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Monograph
Finally.
TIROSINT Product Monograph
2
Table of Contents
1. EXECUTIVE SUMMARY.................................................................................................................5
2. DISEASE DESCRIPTION ................................................................................................................6
2.1 Epidemiology ........................................................................................................................6
2.2 Pathophysiology ..................................................................................................................6
2.2.1 Hashimoto’s Disease .............................................................................................7
2.2.2 Secondary/Central Hypothyroidism ...............................................................8
2.2.3 Nontoxic goiter .......................................................................................................9
2.3 Clinical Importance .............................................................................................................9
2.4 Treatment Goals.................................................................................................................11
2.5 Treatment Options ............................................................................................................11
3. PLACE IN THERAPY .....................................................................................................................12
3.1 Narrow Therapeutic Index..............................................................................................12
3.2 Bioequivalence...................................................................................................................14
3.3 Gastric pH: Significant Effect on Dissolution and Absorption...........................14
3.4 Uniform Delivery With TIROSINT Gel Capsules .......................................................15
4. PRODUCT DESCRIPTION...........................................................................................................16
4.1 Generic Name, Brand Name, and Therapeutic Class.............................................16
4.2 Dosage Forms and Package Sizes................................................................................16
4.3 NDC for All Formulations ................................................................................................16
4.4 WAC Cost Per Unit .............................................................................................................16
4.5 AHFS or Other Drug Classification ..............................................................................16
4.6 FDA-Approved Indications.............................................................................................16
4.7 Use in Special Populations .............................................................................................17
4.8 Pharmacology.....................................................................................................................17
4.9 Pharmacokinetics/Bioequivalence..............................................................................17
4.10 Manufacturing and Purification.................................................................................18
4.11 Contraindications............................................................................................................18
4.12 Warnings/Precautions ...................................................................................................19
4.13 Adverse Events.................................................................................................................22
4.14 Drug/Food/Disease Interactions ...............................................................................23
4.15 Dosing and Administration .........................................................................................28
4.15.1 Specific Patient Populations..........................................................................28
4.15.2 Pediatric Dosage................................................................................................29
3
Table of Contents
Finally.
TIROSINT Product Monograph
Table of Contents (cont’d)
5. OTHER STUDIED USES.............................................................................................................32
5.1 Subclinical Hypothyroidism ...........................................................................................32
6. REFERENCES ...............................................................................................................................33
4
Executive 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
Summary
Finally.
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 hypothyroidism7
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
Disease Description (cont’d)
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
Figure 1: Major steps in thyroid hormone regulation9
Hypothalamus
TRH
Pituitary Gland
TSH
Thyroid
T3, T4 in Blood
and Tissue
2.2.1 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
Disease Description
Finally.
TIROSINT Product Monograph
Disease Description (cont’d)
2.2.2 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 hypothyroidism1
High
Values
Normal
Range
Set Key
Low
Values
TSH
T3
T4
Normal
Mild
Moderate
Severe
Severity of Hypothyroidism
Figure 2B:
Hormone changes occurring during the development of central hypothyroidism1
High
Values
Normal
Range
Set Key
Low
Values
TSH
T3
T4
Normal
Mild
Moderate
Severe
Severity of Hypothyroidism
8
Disease Description (cont’d)
2.2.3 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.4
2.3 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
9
Disease Description
Finally.
TIROSINT Product Monograph
Disease Description (cont’d)
Table 2: Clinical presentation of hypothyroidism2
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
Weakness
Muscle cramps
Joint pain
Delayed relaxation of deep
tendon reflexes
Carpal tunnel syndrome
Gastrointestinal system
Nausea
Constipation
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
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
Skin and appendages
10
Disease Description (cont’d)
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.11
2.5 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 withT3 (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
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
Disease Description
Finally.
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.17
3.1 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
Place in Therapy (cont’d)
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
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
Place in Therapy
Finally.
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, 2000.20
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.19
14
Place in Therapy (cont’d)
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*
Figure 3: An in vitro dissolution study showed that Tirosint gel caps were unaffected
by gastric pH23*
120
pH 1.2
T4 dissolved (%)
100
pH 2.4
80
pH 4.0
60
pH 5.0
pH 6.0
40
pH 7.0
20
0
pH 8.0
0
20
40
60
80
100
120
140
160
180
200
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 disorders26 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.17
15
Place in Therapy
Finally.
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)
13
25
50
75
88
100
112
125
137
150
Color
Olive
Orange
White
Purple
Green
Yellow
Rose
Brown
Blue
Turquoise
NDC
24090-490-84
24090-491-84
24090-492-84
24090-493-84
24090-494-84
24090-495-84
24090-496-84
24090-497-84
24090-498-84
24090-499-84
4.4 WAC Cost Per Unit
WAC cost per unit is $17.36.
4.5 AHFS or Other Drug Classification
68.36.04
4.6 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
Product Description (cont’d)
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
Ratio (%)
(Test/Reference)
90% Confidence
Interval
AUC0-t (n=24; adjusted with the baseline)
103.0
92.8-114.4
Cmax (n=24; adjusted with the baseline)
106.8
100.7-113.2
Parameter
17
Product Description
Finally.
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 concentrations17
Ratio (90% CI)
Parameter
50 μg vs 100 μg
150 μg vs 100 μg
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)
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.
4.11 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
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/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.
19
Product Description
Finally.
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 cardiovascular anomalies (pulmonary stenosis, atrial septal
defect, and ventricular septal defect) being the most common association.
20
Product Description (cont’d)
LABORATORY TESTS
General
The diagnosis of hypothyroidism is confirmed by measuring TSH levels using a sensitive
assay (second-generation assay sensitivity ≤0.1 mIU/L or third-generation assay
sensitivity ≤0.01 mIU/L) and measurement of free T4.
The adequacy of therapy is determined by periodic assessment of appropriate laboratory
tests and clinical evaluation. The choice of laboratory tests depends on various factors
including the etiology of the underlying thyroid disease, the presence of concomitant
medical conditions, including pregnancy, and the use of concomitant medications (see
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
Finally.
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.
4.13 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
Product Description (cont’d)
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.
4.14 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
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
Product Description
Finally.
TIROSINT Product Monograph
Product Description (cont’d)
Table 7: Drug—Thyroid axis interaction (cont’d)
Drugs that alter thyroid hormone secretion
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.
Aminoglutethimide
Amiodarone
Iodide (including iodine-containing radiographic
contrast agents)
Lithium
Methimazole
Propylthiouracil (PTU) Sulfonamides
Tolbutamide
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
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.
Amiodarone
Iodide (including iodine-containing radiographic
contrast agents)
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
Product Description (cont’d)
Table 7: Drug—Thyroid axis interaction (cont’d)
Drugs that may cause protein-binding site displacement
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
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.
Carbamazepine
Hydantoins
Phenobarbital
Rifampin
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
Product Description
Finally.
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)
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.
Antidiabetic Agents
- Iguanides
- Sulfonylureas
- Thiazolidinediones
- Insulin
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.
Cardiac Glycosides
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.
Cytokines
- interferon-α
- interleukin-2
Therapy with interferon-α has been associated with the
development of antithyroid microsomal antibodies in
20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who
have antithyroid antibodies before treatment are at
higher risk for thyroid dysfunction during treatment.
Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients; interferon-β and –γ
have not been reported to cause thyroid dysfunction.
Growth Hormones
- Somatrem
- Somatropin
Excessive use of thyroid hormones with growth
hormones may accelerate epiphyseal closure.
However, untreated hypothyroidism may interfere
with growth response to growth hormone.
Ketamine
Concurrent use may produce marked hypertension
and tachycardia; cautious administration to patients
receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
(eg, theophylline)
Decreased theophylline clearance may occur in
hypothyroid patients; clearance returns to normal
when the euthyroid state is achieved.
Radiographic Agents
Thyroid hormones may reduce the uptake of 123 I, 131 I,
and 99TC
Sympathomimetics
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.
Chloral hydrate
Diazepam
Ethionamide
Lovastatin
Metoclopramide
6-mercaptopurine
Nitroprusside
Para-aminosalicylate sodium
Perphenazine
Resorcinol (excessive topical use)
Thiazide diuretics
These agents have been associated with thyroid
hormone and/or TSH level alterations by various
mechanisms.
26
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 of
the hypothyroid state or when the TIROSINT dose is increased. Prothrombin time should
be closely monitored to permit appropriate and timely dosage adjustments (see Table 7).
Digitalis glycosides – The therapeutic effects of digitalis glycosides may be reduced by
levothyroxine. Serum digitalis glycoside levels may be decreased when a hypothyroid
patient becomes euthyroid, necessitating an increase in the dose of digitalis glycosides
(see Table 7).
Drug-food interactions – Consumption of certain foods may affect levothyroxine
absorption thereby necessitating adjustments in dosing. Soybean flour (infant formula),
cottonseed meal, walnuts, and dietary fiber may bind and decrease the absorption of
levothyroxine 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 necessitates
measurement and evaluation of unbound (free) hormone and/or determination of the
free T4 index (FT4I). Pregnancy, infectious hepatitis, estrogens, estrogen-containing oral
contraceptives, and acute intermittent porphyria increase TBG concentrations. Decreases
in TBG concentrations are observed in nephrosis, severe hypoproteinemia, severe liver
disease, acromegaly, and after androgen or corticosteroid therapy (see also Table 7).
Familial hyper- or hypothyroxine binding globulinemias have been described, with the
incidence of TBG deficiency approximating 1 in 9000.
Carcinogenesis, Mutagenesis, and Impairment of Fertility – Animal studies have not been
performed to evaluate the carcinogenic potential, mutagenic potential, or effects on
fertility of levothyroxine. The synthetic T4 in TIROSINT is identical to that produced
naturally by the human thyroid gland. Although there has been a reported association
between prolonged thyroid hormone therapy and breast cancer, this has not been
confirmed. Patients receiving TIROSINT for appropriate clinical indications should be
titrated to the lowest effective replacement dose.
27
Product Description
Finally.
TIROSINT Product Monograph
Product Description (cont’d)
4.15 Dosing and Administration
General Principles
The goal of replacement therapy is to achieve and maintain a clinical and biochemical
euthyroid state. The goal of suppressive therapy is to inhibit growth and/or function of
abnormal thyroid tissue. The dose of TIROSINT that is adequate to achieve these goals
depends on a variety of factors, including the patient's age, body weight, cardiovascular
status, concomitant medical conditions including pregnancy, concomitant medications,
and the specific nature of the condition being treated (see WARNINGS and
PRECAUTIONS). Hence, the following recommendations serve only as dosing guidelines.
Dosing must be individualized and adjustments made based on periodic assessment of
the patient’s clinical response and laboratory parameters (see PRECAUTIONS, Laboratory
Tests).
TIROSINT is administered as a single daily dose, preferably one-half to one hour before
breakfast. TIROSINT should be taken at least 4 hours apart from drugs that are known to
interfere with its absorption (see PRECAUTIONS, Drug Interactions). TIROSINT capsules
cannot be cut or crushed.
Due to the long half-life of levothyroxine, the peak therapeutic effect at a given dose of
levothyroxine sodium may not be attained for 4 to 6 weeks.
Caution should be exercised when administering TIROSINT to patients with underlying
cardiovascular disease, to the elderly, and to those with concomitant adrenal
insufficiency (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 years
of age and in >50 years of age who have been recently treated for hyperthyroidism or
who 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. An
inadequate response to daily doses ≥300 mcg/day is rare and may indicate poor
compliance, malabsorption, and/or drug interactions.
28
Product Description (cont’d)
For most patients older than 50 years or for patients <50 years of age with underlying
cardiac disease, an initial starting dose of 25-50 mcg/day of levothyroxine sodium is
recommended, with gradual increments in dose at 6-8 week intervals, as needed. The
recommended starting dose of levothyroxine sodium in elderly patients with cardiac
disease is 12.5-25 mcg/day, with gradual dose increments at 4- to 6-week intervals. The
levothyroxine sodium dose is generally adjusted in 12.5-25 mcg increments until the
patient with primary hypothyroidism is clinically euthyroid and the serum TSH has
normalized. Unlike levothyroxine sodium tablets, TIROSINT capsules cannot be cut in half.
In patients with severe hypothyroidism, the recommended initial levothyroxine sodium
dose is 12.5-25 mcg/day with increases of 25 mcg/day every 2 to 4 weeks, accompanied
by clinical and laboratory assessment, until the TSH level is normalized.
In patients with secondary (pituitary) or tertiary (hypothalamic) hypothyroidism, the
levothyroxine sodium dose should be titrated until the patient is clinically euthyroid and
the 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 Principles
In general, levothyroxine therapy should be instituted at full replacement doses as soon
as possible. Delays in diagnosis and institution of therapy may have deleterious effects
on 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 to
swallow an intact capsule. Unlike levothyroxine sodium tablets, TIROSINT capsules
cannot be crushed and suspended in a small amount of water, nor can they be dissolved
by placing in water prior to administration (see CONTRAINDICATIONS).
Newborns
TIROSINT is not recommended for the treatment of newborns as they maybe unable to
swallow a capsule.
Infants and Children
Levothyroxine therapy is usually initiated at full replacement doses, with the
recommended dose per body weight decreasing with age (see Table 8). However, in
children with chronic or severe hypothyroidism, an initial dose of 25 mcg/day of
levothyroxine sodium is recommended with increments of 25 mcg every 24 weeks until
the desired effect is achieved.
29
Product Description
Finally.
TIROSINT Product Monograph
Product Description (cont’d)
Hyperactivity in an older child can be minimized if the starting dose is one-fourth of the
recommended full replacement dose, and the dose is then increased on a weekly basis
by an amount equal to one-fourth the full-recommended replacement dose until the
full recommended replacement dose is reached.
Table 8: Levothyroxine sodium dosing guidelines for pediatric hypothyroidism
Age
Daily dose per kg body weight*
0-3 months
10-15 mcg/kg/day
3-6 months
8-10 mcg/kg/day
6-12 months
6-8 mcg/kg/day
>12 years but growth and puberty incomplete
2-3 mcg/kg/day
Growth and puberty complete
1.7 mcg/kg/day
*The dose should be adjusted based on clinical response and laboratory parameters (see Precautions,
Laboratory Tests and Pediatric Use).
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 sodium
dose (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 yearly
for changes in clinical status and thyroid laboratory parameters.
TSH suppression in well-differentiated thyroid cancer and thyroid nodules – The target level
for 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 should
be 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 is
suppressed 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.
30
Product Description (cont’d)
In the treatment of benign nodules and nontoxic multinodular goiter, TSH is generally
suppressed to a higher target (eg, 0.1 to either 0.5 or 1.0 mIU/L) than that used for the
treatment 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 by
poor circulation and hypometabolism, and may result in unpredictable absorption of
levothyroxine sodium from the gastrointestinal tract. Therefore, oral thyroid hormone
drug products are not recommended to treat this condition. Thyroid hormone
products formulated for intravenous administration should be administered.
31
Product Description
Finally.
Other Studied Uses
TIROSINT Product Monograph
Other Studied Uses
5.1 Subclinical Hypothyroidism
Subclinical hypothyroidism is characterized by mildly increased serum TSH levels with
normal free T4 and T3 findings. Prevalence estimates range from 1% to 10% of the
population.6 Though symptoms may not be present, potential risks induce progression
to overt hypothyroidism, cardiovascular effects, hyperlipidemia, and neuropsychiatric
effects.6 Treatment is controversial; however, AACE treatment guidelines state that
treatment is indicated with TSH levels >10 μIU/mL or in patients with TSH levels between
5 and 10 μIU/mL and goiter, or positive anti-TPO, or both. These patients represent the
highest risk for progress to overt hypothyroism.6
32
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17. Data on file. Akrimax Pharmaceuticals, LLC. 2010.
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20. American Association of Clinical Endocrinologists, The Endocrine Society, and
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state. Pharm Res. 1992:9(11):131-137.
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34
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24. Olveira G, Almaraz MC, Soriguer F, et al. Altered bioavailability due to changes in
the formulation of a commercial preparation of levothyroxine in patients with
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25. Lahner E, Annibale B, Delle Fave G. Systematic review: Helicobacter pylori infection
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Finally.
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