Advisory Committee for Pharmaceutical Science

Briefing Document

Levothyroxine Bioequivalence

Advisory Committee Meeting -- 12-13 March 2003

THIS DOCUMENT CONTAINS FULLY RELEASABLE INFORMATION

![](media/image1.wmf) **Abbott Laboratories**

Table of Contents

Page

**1.0** **Executive Summary [1](#executive-summary)**

2.0 Thyroid Biology [2](#thyroid-biology)

3.0 Assessment of the Current Guidance for LT~4~ Bioequivalence
[4](#assessment-of-the-current-guidance-for-lt4-bioequivalence)

3.1 Background and rationale for M02-417 study
[4](#background-and-rationale-for-m02-417-study)

3.2 Results of M02-417 study [5](#results-of-m02-417-study)

3.2.1 T~4~ without correcting for endogenous T~4~ baseline
concentrations
[5](#t4-without-correcting-for-endogenous-t4-baseline-concentrations)

3.2.2 T~4~ after correction for endogenous T~4~ baseline concentrations
[6](#t4-after-correction-for-endogenous-t4-baseline-concentrations)

3.2.3 Other observations [6](#other-observations)

3.3 Conclusions from M02-417 study [7](#conclusions-from-m02-417-study)

4.0 LT~4~ Therapy and the Clinical Consequences of Under- or
Over-Treatment
[8](#lt4-therapy-and-the-clinical-consequences-of-under--or-over-treatment)

4.1 TSH is the measurement of adequacy of treatment
[8](#tsh-is-the-measurement-of-adequacy-of-treatment)

4.2 LT~4~ therapy is individualized and carefully titrated
[9](#lt4-therapy-is-individualized-and-carefully-titrated)

4.3 Fine-dosing increments -- importance and medical use
[10](#fine-dosing-increments-importance-and-medical-use)

4.4 Clinical consequences of hypothyroidism and hyperthyroidism
[12](#clinical-consequences-of-hypothyroidism-and-hyperthyroidism)

4.4.1 Patient populations treated with LT~4~ products
[12](#patient-populations-treated-with-lt4-products)

4.4.2 Consequences of hypothyroidism and hyperthyroidism
[12](#consequences-of-hypothyroidism-and-hyperthyroidism)

4.5 Summary of LT~4~ therapy and clinical consequences
[14](#summary-of-lt4-therapy-and-clinical-consequences)

5.0 Conclusions [14](#conclusions)

6.0 References [16](#references)

List of Figures

Figure 1. Basic Schematic of the Thyroid Hormone System
[3](#__RefHeading___Toc32381336)

Figure 2. The Relationship Between Serum TSH And Free T~4~
Concentrations in Individuals With Stable Thyroid Status and Normal
Hypothalamic-Pituitary Function. [4](#__RefHeading___Toc32381337)

Figure 3. Resultant TSH levels With Incremental 25 µg Changes in LT~4~
Dosage [11](#__RefHeading___Toc32381338)

1.  

Table 1. Bioequivalence and Relative Bioavailability--Uncorrected
Levothyroxine (T4) 5

Table 2. Bioequivalence and Relative Bioavailability for T4 (Correction
Method 3) 6

Appendix A Abbott Laboratories. Study M02-417 Synopsis and Discussion 19

#  Executive Summary

The purpose of this document, and Abbott\'s participation in the March
13, 2003 Pharmaceutical Science Advisory Committee meeting, is to
identify and discuss scientific issues related to the bioequivalence
assessment criteria of levothyroxine sodium (LT~4~) products.

Levothyroxine or thyroxine (T~4~) is an endogenous hormone secreted from
the thyroid gland and is subject to complex biologic regulation. As
such, it has characteristics different from drugs for which there are no
endogenous levels. Exogenously administered LT~4~ hormone is
indistinguishable from endogenously secreted T~4~, both in its
physiologic effects and its quantification as measured in blood. The
current FDA guidance for assessment of bioequivalence of administered
LT~4~ products does not take into account the contribution of endogenous
T~4~. The presence of endogenous T~4~ and its dynamic regulation
confound the assessment of bioequivalence of LT~4~ products in healthy
normal subjects, and consequently, preclude any conclusions about their
therapeutic substitution in patients.

We describe a recent study conducted by Abbott Laboratories that
highlights these issues with the current FDA Guidance for assessing
bioequivalence of LT~4~ products. The study demonstrates that, following
the current FDA criterion for levothyroxine sodium products, the use of
T~4~ pharmacokinetic parameters uncorrected for endogenous T~4~ would
result in declaring two products bioequivalent when they actually differ
in drug content by as much as 33%. Considering the margin by which the
conditions for declaring bioequivalence were passed in this study,
products that differ by even more than 33% would also have a high
likelihood of being declared bioequivalent. Three methods of correction
for endogenous T~4~ levels were evaluated, but none of the methods could
discern products that differ by 12.5%; dosage changes of such magnitude
are clinically important.

The clinical relevance of a 12.5% difference in dose is substantiated by
product labeling, standard medical management of thyroid patients, and
data from clinical studies. In class labeling for all LT~4~ products, it
is recommended that titration be done in 12.5 to 25 µg increments for
elderly patients with cardiac disease; who represent a significant
number of the 13 million LT~4~-treated patients in the U.S. In fact, the
FDA has explicitly recognized the clinical relevance of these dosage
increments particularly with respect to patient safety. In addition,
physicians employ a large number of dosage strengths to effectively
titrate patients to normal thyroid status, which generally requires a
dose between 100 and 150 µg. In this dose titration process, 12-13 µg is
the second most commonly used dose increment or decrement. Finally,
mildly abnormal thyroid function, which may result from slight under- or
over-dosing, has been demonstrated in clinical studies to have adverse
effects on fetal development, lipids, and cardiovascular disease. For
patients with thyroid cancer there is an extra concern, in that slight
under-treatment increases the risk of cancer recurrence and metastatic
disease.

Careful consideration should be given to developing a specific guidance
for the assessment of bioequivalence of levothyroxine sodium products.
This guidance must adequately consider the unique nature of the thyroid
hormone system and the demonstrated limitations of the current guidance
not adequately remedied by simple methods for baseline correction.

#  Thyroid Biology

Thyroxine (T~4~) is an endogenous molecule that is synthesized and
released from the thyroid gland in response to thyrotropin or
thyroid-stimulating hormone (TSH) (Figure 1). T~4~ is a "pro-hormone"
that is converted via deiodination in tissues to triiodothyronine
(T~3~), the most biologically potent form of thyroid hormone. Thyroid
hormones (T~4~ and T~3~) affect protein, lipid, and carbohydrate
metabolism, growth, and development. They stimulate the oxygen
consumption of most cells of the body, resulting in increased energy
expenditure and heat production, and possess a cardiac stimulatory
effect that may be the result of a direct action on the heart. Thyroid
hormones, T~4~ and T~3~, are specifically bound by three different
plasma transport proteins, each with its specific affinity and capacity
for T~4~ and T~3~. T~3~ controls the transcription of numerous genes
that are vital to growth and development. With thyroid hormone receptors
in virtually every tissue in the body, thyroid hormone affects, via
control of specific genes, proper brain development (myelin basic
protein gene) and growth (growth hormone gene), and muscle function
(myosin heavy chain gene, sarcoplasmic reticulum ATPase gene) and
cholesterol levels (LDL-receptor gene). ^1,\ 2^

![](media/image1.wmf)The thyroid hormone system is under the tight
feedback regulation by the hypothalamic-pituitary axis, which senses the
levels of T~3~ and T~4~, and modulates the release of hypothalamic
thyrotropin-releasing hormone (TRH) and pituitary TSH (Figure 1).

[]{#__RefHeading___Toc32381336 .anchor}Figure 1. Basic Schematic of the
Thyroid Hormone System

The pituitary is the key "biosensor" in the feedback loop, with the
magnitude of TSH release controlled primarily by blood levels of T~4~
and T~3~ and some "fine-tuning"contributed by the TRH level. Figure 2
demonstrates the inverse relationship between TSH and free T~4~ levels,
as observed in over 500 ambulatory subjects. ^3^

Linear regression analysis of the data points demonstrates that, for
every 2-fold change in free T~4~, the TSH level will change 100-fold
(refer to triangle on the graph). Thus, TSH is considered to be the most
sensitive measure of thyroid function, and is used clinically for the
diagnosis and monitoring of thyroid patients. In fact, the diagnosis of
hypo- or hyperthyroidism rests on the finding of an abnormal TSH, which
is more sensitive than an abnormal T~4~. Furthermore, titration of LT~4~
dosage is performed by monitoring TSH levels, and a euthyroid state is
considered achieved when TSH levels move to within the normal range (see
Section 4.1).

[]{#__RefHeading___Toc32381337
.anchor}![](media/image2.png){width="4.02007874015748in"
height="2.796456692913386in"}Figure 2. The Relationship Between Serum
TSH And Free T~4~ Concentrations in Individuals With Stable Thyroid
Status and Normal Hypothalamic-Pituitary Function.

In summary, thyroid hormones are produced by the thyroid gland and
regulated by a complex control system such that, in healthy subjects
with normal thyroid function (euthyroid), T~4~ and T~3~ are tightly
controlled within narrow ranges.

#  Assessment of the Current Guidance for LT~4~ Bioequivalence

## Background and rationale for M02-417 study

Evaluation of the pharmacokinetic curves generated for the NDA filings
of LT~4~ products led Abbott to question the sensitivity of
bioavailability studies done in healthy volunteers with no adjustment
made for the endogenous baseline concentrations of T~4~. We hypothesized
that given the magnitude of the endogenous T~4~ measured at baseline,
LT~4~ products with large differences in bioavailability could be
declared bioequivalent if this method were used. The current FDA
bioequivalence methodology is to evaluate pharmacokinetic (PK)
parameters using healthy volunteers, comparing 600 µg of the test
compound to 600 µg of the reference compound in a crossover study,
without correction for endogenous T~4~ baseline level. ^4^ Abbott
conducted a "bioequivalence" study in healthy volunteers using known
dosages of a single formulation of LT~4~ (Synthroid^®^) to test the
sensitivity of the current FDA Guidance. We evaluated if the current
methodology was able to differentiate two known lower dosages (400 and
450 µg) from the reference dose of 600 µg. We went on to evaluate the
impact of various methods of correcting for endogenous T~4~ baseline on
the bioequivalence assessment in this study.

## Results of M02-417 study

Results for bioequivalence assessment are presented below for 400 µg
*versus* 600 µg, 450 µg *versus* 600µg, and 450 µg *versus* 400 µg,
using PK parameters uncorrected for baseline T~4~ levels and corrected
for baseline T~4~ levels are listed below.

### T~4~ without correcting for endogenous T~4~ baseline concentrations

The relative bioavailabilities for the 450 µg and 400 µg doses as
compared to the reference dose of 600 µg, using PK parameters (Cmax and
AUC~48~) of T~4~ without correction of the baseline are listed in
Table 1. In addition, the relative bioavailability of 450 µg compared to
the 400 µg is listed.

+-------------+-------------+----+--------+---------+----------------+
| Table 1.    |             |    |        |         |                |
| Bio         |             |    |        |         |                |
| equivalence |             |    |        |         |                |
| and         |             |    |        |         |                |
| Relative    |             |    |        |         |                |
| Bioava      |             |    |        |         |                |
| ilability-- |             |    |        |         |                |
| Uncorrected |             |    |        |         |                |
| Le          |             |    |        |         |                |
| vothyroxine |             |    |        |         |                |
| (T4)        |             |    |        |         |                |
+-------------+-------------+----+--------+---------+----------------+
| Regimens    |             |    |        | R       |                |
|             |             |    |        | elative |                |
|             |             |    |        | B       |                |
|             |             |    |        | ioavail |                |
|             |             |    |        | ability |                |
+-------------+-------------+----+--------+---------+----------------+
| Test *vs.*  | Phar        | C  |        | Point   | 90% Confidence |
|             | macokinetic | en |        |         |                |
|             |             | tr |        |         |                |
|             |             | al |        |         |                |
|             |             | V  |        |         |                |
|             |             | al |        |         |                |
|             |             | ue |        |         |                |
|             |             | \* |        |         |                |
+-------------+-------------+----+--------+---------+----------------+
| Reference   | Parameter   | Te | Ref    | Es      | Interval       |
|             |             | st | erence | timate+ |                |
+-------------+-------------+----+--------+---------+----------------+
| 450 µg      | Cmax        | 13 | 14.0   | 0.928   | 0.890 -- 0.968 |
| *vs.*600 µg |             | .0 |        |         |                |
+-------------+-------------+----+--------+---------+----------------+
|             | AUC48       | 4  | 504.8  | 0.954   | 0.927 -- 0.982 |
|             |             | 81 |        |         |                |
|             |             | .7 |        |         |                |
+-------------+-------------+----+--------+---------+----------------+
| 400 µg      | Cmax        | 12 | 14.0   | 0.921   | 0.883 -- 0.960 |
| *vs.* 600   |             | .9 |        |         |                |
| µg          |             |    |        |         |                |
+-------------+-------------+----+--------+---------+----------------+
|             | AUC48       | 4  | 504.8  | 0.930   | 0.904 -- 0.958 |
|             |             | 69 |        |         |                |
|             |             | .6 |        |         |                |
+-------------+-------------+----+--------+---------+----------------+
| 450 µg      | Cmax        | 13 | 12.9   | 1.007   | 0.967 -- 1.050 |
| *vs.* 400   |             | .0 |        |         |                |
| µg          |             |    |        |         |                |
+-------------+-------------+----+--------+---------+----------------+
|             | AUC48       | 4  | 469.6  | 1.026   | 0.997 -- 1.055 |
|             |             | 81 |        |         |                |
|             |             | .7 |        |         |                |
+-------------+-------------+----+--------+---------+----------------+
| \*          |             |    |        |         |                |
| An          |             |    |        |         |                |
| tilogarithm |             |    |        |         |                |
| of the      |             |    |        |         |                |
| least       |             |    |        |         |                |
| squares     |             |    |        |         |                |
| means for   |             |    |        |         |                |
| logarithms. |             |    |        |         |                |
|             |             |    |        |         |                |
| \+          |             |    |        |         |                |
| An          |             |    |        |         |                |
| tilogarithm |             |    |        |         |                |
| of the      |             |    |        |         |                |
| difference  |             |    |        |         |                |
| (test minus |             |    |        |         |                |
| reference)  |             |    |        |         |                |
| of the      |             |    |        |         |                |
| least       |             |    |        |         |                |
| squares     |             |    |        |         |                |
| means for   |             |    |        |         |                |
| logarithms. |             |    |        |         |                |
+-------------+-------------+----+--------+---------+----------------+

Bioequivalence is concluded for each of the comparator pairs (450 µg
*versus* 600 µg; 400 µg *versus* 600 µg and 450 µg *versus* 400 µg)
because the 90% confidence intervals from the analyses of the natural
logarithms of Cmax and AUC~48~ are within the 0.80 to 1.25 range.

### T~4~ after correction for endogenous T~4~ baseline concentrations

Three methods of correction were evaluated. These three methods are
defined in Appendix A, Criteria for Evaluation. The relative
bioavailabilities for the 450 µg and 400 µg doses as compared to the
reference dose of 600 µg, using PK parameters (Cmax and AUC~48~) of T~4~
with correction of the baseline (Correction Method 3) are listed in
Table 2. The relative bioavailability of 450 µg compared to the 400 µg
is also listed.

Results using Correction Method 3 are listed here because the point
estimates for relative bioavailability as defined by AUC~48~ were
generally further from unity than were the point estimates for that
parameter using Corrections Method 1 and 2. The results using the other
correction methods are listed in the expanded summary of the M02-417
study (see Appendix A for details). The determination for bioequivalence
did not differ, no matter which correction method was used.

+-------------+-------------+----+--------+---------+----------------+
| Table 2.    |             |    |        |         |                |
| Bio         |             |    |        |         |                |
| equivalence |             |    |        |         |                |
| and         |             |    |        |         |                |
| Relative    |             |    |        |         |                |
| Bioa        |             |    |        |         |                |
| vailability |             |    |        |         |                |
| for T4      |             |    |        |         |                |
| (Correction |             |    |        |         |                |
| Method 3)   |             |    |        |         |                |
+-------------+-------------+----+--------+---------+----------------+
| Regimens    |             |    |        | R       |                |
|             |             |    |        | elative |                |
|             |             |    |        | B       |                |
|             |             |    |        | ioavail |                |
|             |             |    |        | ability |                |
+-------------+-------------+----+--------+---------+----------------+
| Test *vs.*  | Phar        | C  |        | Point   | 90% Confidence |
|             | macokinetic | en |        |         |                |
|             |             | tr |        |         |                |
|             |             | al |        |         |                |
|             |             | V  |        |         |                |
|             |             | al |        |         |                |
|             |             | ue |        |         |                |
|             |             | \* |        |         |                |
+-------------+-------------+----+--------+---------+----------------+
| Reference   | Parameter   | Te | Ref    | Es      | Interval       |
|             |             | st | erence | timate+ |                |
+-------------+-------------+----+--------+---------+----------------+
| 450 µg      | Cmax        | 5  | 6.9    | 0.820   | 0.757 -- 0.888 |
| *vs.*600 µg |             | .7 |        |         |                |
+-------------+-------------+----+--------+---------+----------------+
|             | AUC48       | 1  | 172.9  | 0.723   | 0.672 -- 0.779 |
|             |             | 25 |        |         |                |
|             |             | .1 |        |         |                |
+-------------+-------------+----+--------+---------+----------------+
| 400 µg      | Cmax        | 5  | 6.9    | 0.775   | 0.715 -- 0.839 |
| *vs.* 600   |             | .3 |        |         |                |
| µg          |             |    |        |         |                |
+-------------+-------------+----+--------+---------+----------------+
|             | AUC48       | 1  | 172.9  | 0.667   | 0.620 -- 0.718 |
|             |             | 15 |        |         |                |
|             |             | .4 |        |         |                |
+-------------+-------------+----+--------+---------+----------------+
| 450 µg      | Cmax        | 5  | 5.3    | 1.058   | 0.979 -- 1.145 |
| *vs.* 400   |             | .7 |        |         |                |
| µg          |             |    |        |         |                |
+-------------+-------------+----+--------+---------+----------------+
|             | AUC48       | 1  | 115.4  | 1.084   | 1.008 -- 1.165 |
|             |             | 25 |        |         |                |
|             |             | .1 |        |         |                |
+-------------+-------------+----+--------+---------+----------------+
| \*          |             |    |        |         |                |
| An          |             |    |        |         |                |
| tilogarithm |             |    |        |         |                |
| of the      |             |    |        |         |                |
| least       |             |    |        |         |                |
| squares     |             |    |        |         |                |
| means for   |             |    |        |         |                |
| logarithms. |             |    |        |         |                |
|             |             |    |        |         |                |
| \+          |             |    |        |         |                |
| An          |             |    |        |         |                |
| tilogarithm |             |    |        |         |                |
| of the      |             |    |        |         |                |
| difference  |             |    |        |         |                |
| (test minus |             |    |        |         |                |
| reference)  |             |    |        |         |                |
| of the      |             |    |        |         |                |
| least       |             |    |        |         |                |
| squares     |             |    |        |         |                |
| means for   |             |    |        |         |                |
| logarithms. |             |    |        |         |                |
+-------------+-------------+----+--------+---------+----------------+

These analyses indicate that the use of baseline corrected T~4~
pharmacokinetic parameters allow 400 and 450 µg to be differentiated
from 600 µg. However, analyses using these simple methods of correction,
each method limited by its inherent assumptions, failed to distinguish
450 µg from 400 µg.

### Other observations

Analysis of the T~4~ concentration data obtained during the 24 hours
prior to the administration of the PK dose for each period confirmed
that T~4~ has a diurnal cycle. Likewise, the serum concentrations of TSH
showed a clear diurnal variation for Study Day --1 of each period.
Administration of all three doses had homeostatic effects, but did not
completely suppress the serum TSH concentration during the 24 hours
following the PK dose. Analyses of the AUC~24~ for Study Day --1
revealed that the regimens (dose levels) had statistically significant
different carryover effects from one period to the next (first-order
carryover) and from Period 1 to Period 3 (second-order carryover).

## Conclusions from M02-417 study

First, the results indicate that the use of baseline uncorrected T4
pharmacokinetic parameters would result in declaring two products
bioequivalent when they actually differ by as much as 25% to 33% (450 µg
and 400 µg *versus* 600 µg). Considering the margin by which the
conditions for declaring bioequivalence were passed in this study,
products that differ by even more than 33% would also have a high
likelihood of being declared bioequivalent products, stemming from the
significant and complex contribution of endogenous T4.

Second, the results from this study indicate that the use of baseline
corrected T4 pharmacokinetic parameters would reduce the likelihood that
two products would be declared bioequivalent when they actually differ
by 25% to 33%. However, analyses using three simple methods of
correction, each method limited by its inherent assumptions, failed to
distinguish 450 µg from 400 µg. This is a 12.5% difference which, when
applied to the range of doses typically used in clinical practice, is a
clinically significant difference, as reflected in product labeling,
clinical usage, and data from clinical studies.

Furthermore, it is apparent that simple methods of correction for
endogenous T4 concentrations in healthy volunteers are inadequate since
these concentrations not only fluctuate on a diurnal cycle but may also
be differentially affected by products with different rates and extents
of absorption*.* Additionally, there is evidence of significant
carryover from one dosing period to subsequent periods even with washout
periods up to 53 days.

This study illustrates important flaws in the design and analysis of
single-dose crossover studies in healthy volunteers to assess
bioequivalence of LT~4~ products, stemming from the significant and
complex homeostatic mechanisms associated with administration of
supraphysiologic doses of LT~4~. We now know that better
characterization of and correction for endogenous T~4~ is required to
provide proper interpretation of results in healthy volunteer studies.
Alternative approaches to account for endogenous T~4~ need to be
identified and investigated. A change to the current FDA criterion
beyond adding a simple correction for baseline T~4~ is necessary.

#  LT~4~ Therapy and the Clinical Consequences of Under- or Over-Treatment

Levothyroxine sodium is the treatment of choice as replacement or
supplemental hormone therapy, or to suppress pituitary TSH in the
treatment of thyroid carcinomas and nodules. According to the [[Dosage
and Administration]{.underline}]{.smallcaps} section in the product
labels for all levothyroxine sodium products, ^5-7^ "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 tissues." The
fundamental guiding principle of therapy is the maintenance of TSH in
the desired range by individual titration of LT~4~ dose.

## TSH is the measurement of adequacy of treatment

Professional societies and product labels state that TSH is the
biochemical endpoint to determine the thyroid hormone status. ^5-10^ The
recommended management (under [[Laboratory
Tests]{.underline})]{.smallcaps} is as follows: "The diagnosis of
hypothyroidism is confirmed by measuring TSH levels using a sensitive
assay....and measurement of free-T~4~. The adequacy of therapy is
determined by periodic assessment of appropriate laboratory tests and
clinical evaluation."

The labels recommend testing in [[Adults]{.underline}]{.smallcaps}, as
follows: "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 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..." ^5-7^

The product labels and professional societies recognize the importance
of using TSH measurements as the endpoint for evaluating the biochemical
thyroid status. They state that once the patient is stabilized on an
LT~4~ dose, periodic assessment needs only be done every six to twelve
months. ^5-8,\ 10^

## LT~4~ therapy is individualized and carefully titrated

Treatment with LT~4~ products is individualized for each patient, based
on their underlying thyroid status, age, and presence or absence of
other clinical conditions, particularly their cardiac function. With the
exception of young healthy thyroid patients, the treated hypothyroid
population is initiated with a low LT~4~ dose and titration of the dose
is done in small increments until they are able to achieve their
euthyroid state. Thyroid cancer patients are carefully titrated to keep
their TSH levels in the marginally hyperthyroid range. Recalling the
inverse log-linear relationship of TSH to T~4~ levels, titration to the
marginally hyperthyroid state can require small dose increments.

In recognition of the narrow therapeutic window for serum T~4~ and TSH,
and the log-linear relationship between TSH and T~4~ levels,
professional societies and the product labels recommend that careful
monitoring and titration be done when instituting LT~4~ therapy.
^5-8,\ 10^ Because of the cardiac and cardiovascular consequences of
rapid replacement or over-replacement, definitive recommendations are
provided for special patient populations. Under [[Dosage and
Administration -- Special Patient Populations]{.underline}]{.smallcaps}
the product label recommends "For most patients older than 50 years of
age or for patients under 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 for elderly patients
with cardiac disease is **12.5-25 mcg/day**, with gradual dose
increments at 4-6 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." ^5-7^

The medical literature on which FDA based its decision to approve oral
levothyroxine tablets uniformly emphasizes the clinical need for fine
dosing increments. As FDA stated in its review of Unithroid, "a 25 mcg
dosage strength that meets chemistry and biopharm criteria for approval,
is essential for proper labeling of the product for safe and effective
use given that in certain clinical situations, levothyroxine sodium
dosing is initiated at 12.5-25 mcg/day and increased in 12.5-25 mcg
dosing increments." ^11^

## Fine-dosing increments -- importance and medical use 

The FDA recognizes that multiple dose strengths are required to
accomplish adequate treatment of the thyroid patient population. The
FDA, in a final agency decision regarding the regulatory status of
Synthroid^®^, emphasized that [[Patients Need a Precise Dose of
Levothyroxine Sodium]{.underline}]{.smallcaps}. "The dosage of
replacement therapy is increased in gradual increments until the TSH
test indicates the correct maintenance dosage has been achieved. In
order to allow for fine adjustments of dose, which are necessary due to
levothyroxine sodium's narrow therapeutic range, levothyroxine sodium
products are marketed in an unusually large number of dosage strengths.
Synthroid^®^, for example, comes in 25, 50, 75, 88, 100, 112, 125, 150,
175, 200, and 300 mcg strengths." ^12^

Market research demonstrates that 1 in 5 dosage changes is an increase
or decrease by 12 or 13 µg.

The impact on thyroid hormone status of small deviations from an
optimally titrated dose is demonstrated in a prospective, longitudinal
study by Carr et al. Twenty-one patients on LT~4~ replacement therapy
for hypothyroidism were studied while taking the dose that produced a
normal TSH response, and then the patients were restudied at lower
and/or higher doses (Figure 3). ^14^ Dosage changes of as little as 25
µg rendered the patients either hypothyroid or hyperthyroid, dependent
upon the direction of the dose change from the dose that maintained them
in a euthyroid state.

[]{#__RefHeading___Toc32381338 .anchor}![](media/image1.wmf)Figure 3.
Resultant TSH levels With Incremental 25 µg Changes in LT~4~ Dosage

Applying the inverse log-linear relationship of serum TSH to T~4~
levels, these data would predict that dose changes that were half those
studied in the Carr study would also render some, if not all, of the
patients outside of the normal TSH range (0.4 to 4.0 mIU/L).

The ability to carefully titrate and maintain patients in the desired
thyroid state is of paramount importance. The FDA acknowledged the same
goals when approving the class labeling for all LT~4~ products. In the
product labels under [[Precautions]{.underline}]{.smallcaps} it states,
"Levothyroxine 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 and development, cardiovascular
function, bone metabolism, reproductive function, cognitive function,
emotional state, gastrointestinal function, and on glucose and lipid
metabolism."

## Clinical consequences of hypothyroidism and hyperthyroidism

### Patient populations treated with LT~4~ products

Functional thyroid disease can manifest as either over- or under-active
thyroid hormone status. ^15,\ 16^ In either case, there is a wide
spectrum of the clinical expression of the disease from mild to severe.
However, the clinical consequences of each are more severe the further
the thyroid function has deviated from normal, i.e., severe
thyrotoxicosis (severe hyperthyroidism) and myxedema coma (severe
hypothyroidism). Significant clinical consequences also occur with
milder forms of the disease ("subclinical" thyroid disease) as may be
seen when the patient is not treated to reach and maintain the euthyroid
state. In a large health screening study of 25,862 subjects in Colorado,
18% of all patients treated with LT~4~ products had TSH levels above the
upper limit of the normal range, indicating that those patients were in
a subclinical hypothyroid state despite LT~4~ treatment. ^17^

The American Cancer Society projects the number of new cases of thyroid
cancer in 2003 will reach 22,000 with an annual mortality of 1,400. ^18^
The low mortality rates for this cancer is due in part to the
effectivness care delivered for these patients. Thyroid cancer patients
undergo surgical removal of their thyroid gland and treatment with
radioactive iodine to ablate the remaining thyroid cancer cells.
Thereafter, they are purposefully maintained in a marginally
hyperthyroid state (TSH \< 0.4 mIU/L). ^5-7,\ 9,\ 19^ TSH is a growth
factor for normal and cancerous thyroid cells. The goal of LT~4~
treatment is to deliver adequate LT~4~ to suppress the TSH to just below
the normal range. Lowering TSH levels removes the growth stimulus,
thereby reducing the probability that any remaining thyroid cancer cells
will grow to be of any clinical significance. If these patients are
under-treated, they are at risk of having a recurrence of their thyroid
cancer or development of metastases. Conversely, if they receive too
much LT~4~ they are at risk of the complications of over-treatment,
described below.

### Consequences of hypothyroidism and hyperthyroidism

It is paramount that patients be guaranteed that any LT~4~ product
substitution produce the same therapeutic response such that the
efficacy and safety profile they rely upon is not compromised.

The FDA, in a final agency decision regarding the regulatory status of
Synthroid, described the safety risks when patients are inadvertently
over- or under-treated. "Superpotent tablets of levothyroxine sodium
pose safety risks. Patients who inadvertently receive more levothyroxine
than is necessary to control their condition may experience angina,
tachycardia, or arrhythmias. There is also evidence that overtreatment
can contribute to osteoporosis. Subpotent tablets of levothyroxine
sodium are not adequately effective and, therefore, also pose safety
risks. Patients inadvertently receiving less than their proper dose may
experience such symptoms as fatigue, lethargy, sleepiness, mental
impairment, depression, cold intolerance, hair loss, hoarseness, weight
gain, constipation, decreased appetite, dry skin, increased
perspiration, arthralgia, menstrual disturbances, and paresthesias.
Because of the serious consequences of too much or too little
circulating thyroxine, it is very important that patients receive the
dose of levothyroxine sodium determined by their physicians to be
optimal to replace the amount of hormone that would have been present
naturally." ^12^

The FDA stated that the potential side effects that occur with mild
hypothyroidism and hyperthyroidism involve many different organ systems.
^12^ Some specific examples highlight the importance of maintaining
thyroid hormones in their narrow therapeutic ranges. Maternal thyroid
hormone status, particularly during early pregnancy, is important to the
well being of the pregnant woman's offspring. Early in pregnancy the
fetus is totally dependent on receiving thyroid hormone from the mother.
^20^ Hypothyroidism during pregnancy has been associated with lower IQ
scores in the children. ^21^

Mild thyroid failure is associated with elevated total cholesterol and
LDL-cholesterol levels. ^17,\ 22-26^ This is consistent with the finding
that thyroid hormone is a positive regulator for the production of
LDL-receptors. ^2^ In the hypothyroid state removal of LDL-cholesterol
particles from the plasma into the liver and other tissues would be
limited. Hypothyroidism is an independent risk factor for myocardial
infarction. ^27^

Hypothyroidism is associated with a slow heart rate (bradycardia) and
decreased contractility of heart muscle. ^28^ Thyroid hormone-responsive
genes have been identified that are consistent with these clinical
findings. ^1,\ 28^ Clinical practice guidelines and product labels for
LT~4~ products advise careful monitoring and treatment of thyroid
disease patients who also suffer from heart failure, as both hypo- and
hyperthyroidism can worsen the heart failure. ^5-8,\ 10^ As testing of
cardiac function becomes more sophisticated, it is evident that even
mild thyroid failure has a significant effect on cardiac muscle
contractility. ^29-31^ In the hypothyroid patient, with each heartbeat,
less blood is pumped from the heart to the rest of the body and
increased backward pressure causes fluid to build up in the lungs and
legs. Hyperthyroidism is associated with rapid heartbeat (tachycardia)
and atrial fibrillation. ^28^ Both of these also result in less blood
being pumped to the rest of the body with each heartbeat. Atrial
fibrillation is also associated with an increased risk of stroke. ^32^

## Summary of LT~4~ therapy and clinical consequences

In summary, physicians use the TSH levels to judge the adequacy of
treatment. To achieve treatment goals, physicians and the 13 million
LT~4~ treated patients in the U.S. rely on multiple dosage strengths.
For titration and maintenance of the desired thyroid status, dosage
strengths that differ by only 12 to13 µg are frequently used. Changes in
LT~4~ treatment or potency, with resulting changes in TSH levels, have
significant clinical consequences.

The concerns of the FDA as outlined above and recommendations in the
LT~4~ product labels further emphasize the concern that LT~4~ product
substitution should only be done when LT~4~ can be delivered so as not
to produce over- or under-treatment. This takes on particular
significance for patients who have their TSH monitored every 6 to 12
months. It is possible that LT~4~ product substitution could occur
between two consecutive TSH assessments and the patient's thyroid status
could be changed toward under- or over-treatment. It is these patients
who have an increased health risk from a product that is supra- or
sub-potent.

#  Conclusions

The determination of bioequivalence of LT~4~ products should signify
that, under all circumstances, these products are truly interchangeable
without adverse clinical consequences, and without the need for clinical
monitoring, retesting and retitration. The goal of thyroid hormone
replacement therapy for hypothyroid patients is to safety titrate the
patient to the appropriate dose that achieves and then maintains the
euthyroid state. The goal of TSH suppression for the treatment of
thyroid cancer is to remove the growth-promoting effect of TSH on
thyroid cancer cells such that the patient does not suffer regrowth of
the cancer. For these clinical purposes, patients and their physicians
rely upon serum TSH levels, the most sensitive and easily measurable
parameter of thyroid hormone function. To achieve the optimal TSH
levels, physicians titrate individual patients using a wide range dosage
forms, routinely using dosage increments in the 12-13 µg range. The
clinical evidence presented here demonstrates that small changes in T~4~
dosage result in TSH levels that are correlated with undesirable
clinical consequences.

The current FDA guidance for the assessment of LT4 bioequivalence does
not account for endogenous thyroxine or its biologic regulation. Results
from the "bioequivalence" study (M02-417) reveal that LT~4~ products
approved using the current FDA criterion and based on bioequivalence
data without baseline correction for endogenous T~4~ levels could differ
by as much as 33% from the reference product. Furthermore, simple
corrections of the T~4~ baseline did not sufficiently solve the problem,
because two products that differed by 12.5% in thyroxine content would
be declared bioequivalent. Other methodological flaws were also observed
that could further reduce the reliability of the current guidance to
ensure that products declared bioequivalent will be substitutable in
patients without adverse clinical consequences, and without the need to
remonitor, retest and retitrate.

In summary, we recommend that the new data be taken into account and
careful consideration be given to developing a specific guidance for the
assessment of bioequivalence of levothyroxine sodium products. To do so,
this guidance must adequately consider the unique nature of the thyroid
hormone system and the demonstrated limitations of the current criteria
even with baseline correction. Physicians and patients rely on dosage
strengths that differ by only 12-13 µg. The concerns of the FDA as
outlined in the FDA final action for Synthroid^®^ and recommendations in
the LT~4~ product labels further emphasize the concern that LT~4~
product substitution should only be done when LT~4~ can be delivered so
as not to produce over- or under-treatment. This needs to be ensured
because physicians and patients alike rely on receiving "the correct
dose when filling and refilling their carefully calculated
prescriptions." ^12^ The necessity to deliver bioequivalent LT~4~
products assumes that the methodology used to determine bioequivalence
is robust and sensitive enough to differentiate doses of LT~4~ that are
truly different.

#  References