary insufficiency.

Patients with nontoxic diffuse goiter or nodular thyroid disease – Exercise caution whenadministering levothyroxine to patients with nontoxic diffuse goiter or nodular thyroiddisease in order to prevent precipitation of thyrotoxicosis (see WARNINGS). If the serumTSH is already suppressed, levothyroxine sodium should not be administered (seeCONTRAINDICATIONS).

Associated Endocrine DisordersHypothalamic pituitary hormone deficiencies – In patients with secondary or tertiaryhypothyroidism, additional hypothalamic/pituitary hormone deficiencies should beconsidered, and, if diagnosed, treated (see PRECAUTIONS, Autoimmune polyglandularsyndrome for adrenal insufficiency).

Autoimmune polyglandular syndrome – Occasionally, chronic autoimmune thyroiditismay occur in association with other autoimmune disorders such as adrenal insufficiency,pernicious anemia, and insulin-dependent diabetes mellitus. Patients with concomitantadrenal insufficiency should be treated with replacement glucocorticoids prior toinitiation of treatment with levothyroxine sodium. Failure to do so may precipitate anacute adrenal crisis when thyroid hormone therapy is initiated, due to increasedmetabolic clearance of glucocorticoids by thyroid hormone. Patients with diabetesmellitus may require upward adjustments of their antidiabetic therapeutic regimenswhen treated with levothyroxine (see PRECAUTIONS, Drug Interactions).

Other associated medical conditionsInfants with congenital hypothyroidism appear to be at increased risk for othercongenital anomalies, with cardiovasc ular anomalies (pulmonary stenosis, atrial septaldefect, and ventricular septal defect) being the most common association.

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Product Description

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Product Description (cont’d)LABORATORY TESTS

GeneralThe diagnosis of hypothyroidism is confirmed by measuring TSH levels using a sensitiveassay (second-generation assay sensitivity ≤0.1 mIU/L or third-generation assaysensitivity ≤0.01 mIU/L) and measurement of free T4.

The adequacy of therapy is determined by periodic assessment of appropriate laboratorytests and clinical evaluation. The choice of laboratory tests depends on various factorsincluding the etiology of the underlying thyroid disease, the presence of concomitantmedical conditions, including pregnancy, and the use of concomitant medications (seePRECAUTIONS, Drug Interactions and Drug-Laboratory Test Interactions). Persistentclinical and laboratory evidence of hypothyroidism despite an apparent adequatereplacement dose of TIROSINT may be evidence of inadequate absorption, poorcompliance, drug interactions, or decreased T4 potency of the drug product.

AdultsIn adult patients with primary (thyroidal) hypothyroidism, serum TSH levels (using asensitive assay) alone may be used to monitor therapy. The frequency of TSH monitoringduring levothyroxine dose titration depends on the clinical situation but it is generallyrecommended at 6-8 week intervals until normalization. For patients who have recentlyinitiated levothyroxine therapy and whose serum TSH has normalized or in patients whohave had their dosage or brand of levothyroxine changed, the serum TSH concentrationshould be measured after 8-12 weeks. When the optimum replacement dose has beenattained, clinical (physical examination) and biochemical monitoring may be performedevery 6-12 months, depending on the clinical situation, and whenever there is a changein 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).

PediatricsIn patients with congenital hypothyroidism, the adequacy of replacement therapy shouldbe 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 alltimes in the upper half of the normal range. While the aim of therapy is to also normalizethe 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 resettingof the pituitary-thyroid feedback threshold as a result of in utero hypothyroidism. Failureof the serum T4 to increase into the upper half of the normal range within 2 weeks ofinitiation of TIROSINT therapy and/or of the serum TSH to decrease below 20 mIU/Lwithin 4 weeks should alert the physician to the possibility that the child is not receivingadequate therapy. Careful inquiry should then be made regarding compliance, dose of medication administered, and method of administration prior to raising the dose of TIROSINT.

The recommended frequency of monitoring of TSH and total or free- T4 in children is asfollows: at 2 and 4 weeks after the initiation of treatment; every 1-2 months during thefirst year of life; every 2-3 months between 1 and 3 years of age; and every 3 to 12 monthsthereafter until growth is completed. More frequent intervals of monitoring may benecessary if poor compliance is suspected or abnormal values are obtained. It isrecommended that TSH and T4 levels, and a physical examination, if indicated, beperformed 2 weeks after any change in TIROSINT dosage. Routine clinical examination,including assessment of mental and physical growth and development, and bonematuration, should be performed at regular intervals (see PRECAUTIONS, Pediatric Useand DOSAGE AND ADMINISTRATION).

Secondary (pituitary) and tertiary (hypothalamic) hypothyroidismAdequacy of therapy should be assessed by measuring serum free- T4 levels, whichshould be maintained in the upper half of the normal range in these patients.

Geriatric UseBecause of the increased prevalence of cardiovascular disease among the elderly,levothyroxine therapy should not be initiated at the full replacement dose.

4.13 Adverse Events

ADVERSE REACTIONS

Adverse reactions associated with levothyroxine therapy are primarily those ofhyperthyroidism due to therapeutic overdosage (see PRECAUTIONS and OVERDOSAGE).They include the following:

General: fatigue, increased appetite, weight loss, heat intolerance, fever, excessivesweating; Central nervous system: headache, hyperactivity, nervousness, anxiety,irritability, emotional lability, insomnia; Musculoskeletal: tremors, muscle weakness;Cardiovascular: palpitations, tachycardia, arrhythmias, increased pulse and bloodpressure, heart failure, angina, myocardial infarction, cardiac arrest; Respiratory: dyspnea;Gastrointestinal: diarrhea, vomiting, abdominal cramps, and elevations in liver functiontests; Dermatologic: hair loss, flushing; Endocrine: decreased bone mineral density;Reproductive: menstrual irregularities, impaired fertility.

Pseudotumor cerebri and slipped capital femoral epiphysis have been reported inchildren receiving levothyroxine therapy. Overtreatment may result in craniosynostosisin infants and premature closure of the epiphyses in children with resultant compromisedadult height. Seizures have been reported rarely with the institution of levothyroxinetherapy. Inadequate levothyroxine dosage will produce or fail to ameliorate the signsand symptoms of hypothyroidism. Hypersensitivity reactions to inactive ingredients haveoccurred in patients treated with thyroid hormone products. These include urticaria,pruritus, skin rash, flushing, angioedema, various GI symptoms (abdominal pain, nausea,

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Product Description

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Product Description (cont’d)vomiting, and diarrhea), fever, arthralgia, serum sickness, and wheezing. Hypersensitivityto levothyroxine itself is not known to occur.

OverdosageThe signs and symptoms of overdosage are those of hyperthyroidism (see PRECAUTIONSand ADVERSE REACTIONS). In addition, confusion and disorientation may occur. Cerebralembolism, shock, coma, and death have been reported. Seizures have occurred in a childingesting 18 mg of levothyroxine. Symptoms may not necessarily be evident or may notappear until several days after ingestion of levothyroxine sodium.

4.14 Drug/Food/Disease Interactions

DRUG INTERACTIONSMany drugs affect thyroid hormone pharmacokinetics and metabolism (eg, absorption,synthesis, secretion, catabolism, protein binding, and target tissue response) and mayalter the therapeutic response to TIROSINT. In addition, thyroid hormones and thyroidstatus have varied effects on the pharmacokinetics and actions of other drugs. A listingof drug-thyroidal axis interactions is contained in Table 7. The list of drug-thyroidal axisinteractions in Table 7 may not be comprehensive due to the introduction of new drugsthat interact with the thyroidal axis or the discovery of previously unknown interactions.The prescriber should be aware of this fact and should consult appropriate referencesources (eg, package inserts of newly approved drugs, medical literature) for additionalinformation if a drug-drug interaction with levothyroxine is suspected.

Table 7: Drug—Thyroid axis interaction

Drug or drug class Effect

Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur

Dopamine/Dopamine agonistsGlucocorticoidsOctreotide

Use of these agents may result in a transient reductionin TSH secretion when administered at the followingdoses: Dopamine (≥1 mcg/kg/min); Glucocorticoids(hydrocortisone ≥100 mg/day or equivalent); Octreotide (>100 mcg/day).

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Drugs that alter thyroid hormone secretion

AminoglutethimideAmiodaroneIodide (including iodine-containing radiographic contrast agents)LithiumMethimazolePropylthiouracil (PTU) SulfonamidesTolbutamide

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. Thefetus, neonate, elderly and euthyroid patients with underlying thyroid disease (eg, Hashimoto's thyroiditisor with Grave's disease previously treated with radioiodine or surgery) are among those individualswho are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents andamiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-termaminoglutethimide therapy may minimally decreaseT4 and T3) levels and increase TSH, although all valuesremain 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 amountsof iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated withantithyroid drugs or in euthyroid patients with thyroidautonomy (eg, multinodular goiter or hyperfunctioningthyroid adenoma). Hyperthyroidism may develop overseveral weeks and may persist for several months aftertherapy 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 CarbonateCation Exchange Resins

- Kayexalate- Ferrous Sulfate - Orlistat - Sucralfate

Concurrent use may reduce the efficacy of levothyroxineby binding and delaying or preventing absorption,potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate withlevothyroxine 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 Drugs that decrease serum TBG concentration

ClofibrateEstrogen-containing Oral ContraceptivesEstrogens (oral)Heroine/Methadone5-fluorouracilMitotaneTamoxifen

Androgen/Anabolic SteroidsAsparaginaseGlucocorticoidsSlow release nicotinic acid


Table 7: Drug—Thyroid axis interaction (cont’d)


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Product Description

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Drugs that may cause protein-binding site displacement

Furosemide (>80 mg IV)HeparinHydantoinsNonsteroidal Anti-inflammatory Drugs

- Fenamates- Phenylbutazone

Salicyclate (>2 g/day)

Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continuedadministration results in a decrease in serum T4 andnormal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibitbinding 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 maydecrease by as much as 30%.

Drugs that may alter T4 and T3 metabolism

Drugs that may increase hepatic metabolism which may result in hypothyroidism

CarbamazepineHydantoinsPhenobarbitalRifampin

Stimulation of hepatic microsomal drug-metabolizingenzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increasedlevothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding oflevothyroxine, and total- and free- T4 may be reducedby 20% - 40%, but most patients have normal serumTSH levels and are clinically euthyroid.

Drugs that may decrease T4 5'-deiodinase activity

AmiodaroneBeta-adrenergic antagonists(eg, propranolol >160 mg/day) Glucocorticoids(eg, dexamethasone ≥4 mg/day)Propylthioracil (PTU)

Administration of these enzyme inhibitors decreasesthe 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 changeslightly, TSH levels remain normal and patients areclinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is convertedto the euthyroid state. Short-term administration oflarge doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change inserum T4 levels. However, long-term glucocorticoidstherapy 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 catabolismof vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oralanticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factorsynthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oralanticoagulants and the dose of anticoagulant therapyadjusted accordingly.


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Antidepressants- Tricyclics (eg, amitriptyline)- Tetracyclics (eg, maprotiline)- Selective Serotonin Reuptake Inhibitors

(SSRIs; eg, sertraline)

Concurrent use of tri/tetracyclic antidepressants andlevothyroxine may increase the therapeutic and toxiceffects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effectsmay include increased risk of cardiac arrhythmias andCNS stimulation; onset of action of tricyclics may beaccelerated. Administration of sertraline in patientsstabilized on levothyroxine may result in increasedlevothyroxine requirements.

Antidiabetic Agents- Iguanides- Sulfonylureas- Thiazolidinediones- Insulin

Addition of levothyroxine to antidiabetic or insulintherapy may result in increased antidiabetic agent orinsulin requirements. Careful monitoring of diabeticcontrol is recommended, especially when thyroid therapy is started, changed, or discontinued.

Cardiac Glycosides

Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient isconverted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.

Cytokines- interferon-α- interleukin-2

Therapy with interferon-α has been associated with thedevelopment of antithyroid microsomal antibodies in20% of patients and some have transient hypothy-roidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are athigher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient pain-less thyroiditis in 20% of patients; interferon-β and –γhave not been reported to cause thyroid dysfunction.

Growth Hormones- Somatrem- Somatropin

Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interferewith growth response to growth hormone.

KetamineConcurrent use may produce marked hypertensionand tachycardia; cautious administration to patientsreceiving thyroid hormone therapy is recommended.

Methylxanthine Bronchodilators(eg, theophylline)

Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normalwhen the euthyroid state is achieved.

Radiographic Agents Thyroid hormones may reduce the uptake of 123 I, 131I,and 99TC

Sympathomimetics

Concurrent use may increase the effects of sympath-omimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency whensympathomimetic agents are administered to patientswith coronary artery disease.

Chloral hydrateDiazepamEthionamideLovastatinMetoclopramide6-mercaptopurineNitroprussidePara-aminosalicylate sodiumPerphenazineResorcinol (excessive topical use)Thiazide diuretics

These agents have been associated with thyroid hormone and/or TSH level alterations by variousmechanisms.



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Product Description

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Product Description (cont’d)Oral anticoagulants – Levothyroxine increases the response to oral anticoagulant therapy.Therefore, a decrease in the dose of anticoagulant may be warranted with correction ofthe hypothyroid state or when the TIROSINT dose is increased. Prothrombin time shouldbe closely monitored to permit appropriate and timely dosage adjustments (see Table 7).

Digitalis glycosides – The therapeutic effects of digitalis glycosides may be reduced bylevothyroxine. Serum digitalis glycoside levels may be decreased when a hypothyroidpatient becomes euthyroid, necessitating an increase in the dose of digitalis glycosides(see Table 7).

Drug-food interactions – Consumption of certain foods may affect levothyroxineabsorption thereby necessitating adjustments in dosing. Soybean flour (infant formula),cottonseed meal, walnuts, and dietary fiber may bind and decrease the absorption oflevothyroxine sodium from the GI tract.

Drug-laboratory test interactions – Changes in thyroxine binding globulins (TBG)concentration must be considered when interpreting T4 and T3 values, which necessitatesmeasurement and evaluation of unbound (free) hormone and/or determination of thefree T4 index (FT4I). Pregnancy, infectious hepatitis, estrogens, estrogen-containing oralcontraceptives, and acute intermittent porphyria increase TBG concentrations. Decreasesin TBG concentrations are observed in nephrosis, severe hypoproteinemia, severe liverdisease, acromegaly, and after androgen or corticosteroid therapy (see also Table 7).Familial hyper- or hypothyroxine binding globulinemias have been described, with theincidence of TBG deficiency approximating 1 in 9000.

Carcinogenesis, Mutagenesis, and Impairment of Fertility – Animal studies have not beenperformed to evaluate the carcinogenic potential, mutagenic potential, or effects onfertility of levothyroxine. The synthetic T4 in TIROSINT is identical to that producednaturally by the human thyroid gland. Although there has been a reported associationbetween prolonged thyroid hormone therapy and breast cancer, this has not beenconfirmed. Patients receiving TIROSINT for appropriate clinical indications should betitrated to the lowest effective replacement dose.

4.15 Dosing and Administration

General PrinciplesThe goal of replacement therapy is to achieve and maintain a clinical and biochemicaleuthyroid state. The goal of suppressive therapy is to inhibit growth and/or function ofabnormal thyroid tissue. The dose of TIROSINT that is adequate to achieve these goalsdepends on a variety of factors, including the patient's age, body weight, cardiovascularstatus, concomitant medical conditions including pregnancy, concomitant medications,and the specific nature of the condition being treated (see WARNINGS andPRECAUTIONS). Hence, the following recommendations serve only as dosing guidelines.Dosing must be individualized and adjustments made based on periodic assessment ofthe patient’s clinical response and laboratory parameters (see PRECAUTIONS, LaboratoryTests).

TIROSINT is administered as a single daily dose, preferably one-half to one hour beforebreakfast. TIROSINT should be taken at least 4 hours apart from drugs that are known tointerfere with its absorption (see PRECAUTIONS, Drug Interactions). TIROSINT capsulescannot be cut or crushed.

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

Caution should be exercised when administering TIROSINT to patients with underlyingcardiovascular disease, to the elderly, and to those with concomitant adrenalinsufficiency (see PRECAUTIONS).

4.15.1 Specific Patient Populations

Hypothyroidism in Adults and in Children in Whom Growth and Puberty are Complete(see WARNINGS and PRECAUTIONS, Laboratory Tests)

Therapy may begin at full replacement doses in otherwise healthy individuals <50 yearsof age and in >50 years of age who have been recently treated for hyperthyroidism orwho have been hypothyroid for only a short time (such as a few months). The average full replacement dose of levothyroxine sodium is approximately 1.7 mcg/kg/day(eg, 100-125 mcg/day for a 70 kg adult). Older patients may require <1 mcg/kg/day.Levothyroxine sodium doses greater than 200 mcg/day are seldom required. Aninadequate response to daily doses ≥300 mcg/day is rare and may indicate poorcompliance, malabsorption, and/or drug interactions.

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Product Description

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Product Description (cont’d)For most patients older than 50 years or for patients <50 years of age with underlyingcardiac disease, an initial starting dose of 25-50 mcg/day of levothyroxine sodium isrecommended, with gradual increments in dose at 6-8 week intervals, as needed. Therecommended starting dose of levothyroxine sodium in elderly patients with cardiacdisease is 12.5-25 mcg/day, with gradual dose increments at 4- to 6-week intervals. Thelevothyroxine sodium dose is generally adjusted in 12.5-25 mcg increments until thepatient with primary hypothyroidism is clinically euthyroid and the serum TSH hasnormalized. Unlike levothyroxine sodium tablets, TIROSINT capsules cannot be cut in half.

In patients with severe hypothyroidism, the recommended initial levothyroxine sodiumdose is 12.5-25 mcg/day with increases of 25 mcg/day every 2 to 4 weeks, accompaniedby clinical and laboratory assessment, until the TSH level is normalized.

In patients with secondary (pituitary) or tertiary (hypothalamic) hypothyroidism, thelevothyroxine sodium dose should be titrated until the patient is clinically euthyroid andthe serum free-T4 level is restored to the upper half of the normal range.

4.15.2 Pediatric Dosage – Congenital or Acquired Hypothyroidism (see PRECAUTIONS,Laboratory Tests).

General PrinciplesIn general, levothyroxine therapy should be instituted at full replacement doses as soonas possible. Delays in diagnosis and institution of therapy may have deleterious effectson the child's intellectual and physical growth and development.

Undertreatment and overtreatment should be avoided (see PRECAUTIONS, Pediatric Use).

TIROSINT may be administered to infants and children, but only if they are able toswallow an intact capsule. Unlike levothyroxine sodium tablets, TIROSINT capsulescannot be crushed and suspended in a small amount of water, nor can they be dissolvedby placing in water prior to administration (see CONTRAINDICATIONS).

NewbornsTIROSINT is not recommended for the treatment of newborns as they maybe unable toswallow a capsule.

Infants and ChildrenLevothyroxine therapy is usually initiated at full replacement doses, with therecommended dose per body weight decreasing with age (see Table 8). However, inchildren with chronic or severe hypothyroidism, an initial dose of 25 mcg/day oflevothyroxine sodium is recommended with increments of 25 mcg every 24 weeks untilthe desired effect is achieved.

Hyperactivity in an older child can be minimized if the starting dose is one-fourth of therecommended full replacement dose, and the dose is then increased on a weekly basisby an amount equal to one-fourth the full-recommended replacement dose until thefull recommended replacement dose is reached.

Table 8: Levothyroxine sodium dosing guidelines for pediatric hypothyroidism

Pregnancy – Category A – Studies in women taking levothyroxine sodium during pregnancy have not shown an increased risk of congenital abnormalities. Therefore, the possibility of fetal harm appears remote. TIROSINT should not be discontinued during pregnancy, and hypothyroidism diagnosed during pregnancy should be promptly treated.

Subclinical hypothyroidism – If this condition is treated, a lower levothyroxine sodiumdose (eg, 1 mcg/kg/day) than that used for full replacement may be adequate to normalize the serum TSH level. Patients who are not treated should be monitored yearlyfor changes in clinical status and thyroid laboratory parameters.

TSH suppression in well-differentiated thyroid cancer and thyroid nodules – The target levelfor TSH suppression in these conditions has not been established with controlled studies. In addition, the efficacy of TSH suppression for benign nodular disease is controversial. Therefore, the dose of TIROSINT used for TSH suppression shouldbe individualized based on the specific disease and the patient being treated.

In the treatment of well-differentiated (papillary and follicular) thyroid cancer, levothyroxine is used as an adjunct to surgery and radioiodine therapy. Generally, TSH issuppressed to <0.1 mIU/L, and this usually requires a levothyroxine sodium dose of >2 mcg/kg/day. However, in patients with high-risk tumors, the target level for TSH suppression may be <0.01 mIU/L.

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*The dose should be adjusted based on clinical response and laboratory parameters (see Precautions, Laboratory Tests and Pediatric Use).


Age Daily dose per kg body weight*

0-3 months 10-15 mcg/kg/day



>12 years but growth and puberty incomplete 2-3 mcg/kg/day

Growth and puberty complete 1.7 mcg/kg/day


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Product Description

Finally.

In the treatment of benign nodules and nontoxic multinodular goiter, TSH is generallysuppressed to a higher target (eg, 0.1 to either 0.5 or 1.0 mIU/L) than that used for thetreatment of thyroid cancer. Levothyroxine sodium is contraindicated if the serum TSH is already suppressed due to the risk of precipitating overt thyrotoxicosis (see CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS).

Myxedema Coma – Myxedema coma is a life-threatening emergency characterized bypoor circulation and hypometabolism, and may result in unpredictable absorption oflevothyroxine sodium from the gastrointestinal tract. Therefore, oral thyroid hormonedrug products are not recommended to treat this condition. Thyroid hormone products formulated for intravenous administration should be administered.


Oth

er S

tudi

ed U

ses

5.1 Subclinical HypothyroidismSubclinical hypothyroidism is characterized by mildly increased serum TSH levels withnormal free T4 and T3 findings. Prevalence estimates range from 1% to 10% of thepopulation.6 Though symptoms may not be present, potential risks induce progressionto overt hypothyroidism, cardiovascular effects, hyperlipidemia, and neuropsychiatriceffects.6 Treatment is controversial; however, AACE treatment guidelines state thattreatment is indicated with TSH levels >10 μIU/mL or in patients with TSH levels between5 and 10 μIU/mL and goiter, or positive anti-TPO, or both. These patients represent thehighest risk for progress to overt hypothyroism.6

Other Studied Uses

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Finally.

References

1. McDermott MT. In the clinic: hypothyroidism. Ann Intern Med. 2009;151(11):ITC-6–ITC-14.

2. Shapiro LS, Surks MI. Hypothyroidism. In: Becker KL, ed. Principles and Practice of Endocrinology and Metabolism. 3rd ed. Philadelphia, PA: Lippincott Williams &Wilkins; 2001:445-454.

3. Weetman AP. Hypothyroidism: screening and subclinical disease. BMJ.1997:314(7088):1175-1178.

4. Endocrine and metabolic disorders: thyroid disorders: hypothyroidism. In: MerckManual Professional. www.merck.com/mmpe/print/sec12/chl52f.html. AccessedJanuary 29, 2010.

5. Lamberton P, Jackson I. Thyroiditis. In: Becker KL, ed. Principles and Practice of Endocrinology and Metabolism. 3rd ed. Philadelphia, PA: Lippincott Williams &Wilkins; 412-420.

6. American Association of Clinical Endocrinologists. Medical guidelines for clinicalpractice for the evaluation and treatment of hyperthyroidism and hypothyroidism.Endocrine Practice. 2002;8(6):457-467.

7. Tchong L, Veloski C, Siraj E. Hypothyroidism: management across the continuum. J Clin Outcomes Manag. 2009;16(5):231-235.

8. Blakesley VA. Current methodology to assess bioequivalence of levothyroxinesodium products is inadequate. AAPS J. 2005;7(1):E42-E46.

9. Reed L, Pangaro LN. Physiology of the thyroid gland. In: Becker KL, ed. Principlesand Practice of Endocrinology and Metabolism. 3rd ed. Philadelphia, PA: LippincottWilliams & Wilkins; 285-291.

10. Mandel SJ, Brent GA, Larsen PR. Levothyroxine therapy in patients with thyroid disease. Ann Intern Med. 1993;119(6):492-502.

11. Treatment guidelines. Drugs for thyroid disorders. Med Let. 2009;7(84):57-64.

12. Kabadi UM. Optimal daily levothyroxine dose in primary hypothyroidism: its relation to pretreatment thyroid hormone indexes. Arch Intern Med.1989;149(10):2209-2212.

References

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References (cont’d)13. Kabadi UM, Jackson T. Serum thyrotropin in primary hypothyroidism: a possible

predictor of optimum daily levothyroxine dose in primary hypothyroidism. Arch Intern Med. 1995;155(10):1046-1048.

14. Ain KB, Pucino F, Csako G, et al. Effects of restricting levothyroxine dosage strengthavailability. Pharmacotherapy. 1996;16(6):1103-1110.

15. Jonklas J, Davidson B, Bhagat S, Soldin SJ. Triodothyroxine levels in athyreotic individuals during levothyroxine therapy. JAMA. 2008;299(7):767-777.

16. Grozinsky-Glasberg S, Fraser A, Nahshoni E, Weizman A, Leibovici L. Thyroxine-triiodothyronine combination therapy versus thyroxine monotherapy for clinicalhypothyrodism: meta-analysis of randomized controlled trials. J Clin EndocrinolMetab. 2006:91(7):2592-2599.

17. Data on file. Akrimax Pharmaceuticals, LLC. 2010.

18. Centanni M, Gargano L, Canettieri G, et al. Thyroxine in goiter, helicobacter pyloriinfection, and chronic gastritis. N Eng J Med. 2006;354(17):1787-1795.

19. Sachmechi I, Reich DM, Aninyei M, Wibowo F, Gupta G, Kim PJ. Effect of protonpump inhibitors on serum thyroid-stimulating hormone level in euthyroid patientstreated with levothyroxine for hypothyroidism. Endocr Pract. 2007;13(4):345-349.

20. American Association of Clinical Endocrinologists, The Endocrine Society, andAmerican Thyroid Association. Joint position statement on the use and inter-changeability of thyroxine products. www.aace.com/pub.pdf/guidelines/AACE-TES-ATA-ThyroxineProducts.pdf. Accessed February 27, 2010.

21. Won CM. Kinetics of degradation of levothyroxine in aqueous solution and in solidstate. Pharm Res. 1992:9(11):131-137.

22. Food and Drug Administration. Levothyroxine sodium product information.http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm161257.htm. Accessed March 2, 2010.

23. Pabla D, Akhlaghi F, Zia H. A comparative pH-dissolution profile study of selectedcommercial levothyroxine products using inductively coupled plasma mass spectrometry. Eur J Pharm Biopharm. 2009;72(1):105-110.

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References

Finally.

24. Olveira G, Almaraz MC, Soriguer F, et al. Altered bioavailability due to changes inthe formulation of a commercial preparation of levothyroxine in patients with differentiated thyroid carcinoma. Clin Endocrinol. 1997;46(6):707-711.

25. Lahner E, Annibale B, Delle Fave G. Systematic review: Helicobacter pylori infectionand impaired drug absorption. Aliment Pharmacol Ther. 2009;29(40):379-386.

26. Lahner E, Annibale B, Delle Fave G. Systematic review: impaired drug absorptionrelated to the co-administration of antisecretory therapy. Aliment Pharmacol Ther.2009;29(12):1219-1229.

27. National Institute of Diabetes and Digestive and Kidney Diseases/National Institutes of Health. Digestive disease statistics. http://digestive.niddk.nih.gov/statistics/statistics.htm. Accessed February 15, 2010.

28. Fennerty MB. Pathophysiology of the upper gastrointestinal tract in the critically illpatient: Rationale for the therapeutic benefits of acid suppression. Crit Care Med.2002;30:S351-S355.

References (cont’d)

Manufactured for Akrimax Pharmaceuticals, LLC by: IBSA Institut Biochimique SA, 6903 Lugano, Switzerland

Tirosint is a registered trademark of IBSA Institut Biochimique SA.

Marketed and Distributed by: Akrimax Pharmaceuticals, LLC, Cranford, NJ 07016 USA

©2010 Akrimax Pharmaceuticals, LLC. June 2010 TIR-012

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